Medicinal Plants with Anti-Leukemic Effects: a Review

molecules

Review Medicinal Plants with Anti-Leukemic Effects: A Review

Tahani Maher 1 , Raha Ahmad Raus 1, Djabir Daddiouaissa 1,2 , Farah Ahmad 1 , Noor Suhana Adzhar 3, Elda Surhaida Latif 4, Ferid Abdulhaﬁz 5 and Arifullah Mohammed 5,*

1 Biotechnology Engineering Department, Kulliyyah of Engineering, International Islamic University, Malaysia (IIUM), P.O. Box 10, Gombak, Kuala Lumpur 50728, Malaysia; [email protected] (T.M.); [email protected] (R.A.R.); [email protected] (D.D.); [email protected] (F.A.) 2 International Institute for Halal Research and Training (INHART), Level 3, KICT Building, International Islamic University Malaysia (IIUM), Jalan Gombak, Kuala Lumpur 53100, Malaysia 3 Faculty of Industrial Sciences and Technology, Universiti Malaysia, Pekan Pahang, Kuantan 26600, Malaysia; [email protected] 4 Centre for Toxicology and Health Risk Studies (CORE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia; [email protected] 5 Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Jeli, Kelantan 17600, Malaysia; [email protected] * Correspondence: [email protected]

Abstract: Leukemia is a leukocyte cancer that is characterized by anarchic growth of immature immune cells in the bone marrow, blood and spleen. There are many forms of leukemia, and the best course of therapy and the chance of a patient’s survival depend on the type of leukemic disease. Different forms of drugs have been used to treat leukemia. Due to the adverse effects associated Citation: Maher, T.; Ahmad Raus, R.; with such therapies and drug resistance, the search for safer and more effective drugs remains Daddiouaissa, D.; Ahmad, F.; Adzhar, one of the most challenging areas of research. Thus, new therapeutic approaches are important to N.S.; Latif, E.S.; Abdulhaﬁz, F.; Mohammed, A. Medicinal Plants improving outcomes. Almost half of the drugs utilized nowadays in treating cancer are from natural with Anti-Leukemic Effects: A products and their derivatives. Medicinal plants have proven to be an effective natural source of Review. Molecules 2021, 26, 2741. anti-leukemic drugs. The cytotoxicity and the mechanisms underlying the toxicity of these plants to https://doi.org/10.3390/ leukemic cells and their isolated compounds were investigated. Effort has been made throughout this molecules26092741 comprehensive review to highlight the recent developments and milestones achieved in leukemia therapies using plant-derived compounds and the crude extracts from various medicinal plants. Academic Editors: Furthermore, the mechanisms of action of these plants are discussed. Salvatore Genovese and Daniela Rigano Keywords: anti-leukemia; leukemia; medicinal plants; alternative medicine; drug discovery

Received: 25 March 2021 Accepted: 4 May 2021 Published: 7 May 2021 1. Introduction

Publisher’s Note: MDPI stays neutral Leukemia is considered to be among the most common cancer types and happens with regard to jurisdictional claims in because of the abnormal proliferation of white blood cells [1,2]. Leukemia can be classified published maps and institutional affil- as acute or chronic according to the patient’s age; and using the blood cell type into chronic iations. (CML) or acute (AML) myeloblastic leukemia; or chronic (CLL) or acute (ALL) lymphoblastic leukemia. ALL appears to be more common in children with a high incidence between two and five years of age, whereas the other categories are more common in adults [3]. A patient suspected of having leukemia needs to consult an oncologist–hematologist to make a diagnosis and start treatment. Chemotherapy drugs, radiation and monoclonal Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. hematopoietic stem cell transplantation are now the most common treatments for each This article is an open access article type of leukemia. The treatment plan varies based on the subtype of leukemia, cytogenetic distributed under the terms and and molecular studies and the age of the patient. Although chemotherapeutic drugs such conditions of the Creative Commons as cyclophosphamide, fludarabine, prednisone, chlorambucil and doxorubicin are used Attribution (CC BY) license (https:// clinically to treat leukemia, they are used in combination instead of being used as single creativecommons.org/licenses/by/ drugs and often do not improve the patient’s overall survival rate. Complications of in- 4.0/). tensive chemotherapeutic treatment for a patient suffering from leukemia include risk of

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death from cardiac and neurological complications [4], oral mucositis [5], gastrointestinal and liver toxicities [6], an infectious complication for ALL patients [7] and reduced bone mineral density at a high rate for children with ALL [8,9]. In spite of causing several side effects, the overuse of these drugs leads to chemotherapeutic drug resistance in leukemia cells [10]. Thus, the production of new therapeutic drugs having higher potency and lower toxicity is important to expanding the overall life expectancy. Medicinal plants have a long history of being used to cure numerous illnesses and different forms of cancer [11–13]. Plant-based bioactive compounds are considered as renewable sources of anti-leukemic agents [14] due to their diversity and availability. Findings on the anti-proliferative effects of pure compounds and crude extracts from plants against leukemia [15] have questioned their ability to replace established drug treatments for leukemia [14]. This article reviews and discusses the current knowledge of the anti-leukemic properties of ethnomedicinal plants and discusses their potential efficacy. Additionally, the possible mechanisms of how the pure compounds and extracts exert their negative effects against leukemia are discussed as well. For this review, we developed a search strategy to identify relevant literature. The search strategy was tailored to five databases—PubMed, Medline, Web of Science, Scopus and Google scholar databases; and the search terms used were the following “Medicinal Plants with Anti-leukemic Effects” or “Cytotoxicity Effects of Medicinal Plants” or “Anti-Cancer Medicinal Plants.” All searches spanned from database inception until 2020 and included journal articles and Research Reports, published in English, full text only. The initial search strategy identified about 147 references. Of them, 113 papers were selected for further screening and met all our inclusion criteria. Each plant presented in this review is presented by explaining the some basic details about it—the taxonomy; a description; its bioactive compounds and their common biological activities, while concentrating on the anticancer and anti-leukemic effects and the mechanisms of action. ChemSkech version 12.01 Software (Advanced Chemistry Development, Toronto, ON, Canada) was used to draw the chemical structures.

2. The Anti-Leukemic Activity of Traditional Medicinal Plants Many ethnomedicinal plants have been recommended to treat leukemic disease in the conventional medicine system [16]. Conventional medicine pursues the use of natural ingredients, thereby offering reinforcements to the cell regularly to revitalize the normal cell for cancer therapy [17]. This review article elaborates different species of plants which have great potential for combating leukemia. The compounds in this review include plant-derived anti-leukemic compounds clinically used as treatments, and others being examined in clinical and pre-clinical studies.

2.1. Medicinal Plants Clinically Used as Treatments for Leukemia In this section, we review several traditional medicinal plants that have established clinical uses for the treatment of leukemia.

2.1.1. Cephalotaxus harringtonia Cephalotaxus harringtonia (family Cephalotaxaceae) is native to the southern provinces of China and is well known in traditional Chinese medicine. C. harringtonia is an evergreen tree consisting of ten subspecies in Asia, and the majority of them are distributed in China. Some compounds isolated from C. harringtonia are reported to have anti-leukemic effects. Among them, homoharringtonine and harringtonine (Figure1) are the most popular alkaloids [18–21]. Several researchers have investigated the Cephalotaxus-derived alkaloids using various cancer cell lines. Takemura et al. [22] investigated the growth-inhibitory effects of harringtonine (HT) in leukemia and lymphoma cell lines, and they reported that HT was active against the HL-60 cell line. The mechanism of action involved a diversion of proliferating blast cells into a differentiation pathway, resulting in the arrest of cellular proliferation. Another study investigated the effects of homoharringtonine (HHT) on the proliferation and differentiation of human leukemic cells in vitro. Their results show Molecules 2021, 26, x FOR PEER REVIEW 3 of 26

Molecules 2021, 26, 2741 the arrest of cellular proliferation. Another study investigated the effects of homoharring-3 of 25 tonine (HHT) on the proliferation and differentiation of human leukemic cells in vitro. Their results show that HTT inhibited colony formation of the HL-60 myeloid cell line [23]. thatFurther HTT studies inhibited showed colony formationthat C. harringtonia of the HL-60 alkaloids myeloid block cell line peptide [23]. Further bond studiesformation and showedaminoacyl that tRNAC. harringtonia binding,alkaloids thereby block inhibiting peptide translation bond formation at elongation. and aminoacyl Similar tRNA evi- dencebinding, shows therebyCephalotaxus inhibiting alkaloids translation exert at their elongation. anticancer Similar effects evidence by inhibiting shows Cephalotaxus protein syn- thesisalkaloids at the elongation exert their anticancer step of translatio effects byn inhibiting [24]. Homoharringtonine protein synthesis at was the elongation subjected step to pre- of translation [24]. Homoharringtonine was subjected to preclinical and clinical studies and clinical and clinical studies and was approved by the US FDA for the treatment of patients was approved by the US FDA for the treatment of patients with chronic myeloid leukemia with(CML) chronic [21 myeloid–24]. leukemia (CML) [21–24].

O O N N O O H O O O O O O O O OH HO HO

HO O O

Homoharringtonine Harringtonine

Figure 1. The structures of homoharringtonine and harringtonine. Figure 1. The structures of homoharringtonine and harringtonine. 2.1.2. Catharanthus roseus 2.1.2. CatharanthusCatharanthus roseus roseus (synonym of Vinca rosea). C. roseus, usually known as Mada- gascar periwinkle, belongs to the Apocynaceae family. The plant has a short stem and Catharanthus roseus (synonym of Vinca rosea). C. roseus, usually known as Madagas- glossy green leaves, and flowers appear in spring and autumn (three colors: pink, pur- car periwinkle,ple and white) belongs[25,26 to]. C.the roseus Apocynaceaeis originally family. endemic The toplant Madagascar, has a short Jamaica stem andand theglossy greenPhilippines leaves, and [27 ].flowers appear in spring and autumn (three colors: pink, purple and white) [25,26].The most C. roseus potentially is originally active chemical endemic constituents to Madagascar, of C. roseus Jamaicaare alkaloids. and the More Philippines than [27]. 400 alkaloids were isolated from this plant. Vinca alkaloids vinblastine and vincristine (TheFigure most2 ) are potentially the two major active active chemical compounds; constituents the two of semi-synthetic C. roseus are analoguesalkaloids.derived More than 400 alkaloidsfrom such activewere compoundsisolated from are vinorelbinethis plant. and Vinca vindesine alkaloids [28–30 vinblastine]. Vincristine and and vinblas-vincristine (Figuretine 2) are are the the first two plant major alkaloids active to compound be clinicallys; used the astwo anticancer semi-synthetic drugs. Vincristine analogues causes derived cell death in acute lymphoblastic leukemia cells without significant prior mitotic arrest [31]. from such active compounds are vinorelbine and vindesine [28–30]. Vincristine and vin- Vinblastine mechanistically encourages the minus-end detachment of microtubules from blastinetheir are organizational the first plant centers; alkaloids this generatesto be clinically microtubule used fragmentsas anticancer [32]. drugs. Vinblastine Vincristine is causesregularly cell death utilized in acute to treat lymphoblastic different types leukemia of cancers, cells including without leukemia, significant breast prior cancers, mitotic arrestsmall-cell [31]. Vinblastine lung cancer, mechanistically Hodgkin’s and enco non-Hodgkin’surages the lymphoma, minus-end nephroblastoma, detachment of tes-micro- tubulesticular from carcinoma, their organizational germ cell tumors centers; and th Ewing’sis generates sarcoma microtubule [30]. Vincristine fragments is used [32]. for Vin- blastineleukemia is regularly in children utilized and its to cytotoxicity treat differen wast examinedtypes of cancers,in vitro in including normal peripheral leukemia, blood breast cancers,mononuclear small-cell cells lung (PBMC) cancer, and Hodgkin’ CLL cellss [and31,32 ].non-Hodgkin’s Vincristine is commonly lymphoma, used nephroblas- to cure toma,a varietytesticular of carcinomas,carcinoma, suchgerm as cell multiple tumors myeloma, and Ewing’s B-cell sarcoma lymphoma, [30]. glioma, Vincristine metastatic is used melanoma, negative estrogen-receptor breast cancer, neuroblastoma, colorectal cancer, for leukemia in children and its cytotoxicity was examined in vitro in normal peripheral Hodgkin’s rhabdomyosarcoma, non-Hodgkin’s lymphoma and Wilms’ tumor [32]. The bloodfirst mononuclear plant-derived cells anticancer (PBMC) agents and CLL certified cells by [31,32]. the US Vincristine FDA were vincristine is commonly sulphate used to cure (Oncovina variety® )of and carcinomas, vinblastine such sulphate as multip (Velbanle®) myeloma, in 1963 and B-cell 1965, respectivelylymphoma, [28 glioma,]. Vinorel- meta- staticbine melanoma, and vindesine negative are usedestrogen-receptor in treating a variety breast of cancer, cancers neuroblastoma, and can be mixed colorectal with other cancer, Hodgkin’schemotherapeutic rhabdomyosarcoma, agents [28] to treat non-Hodg leukemias,kin’s lymphomas, lymphoma breast and andWilms’ lung tumor cancers, [32]. The Hodgkin’sfirst plant-derived lymphoma, anticancer advanced testicularagents ce cancer,rtified Kaposi’sby the US sarcoma, FDA bladderwere vincristine cancer and sul- phatebrain (Oncovin cancer® [)32 and]. vinblastine sulphate (Velban®) in 1963 and 1965, respectively [28]. Vinorelbine and vindesine are used in treating a variety of cancers and can be mixed with

