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Graphical Abstract CG 18-1-MS Send Orders for Reprints to reprints@benthamscience.ae 3 Current Genomics, 2017, 18, 3-26 REVIEW ARTICLE ISSN: 1389-2029 eISSN: 1875-5488 Impact Factor: 2.43 Established Human Cell Lines as Models to Study Anti-leukemic Effects of Flavonoids BENTHAM SCIENCE Katrin Sak* and Hele Everaus Department of Hematology and Oncology, University of Tartu, Tartu, Estonia Abstract: Despite the extensive work on pathological mechanisms and some recent advances in the treatment of different hematological malignancies, leukemia continues to present a significant challenge being frequently considered as incurable disease. Therefore, the development of novel therapeutic agents with high efficacy and low toxicity is urgently needed to improve the overall survival rate of pa- A R T I C L E H I S T O R Y tients. In this comprehensive review article, the current knowledge about the anticancer activities of Received: May 11, 2015 flavonoids as plant secondary polyphenolic metabolites in the most commonly used human established Revised: November 20, 2015 Accepted: November 27, 2015 leukemia cell lines (HL-60, NB4, KG1a, U937, THP-1, K562, Jurkat, CCRF- CEM, MOLT-3, and MOLT-4) is compiled, revealing clear anti-proliferative, pro-apoptotic, cell cycle arresting, and differ- DOI: 10.2174/138920291766616080316 entiation inducing effects for certain compounds. Considering the low toxicity of these substances in 5447 normal blood cells, the presented data show a great potential of flavonoids to be developed into novel anti-leukemia agents applicable also in the malignant cells resistant to the current conventional che- motherapeutic drugs. Keywords: Antiproliferation, Apoptosis, Cell cycle arrest, Cytotoxicity, Differentiation, Flavonoids, Leukemia, Human cell lines. 1. INTRODUCTION development makes leukemia the disease of cell differentia- tion [19]. Moreover, recent studies have shown that tumors Leukemia as a malignant tumor of the hematopoietic of blood-forming tissues can be originated from leukemic system is a commonly diagnosed neoplasm that causes sig- stem cells rendering leukemia also a stem cell disorder [21, nificant harm to human health and represents a major cause 22]. of cancer-related deaths worldwide [1-7]. Leukemia accounts for almost 5% of all cancer cases ranking in the sixth place Leukemia consists of a heterogeneous group of hemato- among various human malignancies [4, 6]. Furthermore, it is logical malignancies affecting the cells of all hematopoietic the most common neoplasm in childhood being the cause of lineages [8, 10, 20, 21]. This complex disease can hit all the about 30% of all cancer-related deaths in children and ado- age groups being somewhat more common in men than in lescents under the age of 14 years [6, 8-10]. women and developing more frequently in Caucasians com- pared to other races [7, 10]. On the ground of involved cell There are multiple risk factors of leukemogenesis includ- types and the temporal progression of disease, four main ing endogenous and exogenous exposures, genetic vulner- ability and susceptibility, but also the chance might play its types of leukemia are distinguished: acute lymphocytic leu- role. However, the precise cause of leukemia is still not kemia (ALL), chronic lymphocytic leukemia (CLL), acute known [7, 8, 11]. Like other cancers, also leukemia is char- myelogenous leukemia (AML) and chronic myelogenous acterized by a succession of mutations in genes that regulate leukemia (CML), as described elsewhere [7, 23-26]. ALL is the processes of cellular division, death and differentiation the most common form of childhood malignancies with the leading to the progressive shift of cells from normal to ma- highest prevalence between the ages of two and five years, lignant state [8, 11-15]. Hematopoietic cancers often emerge constituting about one-third of all pediatric cancers, as indi- in consequence of the uncontrolled growth and accumulation cated in [7, 10, 24, 27, 28]. Although more than 80% of chil- of immature blasts as the cellular differentiation is typically dren with ALL are currently cured, the survival rate of adults blocked at a particular maturation stage leading to the defi- suffering from ALL rarely exceeds 40%, as reviewed in [28, ciency of normal functional blood cells and causing numer- 29]. The other lymphoproliferative malignancy, CLL is the ous serious symptoms [16-20]. Such failure in the cellular most frequent type of leukemia in adult population in the Western countries affecting mainly the people over the age of 55 [24, 30-33]. Despite the numerous studies, this highly *Address correspondence to this author at the Department of Hematology and Oncology, University of Tartu, L. Puusepa 8, 51014 Tartu, Estonia; heterogenous disease is still considered incurable [32-36]. Tel: +372 53 341 381; E-mail: katrin.sak.001@mail.ee Similarly, the overall survival of patients with AML has re- urrent Genomics C 1875-5488/17 $58.00+.00 ©2017 Bentham Science Publishers 4 Current Genomics, 2017, Vol. 18, No. 1 Sak and Everaus mained poor whereas the incidence of this aggressive malig- portant focus for current leukemia research [8, 25, 49, 51-53, nancy is continuously increasing [37-47]. 