Oxalicumone A, a new dihydrothiophene-condensed sulfur chromone induces apoptosis in leukemia cells through endoplasmic reticulum stress pathway

Abstract

Oxalicumone A (POA1), a novel dihydrothiophene-condensed sulfur chromone isolated from the marine fungus Penicillium oxalicum SCSGAF 0023, showed cytotoxicity against several cancer cells previously. In this study, its anti-cancer activity and underlying mechanism of this action were investigated in leukemia cells like KG-1a, HL60, U937, and K562. The results showed that POA1 inhibited dose-/time-dependently cell growth and induced apoptosis in leukemia cells. Also, POA1 caused cleavages of caspase-3, 8, 9 and PARP1, loss of mitochondrial membrane potential, up-regulations of phosphorylated p38 and JNK, and activation of endoplasmic reticulum stress (ER stress). Furthermore, 4-PBA (an ER stress inhibitor) but not SP600125 and SB203580 (JNK and p38 inhibitor, respectively) could largely inhibit POA1-induced growth suppression. Additionally, 4-PBA obstructed mitochondrial depolarization and cleavage of PARP1. These data suggested that ER stress pathway might be an important mediator in POA1-induced apoptosis. In conclusion, POA1 may have antitumor effects in leukemia cells through the induction of ER stress pathway.

Keywords: Apoptosis; ER stress; Leukemia cell; MAPKs; Mechanism of action; Oxalicumone A.