Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (ABL) protooncogene of chromosome 9 with 5′ sequence of truncated break point cluster region (BCR) on chromosome 22. BCR-ABL is a functional oncoprotein p210 that exhibits constitutively activated tyrosine kinase causing genomic alteration of hematopoietic stem cells. BCR-ABL specific tyrosine kinase inhibitors (TKIs) successfully block CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Heat-shock proteins (Hsps) function as molecular chaperones facilitating proper folding of nascent polypeptides. Their increased expression under stressful conditions protects cells by stabilizing unfolded or misfolded peptides. Hsp90 is the major mammalian protein and is required by BCR-ABL for stabilization and maturation. Hsp90 inhibitors destabilize the binding of BCR-ABL protein thus leading to the formation of heteroprotein complex that is eventually degraded by the ubiquitin-proteasome pathway. Results of many novel Hsp90 inhibitors that have entered into various clinical trials are encouraging. The present review targets the current development in the CML treatment by availing Hsp90 specific inhibitors.

Chronic myelogenous leukemia (CML) is characterized by excessive proliferation of myeloid lineage of cells. The abnormality is caused due to constitutive tyrosine kinase activity of fusion protein Bcr-Abl, resulting from reciprocal chromosomal translocations of ABL from chromosome 9 to BCR on chromosome 22 [1]. The normal cellular Abl (c-Abl) is a multi-domain protein that belongs to non-receptor tyrosine kinase family. It phosphorylates proteins at tyrosine residues. Phosphorylation activity of Abl kinase is under allosteric regulation by its SH2 domain [2,3]. Abl influences several protein-protein interactions and enzymatic activity and localization. C-Abl associates a variety of sub cellular proteins including signaling adaptors, kinases, phosphatases, cell cycle regulators, transcription factors and cytoskeletal proteins [2,4]. DNA damage response of c-Abl is mediated by Ataxia Telangiectasia Mutated (ATM) and Abl critically modulates the epigenetic and non-epigenetic regulators of DNA damage and apoptosis [5,6]. Normal c-Abl is auto-regulated both by inter and intra-molecular interactions of its N and C terminal domains [7]. The Bcr-Abl fusion protein, produced as a result of the translocation posses consistently elevated tyrosine kinase activity [8]. Normal cellular Abl p145 shuttles between nuclear and cytoplasm compartments. The fusion protein Bcr-Abl retains in the cytoplasm and activates aberrant cell signaling pathways that leads to the halt of apoptosis and induces proliferation [9]. Furthermore, Bcr-Abl protein directly or indirectly activates of Signal transducer and activator transcription 5 (STAT5)/B-cell lymphoma-extralarge (Bcl-xL), extracellular signal-regulated kinase 1/2 (Erk-1/2), phosphatidylinositide 3-kinase (PI3K)/Ak strain transforming (Akt), Src signaling molecules by Phosphorylation [9,10]. The auto-phosphorylated Bcr-Abl provides the docking site, tyr-177 of Bcr domain, for these signaling molecules [11]. Constitutively active Bcr-Abl further drives several survival pathways that provide proliferative advantage and drug resistance in CML [12]. Src kinases, such as Lyn, Hck, Fgr, gets activated downstream of Bcr-Abl signaling upon direct complex formation with the Bcr-Abl and also involved in the activation of other downstream signaling molecules thus Bcr-Abl requires Src kinases for its transforming activity [13]. Therefore, simultaneously targeting Bcr-Abl and Src kinases is proven an effective strategy by Dasatinib, a dual tyrosine kinase inhibitor [14]. Inhibition of Src family kinase (SFK) with pyrrolo pyrimidine inhibitor, A-419259, inhibits the cell growth and promote apoptosis in CML cell lines which indicates their transforming potential in CML progression [15]. The transition of chronic phase to accelerated blast phase in CML progression requires Src kinases Lyn, Hck, Fgr. Lyn plays a role in cytokine Mini Review

Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (abl) protooncogene on chromosome 9 with 5′ sequence of truncated break point cluster region (bcr) to chromosome 22. The fusion gene product BCR-ABL, a functional oncoprotein p210, is a constitutively activated tyrosine kinase that activates several cell proliferative signaling pathways. BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib and ponatinib potently inhibit CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Natural products are chemical compounds or substances produced by living organisms. They are becoming an important research area for cancer drug discovery due to their low toxicity and cost-effectiveness. Several lines of evidence show that many NPs such as alkaloids, flavonoids, terpenoids, polyketides, lignans and saponins inhibit CML cell proliferation and induce apoptosis. NPs not only differentiate CML cells into monocyte/erythroid lineage but also can reverse the multi-drug resistance (MDR) in CML cells. In this chapter, we review the anti-CML activity of various NPs.

Objective: To investigate the phytoconstituents and in vitro cytotoxicity of methanol (MeOH) and aqueous (AQE) extracts of Benkara malabarica (Lam.) Triveng (BM) plant leaves.Methods: Gas chromatography-mass spectrometry (GC MS) was carried out to disclose the principal phytoconstituents present in MeOH and AQE extracts of BM. In vitro cytotoxicity of BM extracts were determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Acridine orange (AO)/ethidium bromide (EB) and 4', 6-diamidino-2-phenylindole (DAPI) staining were performed to visualize morphological changes upon treatment of BM extracts. Fluorescence-activated cell sorting (FACS) was carried out to determine the apoptosis and cell cycle arrestability of BM extracts.Results: GC MS analysis reported the presence of nine phytoconstituents in MeOH and AQE extracts of BM. The IC50 of BM MeOH, AQE extracts treated K562 cells were 49.78±1.697, 15.47±1.19 µg/ml for 48 h and found to be statistically significant (p<0.001). AO/EB and DAPI staining results anticipated the induction of apoptosis and DNA fragmentation upon treatment of BM extracts. FACS analysis revealed the SubG0 cell populations increased in K562 cells treated by BM MeOH (18.15) and AQE (51.26) extracts.Conclusion: The results of the present study uncovered that the BM AQE extract was more potent in inhibiting K562 cell proliferation through cell cycle arrest and apoptosis compared to the MeOH extract of BM.