GinPolMedProject © 4 (50) 2018: 044-049 • REVIEW ARTICLE

Plant-derived cytostatic drugs

Anna Antosz-Gruszkoś Regional Specialist Hospital Megrez Sp. z o. o. – Hospital pharmacy, Tychy

AUTHORS’ CONTRIBUTION: (A) Study Design · (B) Data INTRODUCTION Collection · (C) Statistical Analysis · (D) Data Interpre- tation · (E) Manuscript Preparation · (F) Literature Se- Neoplastic and cardiovascular diseases are the arch · (G) Funds Collection leading causes of mortality both in Poland and worldwide. Based on the epidemiological data Neoplastic diseases represent the leading causes of mortality in developed countries. A number of pharmacological me- of the Polish Union of Oncology and Institute thods are used to treat neoplasms, and chemotherapy is the of Oncology in Warsaw, which follow WHO most commonly applied method of systemic therapy. Plant- reports, the number of new cancer cases is pro- SUMMARY derived cytostatic drugs used to treat neoplastic diseases include: cytotoxic antibiotics, podophyllotoxin derivatives, jected to double to 20 million, cancer-related antimicrotubule agents, derivatives and enzy- mortality will increase to 70% and complica- mes. : or , and other tions of cancer will increase from 6 to 10 antibiotics, such as , and mitomycin, are of great importance among plant-derived antibiotics. The million to the year 2020. These data clearly above mentioned drugs are mainly used against hematologic illustrate the scale of the problem and empha- malignancies and solid tumors. The examples of plant-derived size how mandatory it is to create a new and compounds whose derivatives are administered to treat some of the neoplasms are podophyllotoxin derived from Podophyl- effective system of cancer treatment [1]. lum pelatum and Podophyllum emodi as well as camptothe- Neoplasm (neoplasma) is, according to cin isolated from Camptotheca acuminata. Inhibition of ma- Williams’ definition, a group of abnormal cells lignant growth by disturbing the activity of the mitotic spin- dle, or more precisely by halting an incorrect process of that grow excessively in the host organism due , applies to Vinca alkaloids, and epothilones. to uncontrolled cell divisions. This excessive Interactions with microtubules of the spindle apparatus are growth is induced by continuous and unstop- most commonly used to treat such neoplasms as ovarian cancer, breast cancer and Hodgkin lymphoma. pable cell proliferation, even when the trigger- is an essential and fundamental used in chemothe- ing factor has been eliminated. Cell prolifera- rapy of acute lymphoblastic leukemia and also of other tion is accompanied by cell differentiation dis- malignancies, such as non-Hodgkin lymphomas. The applica- tion of cytostatic agents is exceedingly limited because of their orders, which are harmful and pointless for the frequent toxicity for healthy cells. Nevertheless, the above organism. A neoplasm may develop from each mentioned plant-derived compounds are successfully used in tissue capable of replication. Carcinogenesis is treatment of many malignancies. Furthermore, comprehensi- ve clinical trials on cytostatic drugs contribute to the impro- a complex and multistep process that usually vement of their characteristics, antineoplastic potential and takes many years with no specific symptoms for safety of chemotherapy. a long time [2]. Three phases of carcinogenesis Key words: chemotherapy; cytostatic drugs; cancer; hospital pharmacy have been distinguished: initiation, promotion and progression. In the first phase – initiation Address for correspondence: Anna Antosz-Gruszkoś – the carcinogenic factor acts upon a healthy Regional Specialist Hospital Megrez Sp. z o.o. – Hospital cell causing a genetic mutation that is fixed in Pharmacy, Edukacji 102, 43-100 Tychy, Poland e-mail: [email protected] subsequent divisions. As a result, the expression of genes engaged in cell cycle regulation: pro- Word count: 2861 Tables: 0 Figures: 0 References: 17 to-oncogenes, suppressor genes or mutator genes, is impaired or enhanced. The promotion Received: 12.11.2018 Accepted: 18.11.2018 phase is characterized by the accumulation of Published: 19.12.2018 genetic and epigenetic changes that lead to conversion of a mutated cell into a neoplastic cell. An altered cell undergoes uncontrolled divisions and becomes resistant to signals direct- ing it towards apoptotic death. This stage may last even several years. The last phase of car- cinogenesis is progression during which a neo- plasm develops and gains the ability to infiltrate tissues and metastasize. This process may last from several months to several years.