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Molecules 2021, 26, x FOR PEER REVIEW 4 of 26 other chemotherapeutic agents [28] to treat leukemias, lymphomas, breast and lung cancers, Hodgkin’s lymphoma, advanced testicular cancer, Kaposi’s sarcoma, bladder cancer and brain cancer [32]. other chemotherapeutic agents [28] to treat leukemias, lymphomas, breast and lung can- Molecules 2021cers,, 26, 2741 Hodgkin’s lymphoma, advanced testicular cancer, Kaposi’s sarcoma, bladder cancer 4 of 25 OH and brain cancer [32]. N N

N OH OH N H H N O O N O N N OH H H O H H N O O O N H N O N H O N O H H O H O N O O O HO H HO N O O O O O N O H H O O O HO O HO O O O O Vinblastine Vincristine O Figure 2. The structures of vinblastine and vincristine. Vinblastine Vincristine

2.2. MedicinalFigure 2. The Plants structures in Clinical of vinblastine Trials and vincristine. Figure 2. The structures2.2.1. of Maytenus vinblastine serrata and vincristine. 2.2. Medicinal Plants in Clinical Trials Maytenus serrata, commonly called Ethiopian shrub, is a flowering plant in the family 2.2. Medicinal Plants2.2.1. in MaytenusClinical Trials serrata of Celastraceae and is widely distributed throughout Africa, Australasia, India and South 2.2.1. Maytenus serrataMaytenus serrata America. The bark ,of commonly Maytenus called has Ethiopianbeen used shrub, for its is medicinal a ﬂowering properties plant in the [33,34]. fam- May- ily of Celastraceae and is widely distributed throughout Africa, Australasia, India and Maytenus serratatenus, commonly Serrata contains called manyEthiopian different shrub, cytotoxic is a flowering compounds—for plant in the example, family Maytansinoids South America. The bark of Maytenus has been used for its medicinal properties [33,34]. of Celastraceae and is widely distributed throughout Africa, Australasia, India and South Maytenus(Figure 3), Serrata whichcontains showed many inhibitory different cytotoxicactivity against compounds—for P-388 lymphocytic example, Maytansi- leukemia cells America. The barknoids[35]. of MaytenusDue (Figure to 3the), has which high been in showed vitroused potency inhibitoryfor its medicinal of activity the maytansinoids, againstproperties P-388 [33,34]. lymphocyticfurther May- clinical leukemia trials are un- tenus Serrata containscellsderway many [35]. to Due differenttest to the high effectivenesscytotoxicin vitro compounds—forpotency in humans. of the maytansinoids, The example, anticancer Maytansinoids further activities clinical of trials maytansinoids are (Figure 3), whichunderwayhave showed been toinhibitory attributed test the effectiveness activity to their against ability in humans. P-388to di Thesrupt lymphocytic anticancer microtubule activitiesleukemia function, of maytansinoidscells and they are also [35]. Due to the highhaveconsidered in been vitro attributed highlypotency potent to of their the tubulin ability maytansinoids, to inhi disruptbitors microtubule further [36,37]. clinical In function, addition trials and to are theyits un- in are vitro also cytotoxic con- po- derway to test thesideredtential effectiveness highlyagainst potent several in humans. tubulin cancer inhibitors The cells, anticancer [maytansine36,37]. In activities addition is considered to of its maytansinoidsin vitro as cytotoxican ansamycin potential antibiotic, have been attributedagainstand toits severaltheirmaytansinoid ability cancer to cells, derivativedisrupt maytansine microtubule exhibits is considered cyto function,toxicity as an andagainst ansamycin they many are antibiotic, alsotumor andcell itslines—for maytansinoid derivative exhibits cytotoxicity against many tumor cell lines—for example, considered highlyexample, potent tubulin acute myeloidinhibitors leukemia [36,37]. In(AML) addition cells to lines—and its in vitro cytotoxicit was reported po- to have an an- acute myeloid leukemia (AML) cells lines—and it was reported to have an antileukemic ef- tential against several cancer cells, maytansine is considered as an ansamycin antibiotic, fecttileukemic in phase effect I and IIin clinical phase trials I and [38 II]. clinical Another trials study [38]. of AVE9633 Another (huMy9-6-DM4), study of AVE9633 which (huMy9- and its maytansinoidis6-DM4), an derivative antibody–maytansinoid which exhibitsis an antibody–maytansinoid cyto conjugatetoxicity andagainst composed many conjugate of tumor a thiol-containing and cell composed lines—for maytansinoid of a thiol-contain- example, acute myeloidderivative,ing maytansinoid leukemia created (AML) by derivative, ImmunoGen, cells lines—andcreated involved by ImmunoGen,it a phasewas reported 1 clinical involved trialto have in adult a an phase an- patients 1 clinical with trial in tileukemic effect inrelapsed/refractoryadult phase patients I and IIwith clinical acute relapsed/refractory myeloidtrials [38]. leukemia, Another acut and studye itmyeloid showed of AVE9633 leukemia, both improved (huMy9- and efﬁcacyit showed and both im- 6-DM4), which is reducedprovedan antibody–maytansinoid systemicefficacy and toxicity reduced of anti-leukemia conjugate systemic andtoxicity therapy composed [of39 anti-leukemia]. of a thiol-contain- therapy [39]. ing maytansinoid derivative, created by ImmunoGen, involved a phase 1 clinical trial in adult patients with relapsed/refractoryO acute myeloid leukemia, and it showed both im- H OH proved efficacy andO reducedN systemic toxicity of anti-leukemia therapy [39].

O O H OH O N H O O O N H Cl H O O O O N O H O Cl O N O FigureO 3. Structure of maytansinoids. O N

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Figure 3. Structure of maytansinoids.

2.2.2. Dysoxylum binectariferum Dysoxylum genus grows naturally in forests and is locally known as Achalkaat con- sidera. It is a small or medium-sized tree up to 5 feet in girth and 50 feet high from the family Meliaceae. It is widely distributed throughout eastern and northern Australia, New Caledonia, South East Asia, Southern, New Guinea, China, the Indian subcontinent, the Philippines, Taiwan and in the western Pacific Ocean [40]. D. binectariferum’s fruits contain rohitukine (C16H19O5N), which is a precursor for the semi-synthetic derivative flavopiridol Molecules 2021, 26, 2741 [40,41]. 5 of 25 Flavopiridol is an alkaloid isolated from the stem bark of Dysoxylum binectariferum. Flavopiridol (Figure 4) has shown potential anti-leukemia effects [42]. Karp et al. [42] stud- 2.2.2. Dysoxylum binectariferum ied the anti-leukemia effects of flavopiridol. Their results show that flavopiridol is a broad Dysoxylum genus grows naturally in forests and is locally known as Achalkaat con- sidera.spectrum It is a smallcytotoxic or medium-sized drug against tree up acute to 5 feet myel in girthoid andleukemia 50 feet high (AML), from the and its mechanism of familyaction Meliaceae. is through It is the widely inhibition distributed of throughout cyclin-dep easternendent and northernkinases. Australia, Flavopiridol has been used Newas a Caledonia, potent antiproliferative South East Asia, Southern, agent; New it Guinea,showed China, antitumor the Indian subcontinent,activity in clinical studies [43]. the Philippines, Taiwan and in the western Pacific Ocean [40]. D. binectariferum’s fruits Flavopiridol induced apoptosis in bone marrow cells taken from 20 adults patients with contain rohitukine (C16H19O5N), which is a precursor for the semi-synthetic derivative flavopiridolrefractory [40 acute,41]. leukemia in vitro [44,45]. FlavopiridolSeveral studies is an alkaloid have isolated also examined from the stem the bark combinational of Dysoxylum binectariferum effects with. a variety of anti- Flavopiridol (Figure4) has shown potential anti-leukemia effects [ 42]. Karp et al. [42] studiedleukemic the anti-leukemia compounds effects to maximize of flavopiridol. the Their cytotoxic results show effects that flavopiridolof flavopiridol-containing is a combi- broadnations spectrum [45]. cytotoxic For example, drug against alvocidib acute myeloid (formerly leukemia flavopiridol) (AML), and its mechanism was evaluated for its thera- ofpeutic action iseffect through on the acute inhibition myeloid of cyclin-dependent leukemia kinases.(AML) Flavopiridol alone and has in been combination used with cytotoxic as a potent antiproliferative agent; it showed antitumor activity in clinical studies [43]. Flavopiridolagents cytarabine induced apoptosis and mitoxantrone in bone marrow (FLAM). cells taken fromAlvocidib 20 adults showed patients withreproducible, encourag- refractorying results acute in leukemia AML patients in vitro [44 ,[46,47].45].

OH HO O

OH O FigureFigure 4. The4. The structure structure of flavopiridol. of flavopiridol. Several studies have also examined the combinational effects with a variety of anti- leukemic2.3. Medicinal compounds Plants to maximize in Pre-Clinical the cytotoxic Inve effectsstigations of flavopiridol-containing (In Vitro) for Leukemia combina- tions [45]. For example, alvocidib (formerly flavopiridol) was evaluated for its therapeutic effect onIn acute this myeloid section, leukemia we highlight (AML) alone various and in combinationmedicinal with plants cytotoxic that agents are in preclinical investi- cytarabinegations and(in mitoxantronevitro) for the (FLAM). treatment Alvocidib of showed leukemia. reproducible, encouraging results in AML patients [46,47].

