The newly synthesized naftopidil analog HUHS1015 has been developed as an anticancer drug. The present study aimed at understanding the mechanism underlying HUHS1015-induced cell death in CW2 and Caco-2 human colonic cancer cells. HUHS1015 reduced cell viability in CW2 and Caco-2 cells in a concentration (10-100 μM)-dependent manner. HUHS1015 decreased pyruvate kinase M2 (PKM2) protein, and the effect was inhibited by the autophagy inhibitor 3-methyladenine. PKM2 deficiency activated caspase-3, -4, -8, and -9 in Caco-2 cells, although such effect was not obtained with CW2 cells. Moreover, PKM2 deficiency induced early apoptosis and late apoptosis/secondary necrosis in CW2 cells and primary necrosis, early apoptosis, and late apoptosis/secondary necrosis in Caco-2 cells. The results of the present study show that HUHS1015 decreases PKM2 protein due to autophagic degradation, to initiate cell death such as necrosis and caspase-dependent and -independent apoptosis in CW2 and Coco-2 cells.
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