44 A. Antosz-Gruszkoś – Plant-derived cytostatic drugs

Methods of pharmacological treatment of plastic action and cardiotoxicity. cancer encompass chemotherapy, hormonal antibiotics, being ones of the more important therapy and immunotherapy. Chemotherapy is anti-cancer medications, are used in treatment the most widely used method and one of the of hematologic neoplasms and solid tumors. fundamental methods of systemic treatment. It Doxorubicin, also called adriamycin, is charac- is used for the treatment of disseminated can- terized by very good pharmacokinetic proper- cers, inoperable tumors and hematologic neo- ties: a rapid distribution phase and a slow elim- plasms, e.g. leukemia of various types. It is ination phase. DOX has a broad spectrum of crucial in cancer treatment and can be applied action and is used for the treatment of leuke- as postoperative therapy or treatment adjuvant mias, breast cancer, lymphomas, sarcomas and to hormonal therapy, immunotherapy or radi- often in multidrug therapies. Adverse effects of ation therapy. doxorubicin include nausea, vomiting, bone Chemotherapy consists in eradicating cancer marrow damage and alopecia, but the most cells by administering cytostatic or cytotoxic serious adverse effect is cardiotoxicity in the drugs to the patient. Cytostatics are anti-cancer form of arrhythmias, conduction disorders and medications that destroy rebel cancer cells by cardiomyopathy. The second cytostatic drug, blocking the cell cycle and activating genetical- i.e. , is produced from Streptomy- ly programmed cell death mechanisms (apop- ces peucetius. It rapidly permeates to tissues tosis). Plant-derived chemotherapeutic agents from blood after intravenous administration. It have contributed to cancer therapy develop- is metabolized in the liver to an active dauno- ment and its progress [3]. rubicinol compound. Due to significant car- diotoxicity, daunorubicin is currently used in CLASSIFICATION OF PLANT-DERI- the treatment of acute lymphoblastic and my- eloid leukemia. With time, other anthracycline VED CYTOSTATICS medications have appeared, namely Cytostatic medications are a very heterogeneous and , but neither of them has a more group of compounds in terms of both structure potent anticancer effect than doxorubicin or and mechanism of action. The best explored daunorubicin and neither meets the expecta- and the most widely used cytostatics are alky- tions regarding cardiotoxicity reduction. Pira- lating agents, and plant-derived rubicin, aclarubucin and zoribicin are used in medications, classified on the basis of the mech- anticancer treatment of acute myeloid, myelo- anism of action. Plant-derived cytostatic drugs blastic and lymphoblastic leukemias as well as constitute over 60% of antineoplastic medica- in organ cancers and lymphomas [4,5]. The final tions and can be divided into: cytostatic anti- synthetic compound belonging to second gen- biotics, podophyllotoxin derivatives, antimicro- eration anthracyclines in the group of cytostat- tubule agents, camptothecin derivatives and ic antibiotics is mitoxantrone (MTX), charac- . terized by anticancer, immunosuppressive and immunomodulating effects. This drug reduces Cytostatic antibiotics the activity of type II , damages Cytostatic antibiotics of the greatest relevance DNA as well as inhibits T cells, B cells, mac- are anthracycline compounds that can be divid- rophages and antibody production. MTX is ed into the first generation drugs (doxorubicin used in the treatment of leukemia, breast can- (DOX), daunorubicin) and second generation cer, liver cancer, ovarian carcinoma, prostate drugs (epirubicin, idarubicin, , acla- cancer and gastric carcinoma. It is also used in rubicin, zoribicin and mitoxantrone). Anthracy- patients with secondary progressive and relaps- clines are cell cycle phase-specific substances ing-remitting multiple sclerosis. High cardiotox- that were first isolated about 50 years ago from icity is also the factor that limits the use of Streptomyces perceturs and Streptomyces case- mitoxantrone in anticancer therapy. Cardiotox- sius. Their mechanism of action consists in icity induced by anthracyclines can be counter- binding with the double DNA helix by inhib- acted by Dexrazoxane (Cardioxane) that, by iting type II topoisomerase, RNA and DNA chelating intracellular iron, prevents the forma- polymerases, helicases and DNA-repairing en- tion of anthracycline–iron complexes, which, in zymes. These compounds cause the production consequence, inhibits the formation of oxygen of free radicals, thus inducing cell oxidative free radicals, thereby protecting the myocardi- stress, which is responsible for their anti-neo- um from damage [6,7].

