Cancer or malignant neoplasia is a broad group of various diseases characterized by uncontrolled and abnormal growth of cells. It can arise in any organ of the body such as lungs, breast, ovary, intestine etc. The cancerous cells can invade nearby tissues and can spread through the blood stream and lymphatic system to other parts of the body and this process is termed as metastasis. The unchecked growth of cancer results in the death of the host, as a rule, in a few months to few years from the first appearance of symptoms depending to a certain extent upon the site of origin.
The cancer of blood or bone marrow is called leukemia which is characterized by abnormal increase of immature white blood cells. Mainly three classes of agents have been most extensively studied in the search of chemical inducers of differentiation of leukemic cells viz. histone deacetylase (HDAC) inhibitors [Zini, R.; Norfo, R.; Ferrari, F.; Bianchi, E.; Salati, S.; Pennucci, V.; Sacchi, G.; Carboni, C.; Ceccherelli, G. B.; Tagliafico, E.; Ferrari, S.; Manfredini, R. Exp Hematol (2012) 40, (12), 1043-1054 e6], Deoxyribose nucleic acid methyl transferase (DNMT) inhibitors [Savickiene, J.; Treigyte, G.; Borutinskaite, V. V.; Navakauskiene, R. Cell Mol Biol Lett (2012) 17, (4), 501-25] and retinoic acid receptor agonists [Brown, G.; Hughes,
P. Leuk Res Treatment (2012), 939021]. (−)-Epigallocatechin 3-gallate (EGCG) is the most intriguing accepted product that exhibit DNMT inhibitory activity though their beneficial anticancer activity may fade due to intercede of its multiple biological effects [Lambert, J. D.; Sang, S.; Yang, C. S. Chem Res Toxicol (2007), 20, (4), 583-5.]. Bexarotene is retinoic acid mimetic DNMT inhibitor and is in preclinical stages for the treatment of cutaneous T-cell lymphoma [Qu, L.; Tang, X. Cancer Chemother Pharmacol (2010) 65, (2), 201-5.]. In addition, tyrosine kinase inhibitors have proved successful in treatment of various kinds of cancers including chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML) as well as solid tumors. Imatinib, an inhibitor of BCR-ABL, a constitutively active tyrosine kinase found in CML patients with Philadelphia chromosome (an abnormal translocation of chromosome 9 and 22 creating a fusion between break-point cluster gene (BCR) and ABL kinase) has been the first choice drug for BCR-ABL-positive CML since 2001. However, occurrence of frequent imatinib resistance in patients has necessitated the search for new chemical entities. Nilotinib has relatively favorable safety profile over imatinib as first line tyrosine kinase inhibitor for the treatment of leukemia [Goldman, J. M.; Marin, D. Oncology (Williston Park). (2012) October; 26(10):901-7]. Dual SRC/BCR-ABL tyrosine kinase inhibitor dasatinib has been approved for use in patients with chronic myelogenous leukemia (CML), especially in imatinib resistant cases [Santos, F. P.; Kantarjian, H.; Quintas-Cardama, A.; Cortes, J. Cancer J (2011) 17, (6), 465-76.]. However, dasatinib also exhibits limited success rate in imatinib resistant patients and there is occurrence of dasatinib-resistance [Soverini, S.; et al. Haematologica. (2007) March; 92(3):401-4]. Dual BCR-ABL/Lyn tyrosine kinase inhibitors like bafetinib or bosutinib have shown strong efficacy in leukemia and solid tumors [Santos, F. P.; Kantarjian, H.; Quintas-Cardama, A.; Cortes, J. Cancer J (2011) 17, (6), 465-76., Amsberg, K. G.; Brummendorf, T. H. Expert Rev anticancer ther (2012) 12, (9), 1121-1127., Daud, A. I.; Krishnamurthi, S. S.; Saleh, M. N.; Gitlitz, B. J.; Borad, M. J.; Gold, P. J.; Chiorean, E. G.; Springett, G. M.; Abbas, R.; Agarwal, S.; Bardy-Bouxin, N.; Hsyu, P. H.; Leip, E.; Turnbull, K.; Zacharchuk, C.; Messersmith, W. A. Clin Cancer Res (2011) 18, (4), 1092-1100]. Inhibitors of type III receptor tyrosine kinase family members including platelet derived growth factor receptors and FMS like tyrosine kinase 3, like tandutinib, sorafenib have been found effective in both leukemia and a number of solid tumors [DeAngelo, D. J.; Stone, R. M.; Heaney, M. L.; Nimer, S. D.; Paquette, R. L.; Klisovic, R. B.; Caligiuri, M. A.; Cooper, M. R.; Lecerf, J. M.; Karol, M. D.; Sheng, S.; Holford, N.; Curtin, P. T.; Druker, B. J.; Heinrich, M. C. Blood (2006), 108, (12), 3674-81]. Dovitinib, a multiple tyrosine kinase inhibitor that also inhibits topoisomerases I and II have been shown to be effective in multiple cancer types [Hasinoff, B. B.; Wu, X.; Nitiss, J. L.; Kanagasabai, R.; Yalowich, J. C. Biochem Pharmacol (2012) 84, (12), 1617-26]. Efficacy of Cyclin dependent kinase (CDK) inhibitors alone or in combination are also being actively pursued for treatment of