The Hydrolysed Products of Iridoid Glycosides Can Enhance Imatinib Mesylate‐Induced Apoptosis in Human Myeloid Leukaemia Cells
2015
Kim, Min‐Beom | Kim, Chʻŏr-wŏn | Chung, Won‐Seok | Cho, Jae‐Heung | Nam, Dongwoo | Kim, Sung‐Hoon | Ahn, Kwang Seok
Several studies have demonstrated that deregulated activation of signal transducer and activator of transcription 3 (STAT3) has been associated with survival, proliferation, chemoresistance and angiogenesis of tumour cells. Thus, inhibition of STAT3 expression could be a potent therapeutic approach for cancer treatment. Using several leukaemia cell lines, the effect of the hydrolysed‐catalpol (H‐catalpol) and hydrolysed‐aucubin (H‐aucubin) products on the STAT3 signalling pathway, inhibition of BCR–ABL activation, cellular proliferation and potentiation of imatinib mesylate‐induced apoptosis was investigated. We found that iridoid glycosides (catalpol and aucubin) did not exert any cytotoxicity in the tumour cells, whereas both H‐catalpol and H‐aucubin exhibited significant cytotoxic effects on K562 human myeloid leukaemia cells. Indeed, H‐catalpol and H‐aucubin down‐regulated BCR–ABL phosphorylation and inhibited constitutive STAT3 activation through abrogating upstream JAK2 and c‐Src and constitutive STAT5 activation leading to apoptosis through caspase‐3 activation. Hydrolysed‐catalpol enhanced the apoptosis induced by imatinib mesylate and this correlated with down‐regulation of gene products that mediate cell proliferation (cyclin D1), and cell survival (Bcl‐2, Bcl‐xL and survivin); all known to be regulated by the STAT3. Overall, our results provide novel insight into the role of hydrolysed iridoids in potentially treating leukaemia through the modulation of STAT3 signalling pathway.
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