2.3.2.3.1. Medicinal Salix Plants Genus in Pre-Clinical (Willows) Investigations (In Vitro) for Leukemia InWillows this section, belongs we highlight to variousthe Salicaceae medicinal plantsfamily that and are inSalix preclinical genus, investiga- which contains about 400 tions (in vitro) for the treatment of leukemia. species. It is also called osiers and sallows [48] depending on the shape of the leaves. Spe- 2.3.1.cies SalixwithGenus narrower (Willows) lance-shaped leaves are known as osiers, and those with rounder lance-shapedWillows belongs leaves to the are Salicaceae known family as sallows. and Salix Willowsgenus, which are containsnative to about cold temperate regions 400 species. It is also called osiers and sallows [48] depending on the shape of the leaves. Speciesof the with Northern narrower Hemisphere. lance-shaped leaves Their are leaves known as and osiers, bark and have those withbeen rounder utilized in treating fevers lance-shapedand as a remedy leaves are for known pain as relief. sallows. Its Willows pain relief are native effect to cold has temperate been studied regions scientifically, and the ofbioactive the Northern compound Hemisphere. salicin Their leaves (Figure and bark5) was have found been utilized to be inresponsible treating fevers for it [49,50]. and as a remedy for pain relief. Its pain relief effect has been studied scientiﬁcally, and the bioactiveWillow compound leaves salicin have (Figure also5) was been found tested to be responsible and evaluated for it [49,50 for]. anti-leukemia activity. The aqueous extract from willow leaves has been reported to have high activity against ALL and AML cells. The extract prevented proliferation by inducing apoptosis and causing DNA fragmentation within both types of tumor cells [51]. The leaf extract is also toxic

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toward human leukemia 60 (HL-60) and significantly reduced the viability of the HL-60 cells in a time and dose-dependent manner [49]. The extract induced toxicity towards HL- 60 cells by increasing the p53 expression in the tumor, initiating cell cycle arrest at G2M and decreasing cell division [51]. Salicin and saligenin (Figure 5) found in the leaf extract killed HL-60 cells by damaging some proteins and enzymes [49]. The anti-leukemic effects Molecules 2021, 26, 2741 of the willow extract are also probably related to salicylic acid derivatives,6 of 25phenols, flavonoids, proanthocyanidins and total tannins that are found in the extract [48].

OH HO OH

HOO O OH

HO OH

Salicin Saligenin

FigureFigure 5. TheThe structures structures of salicin of salicin and saligenin. and saligenin.

Willow leaves have also been tested and evaluated for anti-leukemia activity. The 2.3.2.aqueous Vernonia extract amygdalina from willow leaves has been reported to have high activity against ALL and AMLVernonia cells. amygdalina The extract preventedbelongs proliferationto the Compositae by inducing family apoptosis and and is commonly causing called an AfricanDNA fragmentation medicinal plant within [52]. both typesThe plant of tumor is original cells [51]. to The Nigeria leaf extract (West is alsoAfrica) toxic and is widely toward human leukemia 60 (HL-60) and significantly reduced the viability of the HL-60 distributed in the African countries, especially in South Africa (including Eastern Cape, cells in a time and dose-dependent manner [49]. The extract induced toxicity towards MpumalangaHL-60 cells by increasingand KwaZulu the p53 Natal) expression [52]. in The the tumor,plants initiating usually cell grow cycle in arrest the atwestern part of SudanG2M and during decreasing the summer cell division and [51 can]. Salicin also andbe found saligenin in (Figure Asia,5 particularly) found in the leafin Singapore and Malaysia.extract killed It HL-60is the cellslargest by damaging plant used some in proteins the genus and enzymes of Vernonia [49]. Theand anti-leukemic commonly used to treat gastrointestinaleffects of the willow problems, extract are wounds, also probably hepatitis related toand salicylic diabetes acid derivatives,[52]. Vernonia phenols, genus is the best flavonoids, proanthocyanidins and total tannins that are found in the extract [48]. source of sesquiterpene lactone compounds that have been stated to be cytotoxic and an- ticancer2.3.2. Vernonia [53]. amygdalina InVernonia vitro amygdalinatesting ofbelongs V. amygdalina to the Compositae root extract family showed and is that commonly it possessed called an significant an- tiproliferativeAfrican medicinal activity plant [ 52and]. The killed plant the is original majority to Nigeria (50–75%) (West of Africa) ALL andand is AML widely leukemic cells distributed in the African countries, especially in South Africa (including Eastern Cape, [1]. Vernodaline and vernolide (Figure 6) are sesquiterpene lactones that are commonly Mpumalanga and KwaZulu Natal) [52]. The plants usually grow in the western part of foundSudan in during the root the summer extract and of canV. amygdalina also be found; they in Asia, play particularly a significant in Singapore role in andkilling abnormal leukemicMalaysia. cells It is theby largestpromoting plantused cell inapop thetosis genus [1,52]. of Vernonia A cytotoxicityand commonly study used of to V. amygdalina leaftreat extract gastrointestinal showed problems, that the wounds, extract hepatitis prevents and diabetesthe proliferation [52]. Vernonia ofgenus two iscancer the cell types, AMLbest source and ALL of sesquiterpene [54]. Another lactone study compounds observed that rema haverkable been stated destruction to be cytotoxic of lymphoblasts and after anticancer [53]. treatingIn vitro mononucleartesting of V. ALL amygdalina cells withroot extractV. amygdalina showed thatextract it possessed for 24 h significant[1]. antiproliferativeIt has been activity reported and that killed the the ethanol majority extract (50–75%) of of V. ALL amygdalina and AML contains leukemic phenolic and falconoidcells [1]. Vernodaline compounds, and vernolide glycosides (Figure and6) are many sesquiterpene types of lactones tannin. that Due are commonly to this, V. amygdalina extractfound in used the root alone extract or mixed of V. amygdalina with other; they extracts play a significant or drugs role has in the killing ability abnormal to selectively fight leukemic cells by promoting cell apoptosis [1,52]. A cytotoxicity study of V. amygdalina leaf the leukemic cells [1]. Therefore, V. amygdalina extracts could constitute low-cost cancer extract showed that the extract prevents the proliferation of two cancer cell types, AML and therapyALL [54]. after Another safety study and observed efficacy remarkable studies, destructionand lead to of drug-resistant lymphoblasts after cancer treating treatments [55]. mononuclear ALL cells with V. amygdalina extract for 24 h [1]. It has been reported that the ethanol extract of V. amygdalina contains phenolic and falconoid compounds, glycosidesO and many types of tannin. Due to this, V. amygdalina extractO used alone or mixed with other extracts or drugs has the ability to selectively fight the leukemicH cellsO [1]. Therefore,OHV. amygdalina extracts could constitute low- cost cancer therapy after safety and efficacy studies, and lead to drug-resistant cancer Otreatments [55]. H H O

O Figure 6. The structure of vernodalin.

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toward human leukemia 60 (HL-60) and significantly reduced the viability of the HL-60 cells in a time and dose-dependent manner [49]. The extract induced toxicity towards HL- 60 cells by increasing the p53 expression in the tumor, initiating cell cycle arrest at G2M and decreasing cell division [51]. Salicin and saligenin (Figure 5) found in the leaf extract killed HL-60 cells by damaging some proteins and enzymes [49]. The anti-leukemic effects of the willow extract are also probably related to salicylic acid derivatives, phenols, flavonoids, proanthocyanidins and total tannins that are found in the extract [48].

OH HO OH

HOO O OH

HO OH

Salicin Saligenin Figure 5. The structures of salicin and saligenin.

2.3.2. Vernonia amygdalina Vernonia amygdalina belongs to the Compositae family and is commonly called an African medicinal plant [52]. The plant is original to Nigeria (West Africa) and is widely distributed in the African countries, especially in South Africa (including Eastern Cape, Mpumalanga and KwaZulu Natal) [52]. The plants usually grow in the western part of Sudan during the summer and can also be found in Asia, particularly in Singapore and Malaysia. It is the largest plant used in the genus of Vernonia and commonly used to treat gastrointestinal problems, wounds, hepatitis and diabetes [52]. Vernonia genus is the best source of sesquiterpene lactone compounds that have been stated to be cytotoxic and anticancer [53]. In vitro testing of V. amygdalina root extract showed that it possessed significant antiproliferative activity and killed the majority (50–75%) of ALL and AML leukemic cells [1]. Vernodaline and vernolide (Figure 6) are sesquiterpene lactones that are commonly found in the root extract of V. amygdalina; they play a significant role in killing abnormal leukemic cells by promoting cell apoptosis [1,52]. A cytotoxicity study of V. amygdalina leaf extract showed that the extract prevents the proliferation of two cancer cell types, AML and ALL [54]. Another study observed remarkable destruction of lymphoblasts after treating mononuclear ALL cells with V. amygdalina extract for 24 h [1]. It has been reported that the ethanol extract of V. amygdalina contains phenolic and falconoid compounds, glycosides and many types of tannin. Due to this, V. amygdalina extract used alone or mixed with other extracts or drugs has the ability to selectively fight the leukemic cells [1]. Therefore, V. amygdalina extracts could constitute low-cost cancer Molecules 2021, 26, 2741 7 of 25 therapy after safety and efficacy studies, and lead to drug-resistant cancer treatments [55].

O O H O OH O H H O

O Figure 6. The structure of vernodalin. Figure 6. The structure of vernodalin. 2.3.3. Nyctanthes arbor-tristis Nyctanthes arbor-tristis is also known as night-flowering jasmine. It is a wild shrub- flourishing plant (Family: Oleaceae) [56], and popular medicine in India, West Bengal and Sri Lanka [56]. N. arbor-tristis has been tested by scientists for anti-inflammatory, antioxidant, antidepressant, antiviral, analgesic, anthelmintic, antihistaminic, amoebicidal, antipyretic and anticancer activities [57,58]. It was reported that the cytotoxic activity of seed extracts on CEM and CEM/VLB cells is through cyclin kinase protein up-regulation (WAF1/p21) and cell cycle blockage at G0/G1 phase, resulting in cancer cell death [59]. Flow cytometric analysis of N. abor-tristis extract-treated cells showed that the seed extracts caused sub-G0 and G0/G1 phase arrest. Recently, N. abor-tristis flower aqueous extract has been demonstrated to potently inhibit the cell proliferation of the human T l ymphocyte cell line [60]. The flower extract has also shown cytotoxicity against CML K562 in a dose-dependent manner and caused significant cell death in resistant and sensitive human cancer cell lines [57]. These properties induced by the plant extract are probably because of the presence of various types of phytochemicals, including phenols, tannins, steroids and glycosides. These phytochemicals are projected to be responsible for the antitumor activity [57,58]. The crude extract of N. abor-tristis, and pure compounds such as arbortristoside A, hydroxy hexahydrobenzofuran-one and β-hydroxyloganin that were isolated from the plant seeds, along with a polysaccharide from the leaves and naringenin from the stems, have been reported to possess antioxidant and anticancer properties [60,61]. Due to this, the water extract of N. abor-tristis flowers should be further investigated as a neutral medicine to stop leukemia and to be mixed with other therapeutic drugs.