45 © GinPolMedProject 4 (50) 2018: 093-098

Cytostatic antibiotics also include bleomycin it is not used clinically due to high toxicity. The (BLM), a glycopeptide antibiotic obtained from mechanism of action of podophyllotoxin deriv- Streptomyces verticillus. This compound forms atives is completely different than that of the an active complex with iron, thereby causing mother compound. They act mainly as type II DNA strand breakage and cell cycle inhibition topoisomerase inhibitors, thus suppressing at G2 and S phases, which results in cancer cell DNA-repair processes and replication. This apoptosis. Anticancer therapy makes use of a results in a dose-dependent cessation of cell polypepide mixture of bleomycin A2 and B2 division in S phase or in early G2 phase. (blenoxane) mainly in squamous cell carcinoma is used both intravenously and of the neck, esophagus and head, and Hodgkin orally in the treatment of acute myeloid and lymphoma. Bleomycin is characterized by rel- lymphoblastic leukemia, testicular cancer, gastric atively low toxicity. It does not damage the cancer and lymphomas. When combined with bone marrow, but bleomycin-induced pneumo- , etoposide is used as first-line therapy toxicity is significant [8,10]. in generalized small-cell lung carcinoma. Teni- Dactinomycin is an example of a phase- poside, however, is administered to patients with nonspecific antibiotic that acts on proliferating Hodgkin lymphoma, non-Hodgkin lymphoma, cells in all cycle phases and exerts weaker ac- breast cancer, testicular cancer and CNS cancers. tion on cells in G0 phase. Its mechanism of Lignans induce adverse effects, such as: nausea action consists in the interaction with the DNA and vomiting, myelosuppression, diarrhea, alope- minor groove and inhibition of RNA poly- cia and necrosis at the site of administration [10– merase, thereby suppressing and 12]. ribosomal RNA formation. Dactinomycin is used mainly in the treatment of childhood Antimicrotubule agents cancers, such as Wilm’s tumor, Ewing sarcoma, Drugs used in anticancer therapy disrupt cell as well as germ-cell tumors and hydatidiform nucleus division, which precedes the division of mole. Some of the more significant adverse the entire cell. This inhibits divisions of patho- effects of this drug include: oral mucositis, logical cells, leading them to the apoptotic nausea and vomiting, alopecia, and myelosup- pathway. Restricting cancer cell proliferation by pression [9]. affecting microtubules, which are an element of Mitomycin, also called , is a cy- the karyokinetic spindle, is one of the therapy tostatic antibiotic derived from Streptomyces methods. Inhibition of malignant growth occurs caespitosus. In the organism, it is reduced to its by disturbing the activity of the mitotic spindle, DNA-alkylating derivative and acts in all cell or more precisely by halting an incorrect pro- cycle phases. Mitomycin is broadly used: local- cess of mitosis. Antimicrotubule agents include ly in the treatment of superficial urinary blad- 3 groups of compounds: Vinca alkaloids, tax- der cancer, or in combination with radiother- oids and epothilones. apy and in anal carcinoma, breast Vinca alkaloids are a group of compounds cancer, pancreatic cancer, stomach cancer, and derived from Vinca rosea Linn. They include: squamous cell carcinoma of the cervix. Adverse natural compounds, such as and effects of this drug are specific for alkylating , and semisynthetic compounds, in- drugs: nausea and vomiting, oral mucositis, cluding , and . alopecia and myelosuppression [9,10]. Catharantus roseus G. Don, i.e. rose periwinkle, produces more than 130 terpenoid indole alka- Podophyllotoxin derivatives loids, but only natural vinblastine and vincris- Semisynthetic podophyllotoxin derivatives, i.e. tine have anticancer properties. All Vinca alka- etoposide and , also called lignans, are loids are phase-specific drugs and act on cell important plant-derived cytostatics. They are cycle phase M. Their mechanism of action derived from Podophyllum pelatum and Podo- consists in bonding with tubulin and inhibition phyllum emodi. The mechanism of action of of microtubule formation, and thus karyokinetic podophyllotoxin alone consists in inhibiting spindle formation, resulting in inhibition of tubulin polymerization, as in the case of Vinca mitosis at the metaphase and in apoptosis. alkaloids. Podophyllotoxin consists of a five- These compounds are commonly used in pal- ring system containing a lactone ring where liative cancer treatment and in treatment with modifications at the C-4 position in ring C curative intent. Vinblastine, being a natural result in enhanced anticancer activity. However, alkaloid, is broadly used in the treatment of