62, 87]. The current treatments of leukemia include chemother- 2. NATURAL RESOURCES FOR NOVEL ANTICAN- apy, radiation, and bone marrow transplantation, whereas CER AGENTS chemotherapy has still remained the most important inter- vening strategy in treating different types of hematological Over the past decades, there is an increasing interest in malignancies [4, 8, 10, 26, 48-53]. However, standard che- the use of bioactive components from natural sources as po- motherapy agents are usually expensive and often associated tential novel anticancer agents, and identification of chemi- with toxicity towards normal cells resulting in serious side cal entities, molecular targets and signaling pathways trig- effects and limiting the overall efficacy of drugs [3, 8, 10, gered by these natural products has become a very important 26, 49, 52, 54-56]. In addition, drug resistance also repre- topic of research [2, 10, 11, 30, 88-92]. Nature provides a sents a major problem in the current treatment of leukemia tremendous diversity of candidate compounds for fighting [5, 8, 13, 52, 57-60]. Such chemoresistance can be either cancer, including hematological malignancies, whereas intrinsic or acquired after initial therapy being a main reason modification of these lead molecules can further enhance for treatment failure [13, 61-64]. their efficacy and reduce adverse effects [6, 9, 13, 15, 28, 39, 49, 93-95]. Accordingly, many clinically used anticancer Recently, introduction of targeted therapies have brought drugs are either natural products or obtained by derivatiza- about considerable improvements in survival of patients with tion of naturally occurring lead compounds [62, 96-98]. In- certain types of leukemia; at that, all-trans retinoic acid deed, as a matter of fact, up to 70% of chemotherapeutic (ATRA) for AML and Imatinib against CML represent two drugs approved by the US Federal Drug Administration are examples of the success of target-based therapies [8, 27, 65- derived from natural sources [15, 12, 24, 27, 28, 89, 99-102]. 67]. Using the agents that force immature leukemia cells to Examples of such agents include Vinca alkaloids vincristine undergo terminal differentiation or so-called differentiation and vinblastine, taxanes (Paclitaxel and Docetaxel), podo- therapy, is potentially a less toxic alternative to treat hema- phyllotoxin derivatives (etoposide and teniposide), and topoietic neoplasms [13, 17-19, 40, 53, 54, 68-70]. Indeed, camptothecins like topotecan [11, 24, 28, 37, 95, 103-106]. granulocytic differentiation induced by ATRA is proven to Especially the plant-derived compounds have made a major be clinically effective for treatment of acute promyelocytic contribution to the arsenal of current anticancer drugs; how- leukemia (APL) leading to a breakthrough in cure of this ever, still less than one-tenth of all terrestrial plants is evalu- AML subtype [12, 16, 20, 38, 71-75]. However, application ated for their possible cytotoxic activity [95, 107, 108]. An of differentiation therapy can be effective only in certain important advantage of natural product-based antineoplastic forms of leukemia and the treatment might be accompanied substances for clinical application is their low nonspecific by severe side effects as well as development of resistance toxicity [13, 49, 109, 110]. Moreover, these compounds are [20, 73-77]. usually effective in different phases of carcinogenesis inter- Management strategies of CML have made a significant acting simultaneously with multiple molecular targets and progress after the discovery of Imatinib as a selective protein triggering several cellular pathways [15, 111]. tyrosine kinase inhibitor against a fusion protein, namely breakpoint cluster region-Abelson murine leukemia (BCR- 3. FLAVONOIDS AS PHYTOCHEMICALS WITH PO- ABL) [10, 22, 23, 65, 70, 78-81]. This chimeric protein is TENTIAL ANTICANCER PROPERTIES formed as a consequence of a reciprocal translocation be- Flavonoids are naturally occurring compounds with tween chromosomes 9 and 22, and its constitutive tyrosine abundant occurrence in plants and plant-derived foods repre- kinase activity contributes to antiapoptotic mechanisms, un- senting nutritionally valuable constituents of the daily human controlled cell proliferation and survival advantage in CML diet [38, 81, 82, 87, 100, 112-120]. These low
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