Inhibition Of Autophagy Augments The Anticancer Activity Of Alpha-Mangostin In Chronic Myeloid Leukemia Cells

Natural products possessing anticancer activity have been extensively studied because of their low toxicity and potential effect. alpha-Mangostin, a component of Garcinia mangostana Linn, is a xanthone derivative shown to have antioxidant and antitumor properties. This study was carried out to investigate how to improve the anticancer effects of alpha-mangostin in chronic myeloid leukemia (CML) cell lines bearing wild-type BCR-ABL or BCR-ABL-T315Imutation. We showed that alpha-mangostin inhibited cell proliferation of K562, KBM5 and KBM5-T315I cells in both a time- and dose-dependent manner. Significantly, alpha-mangostin increased the number of apoptotic cells and induced DNA fragmentation compared to control cells. Moreover, alpha-mangostin selectively inhibited proliferation in primary CML cells, while showing limited lethality in normal hematopoietic progenitors. Additionally, alpha-mangostin induced not only apoptosis but also autophagy in CML cells. alpha-Mangostin dramatically increased the expression levels of LC-3II, an autophagosome marker in mammals, and the accumulation of autophagic vacuoles (AVs). Inhibition of autophagy by chloroquine enhanced alpha-mangostin-mediated cytotoxicity through increasing apoptosis. Taken together, our data suggest that targeting the autophagy pathway is a promising therapeutic strategy to enhance alpha-mangostin-induced apoptosis. Our study provides an approach for future studies to explore this combination for the treatment of CML.