46 A. Antosz-Gruszkoś – Plant-derived cytostatic drugs

Hodgkin lymphoma, testicular cancer, breast neurotoxicity, myelosuppression, gastrointestinal and lung cancers, non-Hodgkin lymphomas, disorders, and the occurrence of unfavorable neuroblastoma, and many other types of can- multidrug resistance [12,13]. cer. Its toxicity results in bone marrow injury Epothilones are new generation natural in the form of leukopenia and thrombocytope- compounds derived from soil-dwelling bacteria nia as well as in gastrointestinal injury. Vincris- Sorangium cellulosum, isolated for the first time tine, however, is used in the therapy of acute in 1993. Two compounds are distinguished as myeloid and lymphoblastic leukemia, non- the representatives of the group: epothilone Hodgkin lymphomas, reproductive organ can- A and epothilone B, which differ from each oth- cers, breast cancer, bladder cancer and Hodgkin er in the presence of a methyl group. The lymphoma. Adverse effects of vincristine include mechanism of action is based on cell prolifer- neurotoxicity, peripheral neuropathies and ation inhibition by tubulin aggregation, there- muscle weakness. The group of semisynthetic by preventing microtubule depolymerization. Vinca alkaloids includes vindesine and vinorel- This causes cessation of mitosis at phase G2 and bine, which are vinblastine derivatives. The activation of apoptosis. Epothilones are capa- former substance is used in acute lymphoblas- ble of binding with class I and III ß-tubulin, tic and myeloid leukemia, Hodgkin lymphoma, which supposedly makes them superior to tax- colorectal carcinoma, lung cancer, melanoma, anes in terms of their efficacy. It is believed that lymphomas or metastatic breast cancer. Vinorel- these compounds break cancer cell resistance to bine is characterized by a narrower spectrum of taxoids. Five epothilone analogues can be dis- use, encompassing non-small-cell lung carcino- tinguished: , patupilone, BMS- ma and advanced breast cancer. The latest semi- 310705, epothilone D, and ZK-EPO. These synthetic vinorelbine derivative, i.e. vinflunine, compounds are a subject of clinical trials, par- is used in breast cancer, non-small-cell lung ticularly in breast cancer, ovarian carcinoma, carcinoma and urinary bladder cancer [11,12]. testicular cancer, pancreatic cancer, melanoma, The second group of plant-derived com- colorectal carcinoma and non-small-cell lung pounds acting on the karyokinetic spindle is carcinoma. Epothilones practically always pro- taxoids, also called taxanes, which include duce adverse effects in therapy, such as diarrhe- and . Paclitaxel was first as, neutropenia and neuropathy, but are a huge isolated from the bark of western yew (Taxus step in oncology as they initiate new treatment brevifolia), but is currently produced semisyn- pathways [14,15]. thetically from Taxus baccata, as is its analogue docetaxel. The mechanism of action of taxanes Camptothecin derivatives consists in promoting microtubule formation Camptothecin derivatives are type I topoi- and stabilization through depolymerization in- somerase inhibitors and include and hibition. This leads to suppression of normal cell division in the mitotic phase. The effect is . They are semisynthetic derivatives of dose-dependent. At high concentrations, micro- a natural quinoline alkaloid, i.e. camptothecin, tubule polymerization is stimulated, while at derived from Tibetan tree Camptotheca acumi- low concentrations, the microtubule dynamics nata. The mechanism of action consists in type is stabilized with no increase in their mass. It I topoisomerase inhibition, which leads to the has also been observed that taxoids are addi- formation of one-strand DNA fragments that tionally capable of promoting macrophages to block DNA replication. They stabilize covalent synthesize TNF (tumor necrosis factor) and bonds between DNA and type I topoisomerase, interleukin-1. which is responsible for DNA strand breakage Paclitaxel and docetaxel are used in chemo- during replication. As a result, the lack of the therapy of breast cancer, urinary bladder cancer, DNA helix unity leads to DNA structure dam- ovarian carcinoma, non-small-cell lung carcino- age and cell death. Being well-soluble in water, ma, Kaposi’s sarcoma in the course of AIDS, and camptothecin analogues are phase S-specific. in head and neck cancers. Both these substances The first of the analogues, irinotecan, undergoes are the most effective cytostatics in the treatment enzymatic transformation in the organism to of metastatic breast cancer. Paclitaxel is often SN-38, a compound of greater activity and used in combination with cisplatin or carbopl- more potent cytotoxic action compared to the atin, for instance in chemotherapy of epithelial parent compound. It can be used in the therapy ovarian carcinoma. Despite such a broad usage of gastric and esophageal cancers, but it is of both taxanoids, they are characterized by high mainly applied in combination with 5-fluorou-