2.3.4. Annona glabra Annona glabra L., known as the pond apple, belongs to the Annonaceae family [62]. It is a tropical wild tree native to Asia and the Americas that has been used in traditional Chinese medicine. Its phytochemical constituents, such as acetogenins; diterpenoids like cunabic acid and Ent-kaurenoic acid (Figure7); and alkaloids, have been shown to exhibit antimalarial, anti-HIV and anticancer properties [62,63]. The anti-tumor activity of A. glabra was tested by using the alcoholic extracts of the leaves, pulp and seeds on leukemia cell lines [62]. The study reported that the seed extract of A. glabra was more effective than pulp and leaf extracts against multidrug-resistant leukemia (CEM/VLB) and drug-sensitive leukemia (CEM) cells. These ﬁndings support the traditional utilization of the alcoholic seed extract of A. glabra as a rich source of antitumor drugs. The methanolic extract from A. glabra fruits also showed a potent effect against HL-60 cells by cell cycle arrest at the G1 phase [62]. In HL-60 cells, A. glabra fruit extract was seen to negatively affect Bcl-2 and Bax proteins, and cleaved caspase-3 and PARP to induce cancer cell death. The fruit extract also stimulated apoptosis by reducing AKT phosphorylation and down-regulating c-myc protein [63]. Besides, Liu et al.[64] found that leaf extracts of A. glabra at high concentrations inhibited leukemia cell colony formation Molecules 2021, 26, 2741 8 of 25

Molecules 2021, 26, x FOR PEER REVIEW 8 of 26

and caused more leukemia cells to become apoptotic. Leaf extracts of A. glabra reduced the migratory potential of leukemia cells as well. In vitro biochemical investigations on above, thethe treated-leukemia anticancer potential cells showed of A. glabra that the extracts leaf extract is strong, also stimulated validating the its activity complementary of free and alternativeradical scavenging medicinal and uses. ROS and reduced ATP synthesis [64].

HO O HO O

Cunabic acid Ent-kaur-16-en-19-oic acid Figure 7.Figure The 7.structuresThe structures of cunabic of cunabic acid acid and and Ent-kaur-16-en-19-oic Ent-kaur-16-en-19-oic acid. acid.

Screening of the phytochemical constituents of the ethanolic extracts of A. glabra 2.3.5. Basellaleaves showedalba that the plant leaves contain terpenoids, flavonoids, saponins, glycosides, Basellaanthraquinones, alba is a wildly steroids, cultivated, tannins and cool-season acidic compounds, vegetable and categorized do not contain under alkaloids, the family of Basellaceaephlobatanin [65]. or B. reducing alba issugars known [64 as]. Thevine methanolic spinach, extractsChinese of spinach,A. glabra fruitIndian contain spinach, β β Malabardihydrophaseic spinach and acid Ceylon-d-glucopyranoside, spinach [65]. B. dihydroxybenzoic alba is native to acid, Malaysia, dimethoxyphenyl India, the -d-Philip- glucopyranoside, icariside D2-d-xylopyranoside, cucumegastigmane I, blumenol A and pines, Indonesia,icariside B1. tropical Among theAfrica, compounds tropical found and inSouthA. glabra America,fruit, the Southeast one responsible of Brazil for theand the Caribbean.cytotoxic India effect and on China HL-60 are cell the line two is icariside major D2countries [62]. Indisputably, utilizing the based plant on thefor resultsits medicinal benefitsabove, [66]. the anticancer In India, potential the Ayurvedic of A. glabra treatmentextracts is uses strong, B. validatingalba leaves its against complementary oral cancer, leukemiaand and alternative melanoma medicinal [66]. uses. The plant was reported for its anticonvulsant, anti-inflammatory and antifungal activities, and as an analgesic, an anemia treatment and an andro- 2.3.5. Basella alba genic therapy [67,68]. Basella alba is a wildly cultivated, cool-season vegetable categorized under the family B.of alba Basellaceae contains [ 65various]. B. alba bioactiveis known phytoconstit as vine spinach,uents Chinese with spinach,proven Indiancytotoxic, spinach, antioxidant, hemagglutinatingMalabar spinach and and Ceylon antiproliferative spinach [65]. B. effects alba is native on cancer to Malaysia, cells [69]. India, The the Philip-B. alba leaf and seedpines, extracts Indonesia, have tropicaldifferent Africa, phytoconstitue tropical andnts, South such America, as phenols, Southeast flavonoids, of Brazil saponins, and alkaloids,the Caribbean.tannins, steroids India and and China phytosterols are the two [70]. major The countriesplant also utilizing has many the plantimportant for its phytochemicals,medicinal including benefits [betacyanins,66]. In India, the carotenoids, Ayurvedic treatment triterpene uses oligoglycosides,B. alba leaves against various oral or- cancer, leukemia and melanoma [66]. The plant was reported for its anticonvulsant, anti- ganic acids, basellasapoins A–D, kaempferol and betalin [71]. A different study showed inflammatory and antifungal activities, and as an analgesic, an anemia treatment and an that theandrogenic methanolic therapy plant [67 extract,68]. contained β-sitosterol and lupeol (Figure 8), which were found to beB. cytotoxic alba contains to variouslung cancer bioactive cells phytoconstituents and leukemia with cells proven [72]. cytotoxic,The methanolic antioxidant, leaf extract ofhemagglutinating B. alba displayed and significant antiproliferative growth effects inhibition on cancer of cellsU937 [69 leukemic]. The B. alba cellsleaf in and a dose- dependentseed manner extracts have[73]. different phytoconstituents, such as phenols, flavonoids, saponins, alkaloids, tannins, steroids and phytosterols [70]. The plant also has many important phytochemicals, including betacyanins, carotenoids, triterpene oligoglycosides, various organic acids, basellasapoins A–D, kaempferol and betalin [71]. A different study showed that the methanolic plant extract contained β-sitosterol and lupeol (Figure8), which were found to be cytotoxic to lung cancer cells and leukemia cells [72]. The methanolic leaf extract of B. alba displayed significant growth inhibition of U937 leukemic cellsH in a dose- dependent manner [73]. H H

H H H H HO H

Sitosterol Lupeol Figure 8. The structures of sitosterol and lupeol.

2.3.6. Ferulago angulata

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above, the anticancer potential of A. glabra extracts is strong, validating its complementary and alternative medicinal uses.

HO O HO O

Cunabic acid Ent-kaur-16-en-19-oic acid Figure 7. The structures of cunabic acid and Ent-kaur-16-en-19-oic acid.

2.3.5. Basella alba Basella alba is a wildly cultivated, cool-season vegetable categorized under the family of Basellaceae [65]. B. alba is known as vine spinach, Chinese spinach, Indian spinach, Malabar spinach and Ceylon spinach [65]. B. alba is native to Malaysia, India, the Philip- pines, Indonesia, tropical Africa, tropical and South America, Southeast of Brazil and the Caribbean. India and China are the two major countries utilizing the plant for its medicinal benefits [66]. In India, the Ayurvedic treatment uses B. alba leaves against oral cancer, leukemia and melanoma [66]. The plant was reported for its anticonvulsant, anti-inflammatory and antifungal activities, and as an analgesic, an anemia treatment and an andro- genic therapy [67,68]. B. alba contains various bioactive phytoconstituents with proven cytotoxic, antioxidant, hemagglutinating and antiproliferative effects on cancer cells [69]. The B. alba leaf and seed extracts have different phytoconstituents, such as phenols, flavonoids, saponins, alkaloids, tannins, steroids and phytosterols [70]. The plant also has many important phytochemicals, including betacyanins, carotenoids, triterpene oligoglycosides, various organic acids, basellasapoins A–D, kaempferol and betalin [71]. A different study showed that the methanolic plant extract contained β-sitosterol and lupeol (Figure 8), which were found to be cytotoxic to lung cancer cells and leukemia cells [72]. The methanolic leaf ex- Moleculestract2021, 26 of, 2741 B. alba displayed significant growth inhibition of U937 leukemic cells in a dose-9 of 25 dependent manner [73].

H H

H H H H HO H

Sitosterol Lupeol

Figure 8. The structures of sitosterolFigure 8. Theand structures lupeol. of sitosterol and lupeol.

2.3.6. Ferulago angulata 2.3.6. Ferulago angulata Ferulago angulata also known as chovir is a Persian medicinal herb, a common plant found in Iran, Iraq, Turkey, Serbia, Greece and Macedonia [74]. F. angulata is from the Apiaceae family, and many Ferulago species have traditionally been used to treat intestinal worms, hemorrhoids, ulcers, headaches and snake bites, and act as sedatives. F. angulata is well studied for immunomodulatory, anti-proliferative, anti-apoptotic and cytotoxic activities against various cancer lines [75] (Table1). Many researchers have reported that the methanolic crude extract of F. angulata exhibits cytotoxicity activity, and most probably exerts the effect via an apoptosis-dependent pathway [74]. It was reported that the methanolic extract inhibited the proliferation of B-cell lymphoma (Raji) U937 cells and acute myelocytic leukemia cells (KG-1A), and suppressed them in a time and dose-dependent manner [74]. F. angulata also decreased cell viability and induced anti-proliferative activity against HL-60 cells [76]. Coumarin is the constituent in F. angulata that was identiﬁed to be the bioactive ingredient that inhibits tumor cell growth and may be considered as a herbal alternative to synthetic drugs [77]. Extensive investigations on coumarin’s anti-proliferative activity showed that it inhibits a variety of mechanisms through angiogenesis inhibition, kinase inhibition, antimitotic activity, cell cycle arrest, telomerase inhibition, heat shock protein (HSP90) inhibition, aromatase inhibition, sulfatase inhibition and monocarboxylate transporters inhibition [77].

Table 1. A list of traditionally used medicinal plants demonstrating cytotoxic effects in different leukemia cell lines.

Mechanism of Scientiﬁc Name Family Active Compound Leukemia Cell Line References Action Human Inhibition of drug-sensitive mitochondrial Acetogenins leukemia (CEM), respiratory chain Diterpenoid Annona glabra Annonaceae Multidrug-resistant- complex, Inhibition [62–64] (Cunabic acid, derived (CEM/VLB) of proliferation and Ent-kaur-en-oic acid) cell lines and HL-60 Induce apoptosis cell line and necrosis β-Sitosterol U937 cell line and Anti-leukemic, and Basella alba Basellaceae [67] Terpenoids (Lupeol). Jurkat cell lines Growth Inhibition Molecules 2021, 26, 2741 10 of 25

Table 1. Cont.

Mechanism of Scientiﬁc Name Family Active Compound Leukemia Cell Line References Action Leukemic NB4 cells, Alkaloids Leukemic cell line Induce cell Bisbenzylisoquinoline K562, Chronic apoptosis, group myeloid Apoptosis, K562-r Berberis amurensis Berberidaceae Berbamine,4- Leukemia cell line cell growth arrest [78–80] Chlorobenzoyl KU812, and Cell Berbamine and Gleevec-sensitive proliferation Berberine. and -resistant Ph+ inhibition Leukemia cells Alkaloids, tannins, steroids, gums. K562, L1210, P3HR1, Blumea lacera Asteraceae Terpenoids, Antiproliferation [81] Raji, U937 diterpenoid glycoside L1210, U937, K562, Bidens Pilosa Asteraceae Flavonoids Antiproliferation [82,83] Raji, P3HR1, Alkaloids: Mitotic inhibitor and vincristine, Arrests the cell L1210 and P1534 Catharanthus roseus Apocynaceae vinblastine, division which [84] Leukemia cells. vindesine, causes the death of vinorelbine. the cells Flavonoids: ﬂavanone, chalcones, Antiproliferation Leukemia HL-60 Coreopsis lanceolata Asteraceae and aurones and Apoptosis [85–87] cells 4 induction Methoxylanceoletin. Raji, U937, AML cell lines, PBL cell line, Phenolic Leukemia, Antiproliferation, Flavonoid lymphoma cell lines, Apoptosis induction Ferulago angulata Apiaceae Monoterpenes: [88,89] NHL, Raji, U937, and Autophagy and α-pinene KG-1A, PBMC cell necrosis. β-pinene lines and HL-60 cell line. Flavonoid, tannins, terpenoids, phenol, Ficus deltoidea Moraceae proanthocyanins, HL60 cell line Apoptosis induction [90] lignans, alkaloids and coumarins L1210, U937, K562, P3HR1, Jurkat Antiproliferation, Leukemia cell line, Apoptosis induction Houttuynia cordata Acute T through an Saururaceae Flavonoids [91,92] Thunb lymphoblastic endoplasmic leukemic Molt-4 reticulum stress cells and Human pathway. T-cell Leukemia Phenols Flavonoids Polysaccharides Antiproliferation Litchi chinensis HL-60, U937 and Sapindaceae Tannins: epicatechin, and Apoptosis [93] Sonn K562 cell lines proanthocyanidin B2 induction and proanthocyanidin B4 Molecules 2021, 26, 2741 11 of 25

Table 1. Cont.

