Intrinsic apoptotic pathway is considered to be responsible for cell death induced by
platinum anticancer drugs. While in this study, we found that,
necrosis is an indispensable pathway besides apoptosis in
oxaliplatin-treated
gastric cancer SGC-7901 cells. Upon exposure to
oxaliplatin, both apoptotic and necrotic features were observed. The majority of dead cells were double positive for
Annexin V and
propidium iodide (PI). Moreover, mitochondrial membrane potential collapsed and
caspase cascades were activated. However, ultrastructural changes under transmission electron microscope, coupled with the release of cellular contents, demonstrated the
rupture of the plasma membrane.
Oxaliplatin administration did not stimulate
reactive oxygen species (ROS) production and autophagy, but elevated the
protein level of Bmf. In addition, receptor interacting
protein 1 (RIP1), but not receptor interacting
protein 3 (RIP3) and its downstream components participated in this death process.
Necrostatin-1 (Nec-1) blocked
oxaliplatin-induced cell death nearly completely, whereas
z-VAD-fmk could partially suppress cell death.
Oxaliplatin treatment resulted in
poly(ADP-ribose) polymerase-1 (PARP-1) overactivation, as indicated by the increase of
poly(ADP-ribose) (PAR), which led to
NAD(+) and
ATP depletion. PARP-1 inhibitor,
olaparib, could significantly block
oxaliplatin-induced cell death, thus confirming that PARP-1 activation is mainly responsible for the cytotoxicity of
oxaliplatin. Phosphorylation of H2AX at Ser139 and translocalization of
apoptosis-inducing factor (AIF) are critical for this death process. Taken together, these results indicate that
oxaliplatin can bypass canonical cell death pathways to kill
gastric cancer cells, which may be of therapeutic advantage in the treatment of
gastric cancer.