47 © GinPolMedProject 4 (50) 2018: 044-049

racil and leucovorin in the therapy of metastatic underlines the need for further search for new colon cancer and rectal cancer. Topotecan effective therapeutics. In the era of increasing undergoes hydrolysis in the organism to a phar- cancer incidence and very common resistance macologically active lactam form. It is used to cytostatics, new data on their mechanisms of mainly in second-line treatment of metastatic action are particularly valuable. Plant-derived ovarian cancer and non-small-cell lung carcino- substances have a very broad spectrum of ther- ma. Irinotecan and topotecan are also used in apeutic action and are used in almost all disease the therapy of cervical cancer, breast cancer, entities. There are, however, limitations to their pancreatic cancer, renal carcinoma, liver cancer, use, associated with relatively frequent and and head and neck malignancies. Type I topoi- serious adverse effects. Vinca alkaloid- or pacli- somerase inhibitors cause bone marrow sup- taxel-specific neurotoxicity or myelosuppres- pression, mainly neutropenia, and gastrointes- sion, or cardiotoxicity in anthracycline therapy tinal disorders manifesting with nausea, vomit- serve as the examples. New targeted therapies, ing and diarrheas. The absolute contraindication more and more frequently used in the treatment to the use of irinotecan is gastrointestinal ob- of solid tumors, have a potential to improve struction, as this is life-threatening [11,16]. outcomes and limit adverse effects. Apart from toxicity of natural cytostatics, another obstacle Enzymes in their use is also poor solubility in water, Asparaginase is a natural and crucial enzyme in which concerns, for instance, camptothecin. cancer therapy. It was isolated from Escherichia Cancer cell resistance is a significant issue as- coli and Erwinia carotovora. Asparaginase is sociated with anticancer effect of certain plant- characterized by activity. It catalyzes derived drugs. Drug resistance largely limits or L-asparagine cleavage into aspartic acid and prevents effective treatment, while combined ammonia. Anticancer properties of L-asp were therapies yield better outcomes. discovered in guinea pig serum in the 1960s. This enzyme exerts cytostatic action towards CONCLUSIONS cancer cells characterized by low L-asparagine synthase activity, which results in dependence Apart from plant-derived cytostatics approved on the presence of an exogenous amino acid. clinically for use in oncology, a number of Exogenous asparaginase leads to asparagine plant-derived preparations with anticancer breakage, and then in the inhibition of nucleic properties are believed to soon become dom- acid and protein synthesis in cancer cells. The inant in clinical trials. A careful exploration of greatest activity of proliferation inhibition is anticancer effects of plant-derived substances is observed in cell cycle G1 phase. E. coli-aspar- incessantly being a subject of investigation. That aginase occurs in the native form and in a form is why new innovative analogues or forms of bound with polyethylene glycol. They differ drugs containing the aforementioned cytostat- from each other in pharmacokinetic parameters, ics are expected to emerge. immunogenicity and adverse effects. That is why dose adjustments to these parameters is essential to achieve therapeutic activity of this drug. REFERENCES L-asp is one of the fundamental drugs used 1. Dobrek Ł, Szcześniak P, Thor P et al. Aktualne kierunki w poszukiwaniach nowych leków przeciwnowotworo- in the treatment of acute lymphoblastic leuke- wych. Geriatria 2008;2:37-46. mia and also of other malignancies, such as non- 2. Żółtowska K, Sobczak M. Perspektywy wykorzystania Hodgkin lymphomas. It causes injury to the polimerowych nośników epidoksorubicyny i cyklofosfami- coagulation system, gastrointestinal tract, liver, du w terapii nowotworów. Polimery w Medycynie 2014; 44:51-62. kidneys and pancreas. It often causes hypersen- 3. Domagała W. Molekularne podstawy karcynogenezy i sitivity in the form of local reactions (erythema, ścieżki sygnałowe niektórych nowotworów ośrodkowego rash), and even generalized symptoms, such as układu nerwowego. Polski Przegląd Neurologiczny 2007; 3:127-141. anaphylactic shock or even central nervous 4. Sobotta Ł, Mielcarek J, Sobiak S et al. Antrachinony – system disorders [17]. małe cząsteczki, duże nadzieje. Farmacja Polska 2010; 66:162-167. 5. Staszczyk M, Pasławska U, Hildebrand et al. Kardiotok- DISCUSSION syczność doksorubicyny. Życie weterynaryjne 2013; 88: 118-120. Chemotherapy, being the most common form 6. Losy J, Bartosik-Psujek H, Członkowska A et al. Lecze- nie stwardnienia rozsianego Zalecenia Polskiego Towarzy- of treatment in cancer patients, is undergoing stwa Neurologicznego. Polski Przegląd Neurologiczny constant changes, and its dynamic development 2016;12:92-93.

