Mild oxidative stress induced by a low dose of cisplatin contributes to the escape of TRAIL-mediated apoptosis in the ovarian cancer SKOV3 cell line.

Tumor necrosis factor (TNF)-related apoptosis‑inducing ligand (TRAIL) is expressed in ovarian tissue and is widely thought to exhibit strong antitumor activity in a variety of tumor cell types. Therefore, we hypothesized that the cisplatin resistance of ovarian cancer is linked to the ability to escape from TRAIL-mediated apoptosis. We demonstrated that cisplatin-resistant ovarian cancer cell line SKOV3/DDP tolerated treatment with TRAIL, in contrast to the cisplatin‑sensitive ovarian cancer cell line SKOV3. SKOV3/DDP cells exhibited a much higher cell viability and a lower apoptosis rate than SKOV3 cells after treatment with TRAIL. To determine whether cisplatin induced the tolerance of TRAIL, we pretreated the SKOV3 cells with cisplatin in the presence of TRAIL. This revealed that a low dose of cisplatin (1 µM) increased the TRAIL tolerance of SKOV3 cells. Furthermore, cisplatin induced oxidative stress in both the SKOV3/DDP and SKOV3 cells, although the oxidative stress level of the SKOV3/DDP cells was generally much higher than that noted in the SKOV3 cells. Similarly, a low dose of hydrogen peroxide increased the TRAIL tolerance in SKOV3 cells. Notably, the TRAIL tolerance in the SKOV3 and SKOV3/DDP cells could be abrogated by the oxidative stress scavenger N-acetyl-cysteine. These results suggest that a low dose of cisplatin induces the tolerance of TRAIL in SKOV3 cells at least partly, depending on the oxidative stress signaling pathway.