Inhibition of autophagy augments the anticancer activity of α-mangostin in chronic myeloid leukemia cells

Abstract

Natural products possessing anticancer activity have been extensively studied because of their low toxicity and potential effect. α-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 α-mangostin in chronic myeloid leukemia (CML) cell lines bearing wild-type BCR–ABL or BCR–ABL-T315I mutation. We showed that α-mangostin inhibited cell proliferation of K562, KBM5 and KBM5-T315I cells in both a time- and dose-dependent manner. Significantly, α-mangostin increased the number of apoptotic cells and induced DNA fragmentation compared to control cells. Moreover, α-mangostin selectively inhibited proliferation in primary CML cells, while showing limited lethality in normal hematopoietic progenitors. Additionally, α-mangostin induced not only apoptosis but also autophagy in CML cells. α-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 α-mangostin-mediated cytotoxicity through increasing apoptosis. Taken together, our data suggest that targeting the autophagy pathway is a promising therapeutic strategy to enhance α-mangostin-induced apoptosis. Our study provides an approach for future studies to explore this combination for the treatment of CML.

Keywords::

• α-Mangostin
• chronic myeloid leukemia
• chloroquine
• apoptosis
• autophagy

Acknowledgements

We thank members of Liu Laboratory and the Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University for their critical comments.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

This work was supported by the National Natural Science Foundation of China (No. 81000217 to Z.-J. Long, No. 81130040 to Q. Liu, No. 30973635 to S. X. Qiu), the Fundamental Research Funds for the Central Universities (No. 11ykpy37 to Z.-J. Long), the science and Technology Project of Guangzhou (No. 2012J2200077 to Z.-J. Long) and the National Basic Research Program of China (973 Program; No. 2012CB967000 to Q. Liu).