CWHM-1008 Induces Apoptosis and Protective Autophagy through the Akt/mTOR Axis in LUAD Cells.

Recent studies have revealed that antiparasitic agents showed promising inhibitory effects on tumors, raising a possibility that repositioning this class of drugs may shed new light on clinical therapy against tumors. CWHM-1008 is a novel class of antimalarial drug; however, the inhibitory impact of CWHM-1008 on lung adenocarcinoma (LUAD) cells remains unclear. This study aimed to explore the anticancer effect and underlying mechanisms of CWHM-1008 on LUAD cells in vitro and in vivo. Human LUAD cells, H358 and A549, were treated with varying concentrations of CWHM-1008 at different lengths of time. Cell viability, colony formation, cell count, flow cytometry findings, microtubule-associated protein-1 light chain 3-green- (LC3-) GFP/RFP adenovirus infection status, and the expression of apoptosis and autophagy-related proteins were examined. Potential effects of an autophagy inhibitor (LY294002) and constitutively active Akt plasmid (CA-Akt) on CWHM-1008-induced apoptosis were also examined. Our results showed that CWHM-1008 significantly inhibited proliferation, induced apoptosis, and enhanced autophagy flux by blocking the RAC-alpha serine/threonine-protein kinase/the mammalian target of rapamycin (Akt/mTOR) axis in two LUAD cells. In addition, autophagy inhibited by LY294002 or CA-Akt transfection accelerated CWHM-1008-induced apoptosis in those LUAD cells. Moreover, CWHM-1008 significantly inhibited the growth and induced apoptosis of A549 cell in nude mice in vivo. The present findings provide new insights into anticancer properties of CWHM-1008, suggesting that it may be an adjuvant treatment for LUAD treatment, warranting further study.