48 A. Antosz-Gruszkoś – Plant-derived cytostatic drugs

7. Szwed M. Mitoksantron - antybiotyk antrachinonowy w 13. Huszno J, Nowara E. Farmakokinetyka i farmakogenety- aktywności przeciwnowotworowej stosowany w leczeniu ka w systemowym leczeniu chorych na raka piersi. Onko- stwardnienia rozsianego. Postępy Hig Med Dosw 2014; logia w Praktyce Klinicznej 2010;6:159–170. 68:198-208. 14. Marczak A, Rogalska A. Rola TUBB3 w odpowiedzi ko- 8. Naumczuk B. Synteza i badanie właściwości chemicznych mórek nowotworowych na epotilony i taksany. Postę- i biologicznych potencjalnych inhibitorów topoizomera- py Higieny i Medycyny Doświadczalnej 2015;69:158- zy i oddziaływujących z oligomerami DNA. Dostępny pod 164. adresemhttp://rcin.org.pl. 15. Cortem J, Baselga J. Targeting the Microtubules in Bre- 9. Korbut R. Farmakologia PZWL Warszawa 2017:322. ast Cancer Beyond Taxanes: The Epothilones. Oncologist 10. Jeziorski K. Leki stosowane w farmakoterapii nowotwo- 2007; 12: 271-280. rów przewodu pokarmowego. Gastroenterologia Klinicz- 16. Frant M, Czerwonka A, Żurek A. Cytostatyki w walce z na 2011;3:9-16. nowotworami. W: Olszówka M, Maciąg K (Ed.) Choroby 11. Gurgul A, Lityńska A. Substancje pochodzenia roślinne- nowotworowe: wybrane zagadnienia. Lublin Fundacja na go w terapii nowotworów. Postępy Fitoterapii 2017; 18: rzecz promocji nauki i rozwoju TYGIEL 2015;142-151. 203-208. 17. Walenciak J, Zalewska-Szewczyk B. Czynniki warunku- 12. Świątek Ł. Substancje roślinne w walce z nowotworami. jące aktywność terapeutyczną L-asparaginazy. Acta Ha- Aptekarz Polski 2009;30:12-14. ematologica Polonica 2014;45:35-40.

49