Resistance of Oral Cancer Cells to Paclitaxel and TRAIL-induced Apoptosis

Objectives: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been used as an anti-cancer therapeutic agent because of its minimal cytotoxicity to most normal cells and tissues. TRAIL can bind two apoptosis-inducing receptors, DR4 and DR5, and two additional membrane-bound receptors incapable of transmitting an apoptotic signal, DcR1 and DcR2. TRAIL-induced apoptosis is mediated by the interactions with DR4 and/or DR5. However, considerable numbers of cancer cells including oral squamous cell carcinoma (OSCC) are resistant to TRAIL-induced apoptosis. Paclitaxel, known to induce cell cycle arrest and apoptosis, has been clinically used as a chemotherapeutic agent against many human cancers. Its chemotherapeutic effects against OSCC have been investigated as a single or combination with other anti-cancer drugs. However, synergistic effects of paclitaxel and TRAIL on OSCC cells remain unknown. The purpose of the study was to examine if paclitaxel enhances TRAIL-induced apoptosis in OSCC cells.
Methods: HSC-3 cells were treated with graded doses of paclitaxel with or without human recombinant TRAIL. Twenty-four and 48 hours after the TRAIL stimulation, WST-1 assay was conducted to examine cell proliferation. Cell death and cell cycle were analyzed with flow cytometer. The expression of the TRAIL receptors before the treatment was also examined using flow cytometer.
Results: Despite the fact that HSC-3 cells expressed DR5, TRAIL did not induce apoptosis on these cells. Paclitaxel alone did not induce cell death or cell cycle arrest on HSC-3 cells. In addition, the combination of paclitaxel and TRAIL treatment did not affect either cell viability or cell death.
Conclusions: Paclitaxel did not enhance the TRAIL-induced apoptosis on OSCC cells partly because it failed to arrest cell cycle. The data also suggested that the resistance to TRAIL-induced apoptosis on be regulated at the downstream of the receptors on these cells.