both leukemia and solid tumors; Flavopiridol, a synthetic flavonoid inhibitor of CDKs, arrests cell division and causes apoptosis in non-small lung cancer cells and is currently under phase I clinical trial for combination treatment of CML patients with imatinib [Bose, P.; Perkins, E. B.; Honeycut, C.; Wellons, M. D.; Stefan, T.; Jacobberger, J. W.; Kontopodis, E.; Beumer, J. H.; Egorin, M. J.; Imamura, C. K.; Douglas Figg, W., Sr.; Karp, J. E.; Koc, O. N.; Cooper, B. W.; Luger, S. M.; Colevas, A. D.; Roberts, J. D.; Grant, S. Cancer Chemother Pharmacol (2012) 69, (6), 1657-67], PD 0332991 is an orally available pyridopyrimidine-derived cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity [Leonard, J. P.; LaCasce, A. S.; Smith, M. R.; Noy, A.; Chirieac, L. R.; Rodig, S. J.; Yu, J. Q.; Vallabhajosula, S.; Schoder, H.; English, P.; Neuberg, D. S.; Martin, P.; Millenson, M. M.; Ely, S. A.; Courtney, R.; Shaik, N.; Wilner, K. D.; Randolph, S.; Van den Abbeele, A. D.; Chen-Kiang, S. Y.; Yap, J. T.; Shapiro, G. I. Blood (2012):119(20):4597-607] and RO-3306 reversibly arrests human cells at the G2/M border of the cell cycle [Aarts, M.; Sharpe, R.; Garcia-Murillas, I.; Gevensleben, H.; Hurd, M. S.; Shumway, S. D.; Toniatti, C.; Ashworth, A.; Turner, N. C. Cancer Discov 2, (6), 524-39.].
Imatinib resistance in BCR-ABL-dependent CML can be divided into two types: a. BCR-ABL dependent. b. BCR-ABL independent. BCR-ABL-dependent resistance can occur due to mutations in the BCR-ABL protein which prevents its binding to imatinib, therefore rendering this protein insensitive to the drug (Pricl, S.; Fermeglia, M.; Ferrone, M.; Tamborini, E. Mol Cancer Ther. (2005) 4(8):1167-74). Among the reported mutations, T315I point mutation which occurs at the 315th amino acid of the ABL kinase, where a threonine moiety is substituted by an isoleucine moiety eliminates an essential oxygen molecule that is critical for hydrogen bonding between BCR-ABL. BCR-ABL has been shown to be insensitive to not only imatinib but also to a number of BCR-ABL inhibitors such as dasatinib and bosutinib [(Pricl, S.; Fermeglia, M.; Ferrone, M.; Tamborini, E. Mol Cancer Ther. (2005) 4(8):1167-74). Weisberg, E.; Manley, P. W.; Cowan-Jacob, S. W.; Hochhaus, A.; Griffin, J. D. Nat Rev Cancer. (2007) 7(5):345-56.] Only ponatinib has been shown to be effective against this mutation (O'Hare, T.; Deininger, M. W.; Eide, C. A.; Clackson, T.; Druker, B. J. Clin Cancer Res. (2011) 17(2):212-21). BCR-ABL-independent imatinib resistance can occur due a number of mechanisms including drug efflux by P-glycoprotein or multi drug resistance group of transporter proteins, defects in drug import in the intracellular milieu or activation of alternate signaling pathway such as activation of src family of kinases which have been implicated in imatinib signaling as well as locking imatinib in an active conformation which is incapable of binding to imatinib (Nestal de Moraes, G.; Souza, P. S.; Costas, F. C.; Vasconcelos, F. C.; Reis, F. R.; Maia, R. C. Leuk Res Treatment. (2012); 2012:671702.). In addition, it has been shown that even in imatinib sensitive cells where BCR-ABL activity is downregulated by imatinib an undifferentiated subpopulation of cells expressing the cluster of differentiation (CD) 34 (CD34; a member of the sialomucin group of transmembrane proteins) but are CD38 negantive (CD34+CD38−) are not killed by imatinib and these cells ultimately are responsible for relapse of leukemia (Corbin, A. S.; Agarwal, A.; Loriaux, M.; Cortes, J.; Deininger, M. W.; Druker, B. J. J Clin Invest. (2011); 121(1):396-409). These cells are termed as “cancer stem cells” (CSC) and they typically harbour some stem cell markers on the cell surface and are refractory to drug treatments. Such CSCs are also evident in all cancer types including solid tumors and are responsible for relapse. In colon cancer cells these CSCs harbour CD133 in the cell surface (O'Brien, C. A.; Pollett, A.; Gallinger, S.; Dick, J. E. Nature. (2007) 445(7123):106-10.). Till date therapeutics for CSCs are not available and only salinomycin has been shown to be effective in killing these cells in vitro (Gupta, P. B.; Onder, T. T.; Jiang, G.; Tao, K.; Kuperwasser, C.; Weinberg, R. A.; Lander, E. S. Cell. (2009) 138(4):645-59).
Treatment of cancer by the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent the process of carcinogenesis is termed as chemotherapy. Essentially, effective implementation of this strategy requires cytotoxicity in not only the malignant cells but also in the cancer stem cells to prevent relapse of cancer following chemotherapy.
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