Mechanism of Scientific Name Family Active Compound Leukemia Cell Line References Action Phenols: phenol, (dimethylethyl), AML, CLL and Antiproliferation Nyctanthes hydroxypyridine Oleaceae Jurkat T cells, CML, andApoptosis [57–60] arbor-tristis oxide K562 cell lines. induction Glycosides, tannins, phenols and steroids. Phenols, oleuropeosides oleuropein/verbascoside, Hydroxytyrosol, Antiproliferation, Flavons Flavonols Jurkat, K562 cells Apoptosis induction Olea europaea Oleaceae (rutin), catechin line andHL60 cell and Cell cycle arrest, [94–99] Phenols (vanillin, line. apoptosis induction tyrosol and differentiation hydroxytyrosol, caffeic acid and vanillic acid). HL-60, NB-4, THP-1, U937 cells (Blin-1, Growth inhibition Nalm-6), lymphoma induce apoptosis cell lines (Daudi, and cell cycle arrest, Flavonoid, Baicalein, Raji, Ramos, Induction of Scutellaria Lamiaceae baicalin, and NCEB1), NALM-6 apoptosis and [100,101] baicalensis wogonin. cell line (human, Dose-dependent peripheral blood, reduction of B-type human mitochondrial Leukemia), HL-60 metabolism. cell line. Antiproliferative, Flavonoids and K-562, U937, KG-1A Salvia officinalis Lamiaceae anti-migratory and [102] rosmarinic acid Cell line. antiangiogenic. Sesquiterpene lactones (STLs) HL-60 cell line. Chlorogenic acid Anti-K562, L1210, Antiproliferation Tithonia diversifolia Asteraceae derivatives (CAs) [103,104] P3HR1, Raji and andCytotoxic. Flavonoids, U937 Leukemia cells phenolics, tannins and terpenoids Hexadecanoic acid, gamma sitosterol, phytol¸ Murine Leukemia octadecadienoic acid, WEHI-cancer cell pentadecyne, lines, squalene, eicosane, P388 murine Typhonium Antiproliferation via Araceae octacosane, and Leukemia cells, [105–109] flagelliforme apoptosis induction geranylgeraniol. HL-60 Leukemia Pheophorbide, oleic cells, and human acid, campesterol, T4-lymphoblastoid stigmasterol and cell line CEMss. sitosterol, Linoleic acid. Proteins such as ALL, NALM-6 cell Apoptosis induction Viscum album lectins and Viscacea lines, Jurkat E6.1 and andG2/M cell cycle [110] (Mistletoe) polypeptides like THP-1 cells arrest. viscotoxins Molecules 2021, 26, 2741 12 of 25

Table 1. Cont.

Mechanism of Scientific Name Family Active Compound Leukemia Cell Line References Action HL-60 cell line Sesquiterpene andALL and AML Antiproliferation Vernonia lactones: Compositae immature monocytes DNA damage, and [1,111] Moleculesamygdalina 2021, 26, x(VA) FOR PEER REVIEW vernodaline and 13 of 26 patients, apoptosis induction. vernolide Mononuclear cells. Apoptosis induction ALL and AML cell by causing DNA Willows tree Salicaceae2.3.7. Litchi Salicin chinensis and saligenin Sonn lines [51] damage. b- HL-60 cell line Litchi chinensis Sonn Litchi belongs to the SapindaceaAntiproliferatione family [112], and is known for its delicious fruit in Southeast Asia. The plant is also planted in other semitropical regions 2.3.7.for itsLitchi fruits chinensis [113]. Sonn In China, the plant is popular due to its attractive shape. Often, the fresh andLitchi dried chinensis litchi SonnfruitLitchi extracts belongs are tomade the Sapindaceae into powders family to [112 be], utilized and is known in traditional for Chinese itsmedicine delicious and fruit inIndian Southeast herbal Asia. medicine The plant is[114]. also planted in other semitropical regions for its fruitsL. chinensis [113]. In leaf China, extract the plant has is popularbeen tested due to itsfor attractive cytotoxicity shape. Often,toward the many fresh leukemia cell and dried litchi fruit extracts are made into powders to be utilized in traditional Chinese medicinelines, such and as Indian K562, herbal U937 medicine and HL-60, [114]. and was found to be potent against those cell lines. It wasL. chinensis observedleaf that extract the has leaf been extract tested exerted for cytotoxicity the cytotoxic toward many effect leukemia against cell those cells by in- lines,ducing such apoptosis as K562, U937 via andactivation HL-60, and of mitochondria-mediated was found to be potent against caspase those cell cascades lines. It [115]. A study wason the observed litchi that fruit the pericarp leaf extract extract exerted and the cytotoxic its constituents effect against showed those cells that by both inducing possess anticancer apoptosis via activation of mitochondria-mediated caspase cascades [115]. A study on the litchieffects fruit toward pericarp MCF7 extract and itshepatoce constituentsllular showed carcinoma that both (HCC) possess [115]. anticancer effects towardA MCF7 phytochemical and hepatocellular investigation carcinoma (HCC)of litchis [115 ].revealed a novel phenolic compound and manyA phytochemicalflavonoids, such investigation as flavonols, of litchis isoflavones, revealed a novel flavones phenolic and compound flavanones and [116,117]. Three manynatural flavonoids, flavonoids, such as epicatechin flavonols, isoflavones, (Figure flavones9) and andpro-anthocyanidin flavanones [116,117 B2]. Three and B4, have been naturalisolated flavonoids, from the epicatechin pericarp (Figure of L.9 )chinensis and pro-anthocyanidin and evaluated B2 and for B4, their have anticancer been activities isolated from the pericarp of L. chinensis and evaluated for their anticancer activities against differentagainst cancerdifferent cell linescancer [113 cell]. lines [113]. OH

HO O OH

OH FigureFigure 9. 9.The The structure structure of epicatechin. of epicatechin. 2.3.8. Typhonium flagelliforme 2.3.8.Typhonium Typhonium flagelliforme flagelliformeis native to a tropical region and is in the family Araceae. It is recognizedTyphonium in Malaysia flagelliforme as the “rodent is native tuber”. to a tropicalT. flagelliforme regionis native and is to in Bangladesh, the family Araceae. It is Bhutan, Cambodia and Indonesia and is largely distributed in south India, south-east Asia recognizedand northern in Australia Malaysia [118 as]. T.the flagelliforme “rodent juicetuber”. extract T. flagelliforme is traditionally is usednative orally to Bangladesh, to Bhu- tan,soothe Cambodia coughing, and swelling Indonesia and more and predominantly is largely dist forributed treating different in south cancers India, by south-east the Asia and northernethnic population Australia of Malaysia. [118]. T. The flagelliforme juice is extracted juice fromextract the rootsis traditionally and tubers and used was orally to soothe coughing,found to contain swelling high doses and ofmore arginine predominantly (0.874%) and tryptophan for treating (0.800%) different [119] cancers by the ethnic T. flagelliforme population of Malaysia.plant extract The is juice considered is extracte an anticancerd from herbalthe roots treatment and tubers with a po-and was found to tential anti-leukemic effect [120]. It is also a treatment for heart trouble and has an anti- containinflammatory high effect. doses The of anti-leukemic arginine (0. effect874%) of T.and flagelliforme tryptophanhas been (0.800%) tested both [119]in vivo T. flagelliforme plant extract is considered an anticancer herbal treatment with a potential anti-leukemic effect [120]. It is also a treatment for heart trouble and has an anti- inflammatory effect. The anti-leukemic effect of T. flagelliforme has been tested both in vivo and in vitro in many studies. It was reported that the plant extract was effective against the murine P388 leukemia cell line [121], murine monomyelocytic and effective against WEHI-3 cells and CEM-ss cell lines [121]. Further investigation on the negative effects of T. flagelliforme extract, particularly of the linoleic acid-rich (Figure 10) fraction, on the leukemic CEMss cells demonstrated that the plant fraction arrested the CEM-ss cell cycle at the phase G0/G1 and induced programmed cell death by increasing caspase-3 and caspase-9 and elevating the cytochrome c in the cytosol, which lead to cleavage of poly(ADP-ribose) polymerase (PARP) [122]. The in vivo effect of T. flagelliforme tuber extracts demonstrated that the numbers of immature monocytes and granulocytes decreased significantly in the peripheral blood of BALB/c leukemia mice after the orally administered extract with three concentrations from 200 to 800 mg/kg for 28 days. Different chemical compounds have been isolated from T. flagelliforme, including methyl-13-phenyltridecanoate, phenyltridecanoic acid, conif-

Molecules 2021, 26, x FOR PEER REVIEW 14 of 26

erin, β-sitosterol, some aliphatic esters, methyl derivatives, β-daucosterol and 1-O-b-glu- Molecules 2021, 26, 2741 13 of 25 copyranosy l2 (hydroxyl octadecanoyl) amido-octadecadiene-diol [107]. New anticancer compounds that have shown cytotoxic activity toward breast adenocarcinoma MCF-7 cells, present in leaves and tubers, were identified by GC-MS analysis as octadecadienoic and in vitro in many studies. It was reported that the plant extract was effective against theacid, murine gamma-sitosterol, P388 leukemia cell hexadecanoic line [121], murine acid monomyelocytic methyl ester, and phytol¸ effective geranylgeraniol, against eico- WEHI-3sane, 7-pentadecyne, cells and CEM-ss cellsqualene lines [121 and]. Further octacosa investigationne [107]. on Another the negative GC-MS effects study of T. showed hex- ﬂagelliformeadecene, extract,hexadecanoic particularly acid of theand linoleic phytol acid-rich and it (Figures derivative 10) fraction, in onthe the dichloromethane leukemic extract CEMss(D/F21) cells of demonstrated T. flagelliforme that, thewhich plant was fraction responsible arrested the for CEM-ss the cellinhibition cycle at the of phase non-small cell lung G0/G1 and induced programmed cell death by increasing caspase-3 and caspase-9 and elevatingcarcinoma the (NSCLC) cytochrome cell c in (NCI-H23) the cytosol, whichgrowth. lead However, to cleavage none of poly(ADP-ribose) of the purified compounds polymerasefound above (PARP) was [122 tested]. against leukemia cells [122].

