Artesunate acts as fuel to fire in sensitizing HepG2 cells towards TRAIL mediated apoptosis via STAT3 inhibition and DR4 augmentation.

In the present study, we investigated in vitro, the role of artesunate (ATS) with comparable potency to oxaliplatin (OXP) in sensitizing tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) resistant HepG2 cells towards apoptosis. ATS in consistency with OXP was found to reverse TRAIL resistant HepG2 cells towards TRAIL mediated apoptosis by enhancing caspase-3 and cleavage of PARP. Additionally, ATS also suppressed the nuclear translocation of activated signal transducers and activators of transcription 3 (STAT3) thereby sensitizing the HepG2 cells towards only death receptor 4 (DR4) mediated apoptosis. Furthermore, ATS exposure in TRAIL resistant cells resulted in significant increase of both DR4/DR5 expression and STAT3 inhibition thereby arbitrating TRAIL mediated apoptosis in HepG2 cells. The increase in expression was comparable to that of STAT3 silenced cells. From all the above observations, we conclude that ATS up-regulated DR4 expression by targeting STAT3, which in turn sensitized HepG2 cells to TRAIL mediated apoptosis.