Targeting tyrosine kinases for autophagy induction along with cytoprotective effect in hematopoietic progenitor cells

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Treatment with imatinib mesylate (IM), which is used for targeting therapy for chronic myelogenous leukemia, exhibited an effect of an increased viable cell number of non-BCR-ABL-expressing cell lines by inhibiting spontaneous apoptosis along with autophagy induction. IM attenuated the cytotoxic effects of cytosine arabinoside,tunicamycin, and bortezomib as well as inhibiting cell death with serum-deprived culturein an autophagy-dependent manner. In contrast to autophagy-dependent cytoprotection in response to IM, combined treatment with autophagy inhibitor such as clarithromycin, and proteasome inhibitor, bortezomib potently enhanced endoplasmic reticulum (ER)-stress mediated apoptosis in breast cancer cells and myeloma cells. These lines of evidence suggest that manipulation of autophagy can induce cytoprotective effect via attenuationof ER-stress loading in various kinds of cells including hematopoietic progenitor cells.