FigureFigure 10. 10.The T structurestructure of linoleicof linoleic acid. acid. The in vivo effect of T. flagelliforme tuber extracts demonstrated that the numbers of immature2.3.9. Blumea monocytes lacera and granulocytes decreased significantly in the peripheral blood of BALB/cBlumea leukemia lacera (Asteraceae) mice after the is orally commonly administered usedextract as a medicinal with three plant concentra- in Bangladesh, and tions from 200 to 800 mg/kg for 28 days. Different chemical compounds have been isolatedits Bengali from T.name flagelliforme is Kukurshinga, including methyl-13-phenyltridecanoate, [123]. B. lacera is a yearly phenyltridecanoic herb with a strong odor. Its acid,essential coniferin, oil containsβ-sitosterol, cineol, some aliphaticfenchone esters, and methyl camphor derivatives, [124]. B.β-daucosterol lacera is largely and grown in the 1-O-b-glucopyranosyPhilippines and is l2traditionally (hydroxyl octadecanoyl) used in Taiwan amido-octadecadiene-diol as a medicinal plant [107]. due New to its many bio- anticancerlogical activities, compounds including that have showndiuretic, cytotoxic antiscorbutic, activity toward astringent breast adenocarcinoma and broad anti-leukemic ac- MCF-7 cells, present in leaves and tubers, were identified by GC-MS analysis as octadeca- dienoictivities acid, [123,124]. gamma-sitosterol, hexadecanoic acid methyl ester, phytol¸ geranylgeraniol, eicosane,The 7-pentadecyne, B. lacera aqueous squalene crude and extract octacosane has [ 107been]. Another tested against GC-MS study various showed leukemic cell lines, hexadecene,such as K562, hexadecanoic L1210, P3HR1, acid and phytolRaji and and itsU937 derivative [15]. inThe the aqueous dichloromethane extract extract exhibited extensive (D/F21)cytotoxicity of T. flagelliforme toward ,those which cell was responsiblelines, with for th thee maximum inhibition of non-smalleffect on cell L1210 lung cells. Steroidal carcinomaglycoalkaloid (NSCLC) is a cell well-known, (NCI-H23) growth. effective However, bioactive none compound of the purified isolated compounds from the methanol found above was tested against leukemia cells [122]. leaf extract of B. lacera. The steroidal glycoalkaloid of B. lacera is reported to be responsible 2.3.9.for anti-proliferativeBlumea lacera activity against different cancers, such as human gastric carcinoma, colonBlumea carcinoma, lacera (Asteraceae) HT-29, isbreast commonly adenocarcinoma, used as a medicinal MDA-MB-231 plant in Bangladesh, and MCF-7 and [81]. How- itsever, Bengali the nameB. lacera is Kukurshinga steroidal glycoalkaloid [123]. B. lacera ishas a yearly not been herb selectively with a strong tested odor. Itsagainst leukemia essential oil contains cineol, fenchone and camphor [124]. B. lacera is largely grown in thecells Philippines yet. and is traditionally used in Taiwan as a medicinal plant due to its many biological activities, including diuretic, antiscorbutic, astringent and broad anti-leukemic activities2.3.10. Coreopsis [123,124]. lanceolata B. lacera TheCoreopsis lanceolataaqueous crude is categorized extract has been under tested the against Asterace variousae leukemicfamily; cellit originates from lines, such as K562, L1210, P3HR1, Raji and U937 [15]. The aqueous extract exhibited extensiveAmerica, cytotoxicity South Africa toward and those Eastern cell lines, Asia. with C. thelanceolata maximum flowers effect onare L1210 reported cells. to have strong Steroidalbioactive glycoalkaloid compounds is a that well-known, effect nema effectivetodes bioactive and human compound leukemia isolated fromcells the [85]. C. lanceolata methanolflowers are leaf also extract an of excellentB. lacera. Thenatural steroidal source glycoalkaloid of rare flavonoids, of B. lacera is including reported to flavanone, chal- becones responsible and aurones for anti-proliferative (Figure 11), and activity they against show differentstrong antileukemic cancers, such asproperties human [86]. A study gastric carcinoma, colon carcinoma, HT-29, breast adenocarcinoma, MDA-MB-231 and MCF-7on the [ 81antileukemic]. However, the potentialB. lacera steroidal of the glycoalkaloidethyl acetate has fraction not been of selectively the C. lanceolata tested flowers to- againstward leukemiaHL-60 cells cells yet.by using a CCK-8 assay showed that at 50 µg/mL, the extract causes 50.8% cytotoxicity towards the cells [86]. The fraction also induced apoptosis: condensation of the chromatin and fragmentation of the nuclei were observed in the cells. From the fraction, a flavonoid compound called 4-methoxylanceoletin was isolated. The compound is responsible for the anti-proliferative effect of the plant [87].

Molecules 2021, 26, 2741 14 of 25

2.3.10. Coreopsis lanceolata Coreopsis lanceolata is categorized under the Asteraceae family; it originates from America, South Africa and Eastern Asia. C. lanceolata flowers are reported to have strong bioactive compounds that effect nematodes and human leukemia cells [85]. C. lanceolata flowers are also an excellent natural source of rare flavonoids, including flavanone, chalcones and aurones (Figure 11), and they show strong antileukemic properties [86]. A study on the antileukemic potential of the ethyl acetate fraction of the C. lanceolata flowers toward HL-60 cells by using a CCK-8 assay showed that at 50 µg/mL, the extract causes 50.8% Molecules 2021, 26, x FOR PEER REVIEW cytotoxicity towards the cells [86]. The fraction also induced apoptosis: condensation15 of 26

of the chromatin and fragmentation of the nuclei were observed in the cells. From the fraction, a ﬂavonoid compound called 4-methoxylanceoletin was isolated. The compound is responsible for the anti-proliferative effect of the plant [87].

O H O

O H

Aurones Chalcone

FigureFigure 11. The 11. Thestructures structures of aurones of aurones and and chalcone. chalcone. 2.3.11. Tithonia diversifolia 2.3.11. TithoniaTithonia diversifolia diversifolia belongs to the Asteraceae family and is well-known as the Mexican sunflower.Tithonia diversifolia It is largely belongs distributed to the in Asteraceae tropical and family sub-tropical and is areas, well-known such as South as the and Mexi- can sunflower.North Asia, It Africa, is largely America distributed and parts in of Australiatropical and [125 ].sub-tropicalT. diversifolia areas,is also such considered as South and Northone of theAsia, most Africa, famous America Taiwanese and medicinalparts of Australia plants and [125]. grows T. in diversifolia the sunny is grasslands also considered ofone Taiwan. of the most famous Taiwanese medicinal plants and grows in the sunny grass- Traditionally, T. diversifolia extracts have been used to treat diarrhea, fever, hepatitis, lands of Taiwan. hepatomas, wounds and malaria [103]. Later, many researchers investigated its potential againstTraditionally, cancer, andT. diversifolia the first report extracts about have its been anti-leukemic used to tr propertyeat diarrhea, was infever, 2002 hepatitis, [103]; hepatomas,the next wounds was in 2004 and [ 15malaria]. In the [103]. first Later, report, manyT. diversifolia researchersextract investigated was found toits induce potential againstcellular cancer, differentiation and the first in report HL-60 about cells [ 103its ].anti-leukemic In the second, property a hot water was extractin 2002 of [103];T. di- the next versifoliawas in 2004demonstrated [15]. In the feeble first anti-leukaemicreport, T. diversifolia activity extract against was five differentfound to leukemia induce cellular cell differentiationlines—U937, in P3HR1, HL-60 L1210, cells Raji[103]. and In K562; the second, and exhibited a hot a water selective extract cytotoxic of T. effect diversifolia [15]. demonstratedWhether the feeble existence anti-leukaemic of phytoconstituents activity such against as phenolics, five different flavonoids, leukemia terpenoids cell andlines— U937,tannins P3HR1, in L1210, the ethanolic Raji and leaf K562; extracts and of exhibitedT. diversifolia a selectiveis responsible cytotoxic for its effect cytotoxic [15]. Whether prop- the existenceerty [104] of is notphytoconstituents known, but many such findings as ph indicatedenolics, theflavonoids, potential ofterpenoids flavonoids and as novel tannins anti-leukemia agents. in the ethanolic leaf extracts of T. diversifolia is responsible for its cytotoxic property [104] is not2.3.12. known,Bidens but pilosa many findings indicated the potential of flavonoids as novel anti-leukemia agents.Bidens pilosa is among the most common plants cultivated in the tropics and subtropics around the world, having a soft, hair-like appearance, and it belongs to the Asteraceae 2.3.12.family. Bidens It pilosa is a perennial herb that originates from South America. Folk medicinal use of B.Bidens pilosa pilosahas been is among reported the in most Asia, common Africa, America plants andcultivated Oceania in [ 126the]. tropics A phytochemical and subtrop- investigation indicated the existence of phenolics, phenylpropanoids, polyynes, fatty ics around the world, having a soft, hair-like appearance, and it belongs to the Asteraceae acids and flavonoid compounds in the plant. It was confirmed that these chemicals can family.successfully It is a perennial treat inflammation herb that originates and tumors, from and boostsSouth theAmerica. immune Folk system medicinal [127]. use of B. pilosa hasStudies been reported have shown in Asia, that B. Africa, pilosa possesses America anticancer and Oceania properties, [126]. and A phytochemical various isolated in- vestigationbioactive indicated compounds the from existence the plant of havephenolics, anticancer phenylpropanoids, properties. Thus, studies polyynes, determining fatty acids and flavonoid compounds in the plant. It was confirmed that these chemicals can successfully treat inflammation and tumors, and boosts the immune system [127]. Studies have shown that B. pilosa possesses anticancer properties, and various isolated bioactive compounds from the plant have anticancer properties. Thus, studies determining whether the plant has an anti-leukemia effect were carried out. It was found that the whole-plant water extract inhibited various leukemic cell lines, such as Raji, K562, U937, L1210 and P3HR1, in a concentration-dependent manner [15,82]. As B. pilosa is readily available, Yi et al. [83] suggested that the plant has the potential to be a good health supplement and a resource of natural antileukemic agents.

2.3.13. Olea europaea Olea europaea, also known as the olive, is one of the plants that is used in common, traditional Mediterranean herbal teas to treat many illnesses. O. europaea is in the Oleaceae family, native to coastal areas of southern Asia and Europe, and especially prevalent in the Mediterranean region [128]. O. europaea leaves have many effective pharmacological

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whether the plant has an anti-leukemia effect were carried out. It was found that the whole- plant water extract inhibited various leukemic cell lines, such as Raji, K562, U937, L1210 and P3HR1, in a concentration-dependent manner [15,82]. As B. pilosa is readily available, Yi et al. [83] suggested that the plant has the potential to be a good health supplement and a resource of natural antileukemic agents.

Molecules 2021, 26, x FOR PEER REVIEW2.3.13. Olea europaea 16 of 26

Olea europaea, also known as the olive, is one of the plants that is used in common, traditional Mediterranean herbal teas to treat many illnesses. O. europaea is in the Oleaceae family,abilities, native including to coastal neuroprotective, areas of southern anti-inflammatory, Asia and Europe, and antiviral, especially hypoglycemic, prevalent in the antimi- Mediterranean region [128]. O. europaea leaves have many effective pharmacological abili- crobial and anticancer effects [128]. ties, including neuroprotective, anti-inflammatory, antiviral, hypoglycemic, antimicrobial and anticancerAn investigation effects [128 on]. the cytotoxicity of O. europaea ethanol extract against Jurkat leu- kemicAn cells investigation indicated on that the the cytotoxicity extract inhibits of O. europaea the growthethanol of Jurkat extract cells against and Jurkat causes apop- leukemictosis at non-cytotoxic cells indicated concentrations that the extract inhibits[95]. O. theeuropaea growth leaf of Jurkatextract cells also and inhibited causes human apoptosischronic myelogenous at non-cytotoxic leukemia concentrations K562 cell [ 95growth]. O. europaeaand causedleaf cell extract cycle also arrest inhibited at G0/G1 and humanmetaphase chronic [95]. myelogenous The same leukemialeaf extract K562 also cell stimulated growth and apoptosis caused cell and cycle monocyte/macro- arrest at G0/G1phage anddifferentiation metaphase [of95 ].leukemia The same K562 leaf extract cells. alsoA phytochemical stimulated apoptosis study anddemonstrated mono- the cyte/macrophageexistence of several differentiation bioactive compounds, of leukemia K562 including cells. A phenols, phytochemical flavonoids study and demon- secoiridoid strated the existence of several bioactive compounds, including phenols, flavonoids and glycosides in different parts of O. europaea. Oleuropein is responsible for the health bene- secoiridoid glycosides in different parts of O. europaea. Oleuropein is responsible for the healthfits of benefitsO. europaea of O. europaealeaves (Figureleaves (Figure 12), which 12), which is the is themajor major constituent constituent of of thetheleaves. leaves. Other Otherphytochemical phytochemical presents presents are flavonoids are flavonoids and and hydr hydroxytyrosols,oxytyrosols, such such as as verbascoside and lu- andteolin-7- luteolin-7-O-glucoside,O-glucoside, which which have have been been determined determined to to inhibit inhibit the the proliferation of of cancer cancercells [97]. cells [97].

OH O HO O O O

HO O HO O O

OH HO FigureFigure 12. 12.The The structure structure of oleuropein.of oleuropein. 2.3.14. Houttuynia cordata Thunb 2.3.14. Houttuynia cordata Thunb Houttuynia cordata is considered one of the aromatic medicinal plants in the Sauru- raceaeHouttuynia family. H. cordata cordatais ais local considered plant found one in of Northern the aromatic Thailand, medicinal Japan, Korea, plants Southern in the Sauru- Chinaraceae and family. Southeast H. cordata Asia generally is a local [129 plant]. This found plant in has Northern commonly Thailand, used the world Japan, over Korea, for South- manyern China medical and purposes. Southeast A scientiﬁc Asia generally investigation [129 of]. ThisH. cordata plantshowed has commonly its extract hasused anti- the world leukemicover for many activity medical against purposes. various leukemia A scientific cell lines, investigation including K562,of H. L1210,cordata P3HR1 showed and its extract U937has anti-leukemic [92]. H. cordata extractactivity is against also cytotoxic various against leukemia the human cell lymphoblasticlines, including leukemia K562, L1210, cell line Molt-4, and exerts its effect in a concentration-dependent manner. The plant extract P3HR1 and U937 [92]. H. cordata extract is also cytotoxic against the human lymphoblastic was observed to provoke apoptosis through the endoplasmic reticulum stress pathway leukemia cell line Molt-4, and exerts its effect in a concentration-dependent manner. The plant extract was observed to provoke apoptosis through the endoplasmic reticulum stress pathway in the Molt-4 cells [91]. The negative effect of H. cordata extract towards Jurkat and U937 human leukemic cells was also due to apoptosis [129]. Phytochemical screening of H. cordata extracts demonstrated that the plant’s extracts have many bioactive compounds, such as flavonoids, saponin, alkaloid, tannin and steroid compounds [130]. H. cordata flavonoids have biological activities that include antiproliferation, suppression of carcinogens, disruption of the cell cycle, activation of apoptosis, angiogenic inhibition and antioxidation, which can result in the anti-leukemic property [91,131]. H. cordata also contains phenolic acids called vanillic, gallic, p-hydroxybenzoic, p-coumaric, syringic, sinapinic and ferulic acids, among which, p-coumaric acid is considered as the main compound, followed by ferulic acid. These phenolic acid compounds are responsible for the cytotoxicity toward cancer cells [92]. Due to H. cordata’s cytotoxicity

Molecules 2021, 26, 2741 16 of 25

in the Molt-4 cells [91]. The negative effect of H. cordata extract towards Jurkat and U937 human leukemic cells was also due to apoptosis [129]. Phytochemical screening of H. cordata extracts demonstrated that the plant’s extracts have many bioactive compounds, such as ﬂavonoids, saponin, alkaloid, tannin and steroid compounds [130]. H. cordata ﬂavonoids have biological activities that include antiproliferation, suppression of carcinogens, disruption of the cell cycle, activation of apoptosis, angiogenic inhibition and antioxidation, which can result in the anti-leukemic property [91,131]. H. cordata also contains phenolic acids called vanillic, gallic, p-hydroxybenzoic, p-coumaric, syringic, sinapinic and ferulic acids, among which, p-coumaric acid is considered as the main compound, followed by ferulic acid. These phenolic acid compounds are responsible for the cytotoxicity toward cancer cells [92]. Due to H. cordata’s cytotoxicity against several leukemic cell lines, researchers have suggested its utilization as an alternative medicine in the treatment of leukemia.

2.3.15. Viscum album Viscum album (mistletoe) belongs to the Viscaceae family, is distributed in Europe, southwest and central Asia and northwest Africa and has been used to treat cancer since the 1920s [132]. V. album contains several active phytochemicals, including viscotoxins and lectins, which are essentials in treating cancer because of their antiproliferative and apoptotic effects [133]. It also contains a class of compounds that includes phenylpropanoids, flavonoids and phenolic acids which showed anti-inflammatory and antioxidant effects. Other compounds in V. album include triterpenes, which have been shown to possess cytotoxic and apoptotic properties [132]. V.album is utilized in complementary medicine to treat cancer [134], as V.album extracts enhance the quality of life, improve survival, stimulate the immune system and diminish the side effects of radio and chemotherapy in cancer patients [135]. In vivo and in vitro examination of the V. album treatment efficacy has been conducted on ALL leukemia [110], and it was found that V. album aqueous extract inhibited the ALL NALM-6 cell growth. In vitro inhibition against NALM-6 cell proliferation was concentration-dependent and induced dose-dependent apoptosis that led to cell death [110,133]. Treatment with V. album extract at different concentrations for 4 days (by intraperitoneal injection) for severe combined immunodeficiency (SCID) mice with transplanted NALM-6 cells caused an increase in white blood cell count, indicating that mistletoe extracts have interesting therapeutic effects on hematological malignancies.

2.3.16. Salvia officinalis Salvia officinalis, also known as sage, belongs to the Lamiaceae family and is commonly distributed in the Mediterranean region [136]. It has a therapeutic history and culinary use because of its pharmacological properties. In traditional medicine, S. officinalis showed various pharmacological functions, namely, anti-microbial, antioxidant, hemostatic, anti- inflammatory, analgesic and antitumor activities [137]. S. officinalis has been used on numerous cancer cells and in numerous animal models of cancer. It has shown significant inhibition of proliferation for different cancer cells, such as CML, prostate carcinomas (PC3), MCF7, SCLC, HT29 and hepatocellular carcinoma cells [137,138]. S. officinalis extract also showed anti-migratory and anti-angiogenic effects against human CML cell lines, including HUVEC and K562; and B lymphoma cells, WEHI- 231 [139]. Another study showed S. officinalis affected the proliferation of human AML (KG-1A) and U937 cells in a concentration and time-dependent manner, but no significant effect against PBMCs. An in vivo study showed the S. officinalis water extract possesses pro-apoptotic and anti-proliferative effects on cancer cells [136]. S. officinalis extract contains flavonoids and rosmarinic acid that have shown anticancer effects toward different human cancer cell lines [140]. The S. officinalis essential oil contains trans-caryophyllene and α-humulene, which inhibit tumor cell growth [137]. Molecules 2021, 26, 2741 17 of 25 Molecules 2021, 26, x FOR PEER REVIEW 18 of 26

2.3.17. Ficus deltoidea Ficus deltoidea belongs to the Moraceae family and was widely used as a medici- isovitexin (Figure nal13) plant.[143]. It Vitexin is native was to Southeast tested for Asia anti-proliferative [141] and distributed activity, over many and the regions, find- such ings revealed that asvitexin Malaysia, causes Thailand, apoptosis Indonesia in different and the leukemia Philippines cells, [142]. such In Malaysian as Jurka, traditional ALL, HL-60, AMLK-562medicine, and CML, the fruitso this of this phyto- plantcompound was used for is headache likely to relief, have and a therole leaves in F. are deltoi- chewed dea’s cytotoxicity againstfor toothaches leukemia [143]. cell Often lines the [2 roots]. Therefore, and leaves oftheF. high deltoidea amountsare dried of and flavonoid made into a powder to be used externally for sores and wound healing [144,145]. The leaf of F. del- and phenolic compoundstoidea contains in the a variety leaves of are bioactive responsible compounds, for includingthe cytotoxicity flavonoids, of tannins, these terpenoids,crude extracts [146]. proanthocyanins, phenol, isoflavonoids, lignans, alkaloids and coumarins, along with Moreover, F. vitexindeltoidea and aqueous isovitexin and (Figure ethanolic 13)[143 extracts]. Vitexin showed was tested cytotoxicity for anti-proliferative against dif- activity, ferent cancer cell andlines, the in findingscluding revealed ovarian that carcinoma vitexin causes A2780 apoptosis [146], in different prostate leukemia cancer cells, PC3 such [147], colon canceras (HCT Jurka, ALL,116) HL-60, and breast AMLK-562 adenocarcinoma and CML, so this (MDA-MB phyto-compound 231, isMCF-7 likely toand have a role in F. deltoidea’s cytotoxicity against leukemia cell lines [2]. Therefore, the high amounts HCC 1937) cell linesof flavonoid [148]. F. and deltoidea phenolic is compounds also cytotoxic in the leavesagainst are human responsible leukemia for the cytotoxicity cell line of HL60 and exerts thisthese effect crude by extracts causing [146 ].apoptosis [89].

OH O OH

HO O

O HO O HO HO OH O O OH HO OH OH HO OH OH

Vitexin Isovitexin Figure 13. The structures ofFigure vitexin 13. Theand structures isovitexin. of vitexin and isovitexin. Moreover, F. deltoidea aqueous and ethanolic extracts showed cytotoxicity against dif- 2.3.18. Berberis amurensisferent cancer Rupr cell lines, including ovarian carcinoma A2780 [146], prostate cancer PC3 [147], Berberis amurensiscolon Rupr cancer is (HCT a deciduous 116) and breast shrub, adenocarcinoma and a medicinal (MDA-MB herb 231, that MCF-7 belongs and HCCto the 1937) cell lines [148]. F. deltoidea is also cytotoxic against human leukemia cell line HL60 and Berberidaceae plantexerts family. this effect It is by commonly causing apoptosis cultivated [89]. in northern Korea and the middle part of the Korean peninsula; Northeast and North China; and Russia [149]. B. amurensis’ fruit, leaf, root and2.3.18. stemBerberis extracts amurensis have Ruprbeen utilized in folk medicine to treat hypertonia; dysentery; eczema; inflammatoryBerberis amurensis disorders; Rupr is a deciduous infections shrub, in the and aeyes; medicinal diseases herb thatof the belongs liver, to the intestine and skin;Berberidaceae and digestive plant and family. respirator It is commonlyy diseases. cultivated They in act northern as hemostatic Korea and agents the middle part of the Korean peninsula; Northeast and North China; and Russia [149]. B. amurensis’ and fever reducers,fruit, and leaf, are root utilized and stem in extractsthe treatment have been of utilizedtumors in [150]. folk medicine to treat hypertonia; Alkaloids suchdysentery; as berberine, eczema; inﬂammatoryberbamine (Figure disorders; 14) infections and palmatine in the eyes; have diseases been of the ex- liver, tracted from B. amurensisintestine and [151]. skin; Berberine and digestive is anda benzylisoquinoline respiratory diseases. Theyalkaloid act as hemostaticthat is com- agents monly used for theand synthesis fever reducers, of several and are utilizedbioactiv ine the derivatives. treatment of tumorsA study [150 reported]. that B. Alkaloids such as berberine, berbamine (Figure 14) and palmatine have been extracted amurensis has berbaminefrom B. amurensisderivatives[151 which]. Berberine are considered is a benzylisoquinoline as a new group alkaloid of that metabolites is commonly with anti-leukemicused effects for the [152]. synthesis Berbamine of several bioactivecould selectively derivatives. induce A study programmed reported that B. cell amuren- death via bcr/abl-expressionsis has berbamine in the derivatives imatinib-resistant which are considered K562 cell as a newline groupand ofchronic metabolites mye- with logenous leukemiaanti-leukemic patients [149 effects]. According [152]. Berbamine to these could results, selectively B. amurensis induce programmed could be useful cell death in developing novelvia compounds bcr/abl-expression to fight in the against imatinib-resistant leukemia. K562 cell line and chronic myelogenous leukemia patients [149]. According to these results, B. amurensis could be useful in devel- B. amurensis opingextract novel can compounds induce selectively to ﬁght against the leukemia. apoptosis of resistant and sensitive Gleevec Ph ± CML cells. It was found that berbamine extracted from B. amurensis inhibited the growth of tumors in CML patients [149]. It displayed selective antiproliferative activity in CML patients by inhibiting bcr/abl-positive leukemic cell growth. It was suggested that berbamine induces apoptosis of bcr/abl-positive cells (K562 cells) via the caspase-3- dependent pathway and causes p210 bcr/abl oncoprotein expression down-regulation [153]. It has been shown that other bioactive compounds in B. amurensis that contribute to the anti-leukemic activity are protoberberine alkaloids which belong to benzyl tetrahydro iso quinolines alkaloids [149]. Protoberine alkaloids are widely distributed in vegetables and are also utilized in traditional medicine and food supplements due to their many pharmacological properties, including antidiabetic [151], neuroprotective [153], antidepressive [154] and memory-enhancing [152] effects.

Molecules 2021, 26, x FOR PEER REVIEW 19 of 26

Molecules 2021, 26, 2741 18 of 25

O O O O + N N O O O N

O O

Berbamine Berberine Figure 14. The structures of berbamine and berberine. Figure 14. The structures of berbamine and berberine. B. amurensis extract can induce selectively the apoptosis of resistant and sensitive 2.3.19. Scutellaria baicalensisGleevec Ph ± CML cells. It was found that berbamine extracted from B. amurensis inhib- Scutellaria baicalensisited the growth is a herbaceous of tumors in species CML patients of plant [149 belonging]. It displayed to the selective Lamiaceae antiproliferative fam- activity in CML patients by inhibiting bcr/abl-positive leukemic cell growth. It was sug- ily with a self-supportinggested that growth berbamine habit. induces It has apoptosis simple, ofbroad bcr/abl-positive leaves and cells is largely (K562 cells) used via in the Chinese herbal medicine.caspase-3-dependent It was historically pathway andused causes in clinical p210 bcr/abl applications oncoprotein as an expression anticancer down- and anti-inflammatoryregulation drug. [153 The]. It root has been of the shown plant that shows other potent bioactive antitumor compounds effects in B. amurensis and wasthat proposed for clinicalcontribute trials towith the anti-leukemic several myelomas activity are [155]. protoberberine alkaloids which belong to benzyl The root of S.tetrahydro baicalensis iso also quinolines affects alkaloids B cell leukemia [149]. Protoberine and the alkaloids peripheral are widely blood distributedleuko- in vegetables and are also utilized in traditional medicine and food supplements due to cytes (PBLs) foundtheir in many ALL pharmacological patients. After properties, treatment including with antidiabetic S. baicalensis [151], neuroprotectiveextract supple- [153], mented with baicalin,antidepressive the viability [154] and of memory-enhancingPBLs gained from [152 ALL] effects. patients was reduced, and the NALM-6 (B-type human leukemia) cell line become apoptotic [155]. It was shown that 2.3.19. Scutellaria baicalensis SBE imposed a negative effect by increasing the IFNγ production in PBLs and reduced Scutellaria baicalensis is a herbaceous species of plant belonging to the Lamiaceae family the IL-10 and TNFwithα production a self-supporting in bone growth marrow habit.It cells has simple,(BMC) broad of ALL leaves patients, and is largely and con- used in trolled the productionChinese of herbalcytokines, medicine. which It was stim historicallyulate nonspecific used in clinical resistance applications in ALL as an patients anticancer and have an essentialand anti-inflammatory role in the innate drug. immune The root system of the plant [155]. shows potent antitumor effects and was Phytochemicalproposed analyses for clinicalhave shown trials with that several flavone myelomas compounds [155]. are major constituents in S. baicalensis, whichThe include root of wogonin,S. baicalensis norwogonin,also affects B cell baicalein leukemia andand the baicalin peripheral [156]. blood Aleukocytes study (PBLs) found in ALL patients. After treatment with S. baicalensis extract supplemented with on wogonoside reportedbaicalin, thethat viability it is cytotoxic of PBLs gained toward from HL-60 ALL patientsand U937 was cell reduced, lines. and Wogonoside the NALM-6 (B- exerts its effect throughtype human cell leukemia)cycle arrest cell lineat the become G1 phase apoptotic and [155 promoting]. It was shown differentiation. that SBE imposed It a increases the phospholipidnegative effect scramblase by increasing 1 the(PLS IFNCR1)γ production transcription, in PBLs andupregulates reduced the differentia- IL-10 and TNFα tion-related gene productionp21waf1/cip1 in bone and marrow downregulates cells (BMC) of ALLoncogenic patients, protein and controlled c-myc. the Wogonin production of cytokines, which stimulate nonspecific resistance in ALL patients and have an essential and baicalein (Figurerole in 15), the innatewhich immune are the system aglycones [155]. of wogonoside and baicalin, respectively, also possess anticancerPhytochemical properties. analyses have shown that flavone compounds are major constituents in S. baicalensis, which include wogonin, norwogonin, baicalein and baicalin [156]. A studyO on wogonosideOH reported that it is cytotoxicO toward HL-60 and U937 cell lines. Wogonoside exerts itsOH effect through cell cycle arrest at the G1 phase and promoting differentiation. It increases the phospholipid scramblaseHO 1 (PLSCR1)O transcription, upregulates differentiation-related gene p21waf1/cip1 and downregulates oncogenic protein c-myc. Wogonin and baicalein (Figure 15), which are the aglycones of wogonoside and baicalin, respectively,O also possessOH anticancer properties.

OH O Baicalein Wogonin Figure 15. The structures of baicalein and wogonin.

3. Conclusions With the growing number of newly diagnosed cases of all forms of cancer globally, and in particular, hematological malignancies, there is still a strong need for novel agents that may treat or eliminate cancer. For many reasons, medicinal plants have been used to

Molecules 2021, 26, x FOR PEER REVIEW 19 of 26

O O O O + N N O O O N

O O

Berbamine Berberine

Figure 14. The structures of berbamine and berberine.

2.3.19. Scutellaria baicalensis Scutellaria baicalensis is a herbaceous species of plant belonging to the Lamiaceae family with a self-supporting growth habit. It has simple, broad leaves and is largely used in Chinese herbal medicine. It was historically used in clinical applications as an anticancer and anti-inflammatory drug. The root of the plant shows potent antitumor effects and was proposed for clinical trials with several myelomas [155]. The root of S. baicalensis also affects B cell leukemia and the peripheral blood leukocytes (PBLs) found in ALL patients. After treatment with S. baicalensis extract supplemented with baicalin, the viability of PBLs gained from ALL patients was reduced, and the NALM-6 (B-type human leukemia) cell line become apoptotic [155]. It was shown that SBE imposed a negative effect by increasing the IFNγ production in PBLs and reduced the IL-10 and TNFα production in bone marrow cells (BMC) of ALL patients, and controlled the production of cytokines, which stimulate nonspecific resistance in ALL patients and have an essential role in the innate immune system [155]. Phytochemical analyses have shown that flavone compounds are major constituents in S. baicalensis, which include wogonin, norwogonin, baicalein and baicalin [156]. A study on wogonoside reported that it is cytotoxic toward HL-60 and U937 cell lines. Wogonoside exerts its effect through cell cycle arrest at the G1 phase and promoting differentiation. It increases the phospholipid scramblase 1 (PLSCR1) transcription, upregulates differentiation-related gene p21waf1/cip1 and downregulates oncogenic Molecules 2021, 26, 2741 19 of 25 protein c-myc. Wogonin and baicalein (Figure 15), which are the aglycones of wogonoside and baicalin, respectively, also possess anticancer properties.

O OH O OH HO O

O OH

OH O Baicalein Wogonin Figure 15. FigureThe structures 15. The structures of baicalein of baicalein and wogonin. and wogonin. 3. Conclusions 3. Conclusions With the growing number of newly diagnosed cases of all forms of cancer globally, Withand the in growing particular, number hematological of newly malignancies, diagnosed there cases is of still all a strongforms needof cancer for novel globally, agents and in particular,that may treathematological or eliminate malignancies, cancer. For many there reasons, is still medicinal a strong plantsneed for have novel been agents used to that may curetreat diverse or eliminate illnesses cancer. for centuries, For many due toreasons, the enormous medicinal chemical plants diversity have been and biologicalused to selectivity of the bioactive compounds. This review describes the traditional uses of 20 different plants from different regions in the world that may be/have been used for the treatment of leukemia. It can be concluded that these plants’ extracts and their bioactive compounds effectively kill leukemia cells and have had similar effects in animal studies. These plant extracts and active compounds exert different mechanisms of action: the most common are suppressing proliferation; causing the arrest of the cell cycle; apoptosis; and dose and time-dependent damage to DNA. These plants may be the ideal choice for the development of adequate risk-reward studies for the potential treatment of leukemia based on clinical studies that investigate the side effects, due to easier accessibility for some populations, and better suitability as compared to chemotherapeutic drugs. Hence, more research is needed to elucidate these medicinal plants’ extracts and their active compounds’ potential for chemo-preventive and chemotherapeutic treatments by using cell line and animal studies, as well as clinical trials.

Author Contributions: Writing—original draft preparation, T.M.; writing—review and editing, T.M., R.A.R., D.D., F.A. (Farah Ahmed), N.S.A., E.S.L., F.A. (Ferid Abdulhafiz) and A.M. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The data presented in this study are available within the article. Acknowledgments: The authors are grateful to the International Islamic University of Malaysia. The authors also acknowledge the efforts of all researchers working in the area of alternative medicine against leukemia. The authors apologize to all scientists whose work has not been cited because of the space limitation or unknowingly due to the great amount of literature in the field of anti-leukemic medicinal plants. F.A. and A.M. acknowledge the logistic support from Universiti Malaysia Kelantan. Conflicts of Interest: The authors declare no conflict of interest.

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