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Background: The impact of cell cycle inhibition on cancer cell sensitivity to hyperthermic chemotherapy is unknown. This study investigates the effect of cell cycle inhibition by the cyclin-dependent kinase inhibitor, roscovitine, on the cancer cell-specific cytotoxicity of hyperthermic oxaliplatin.
Methods: DLD colon cancer cells and MCF10A immortalized epithelial cells were treated with combinations of hyperthermia, roscovitine and oxaliplatin over a range of durations (30-120 minutes) and temperatures (37-43°C). Clonogenic assays and MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) were used to assess the impact of these treatments. Propridium iodide was used to quantify the cell cycle effects.
Results: There was minimal toxicity from hyperthermia alone (43°C for 120 minutes) (Table 1). Roscovitine enhanced the sensitivity of DLD cells to hyperthermia at 43°C. There was a time (>90 min) and temperature (>40°C) dependent, cancer-specific, triple synergistic cytotoxicity between roscovitine, hyperthermia and oxaliplatin. Treating with roscovitine prior to hyperthemic oxaliplatin was more cytotoxic than the reverse sequence. There was greater cytotoxicity with the combined treatments in DLD than MCF10A. Roscovitine induced G2-cell cycle arrest in DLD and G1 arrest in MCF10A. Hyperthermia itself did not affect the cell cycle.
Conclusion: This study demonstrates a cancer-specific synergistic cytotoxicity between the cell cycle inhibitor, roscovitine, hyperthermia and hyperthermic oxaliplatin. Clinical trials of roscovitine as an adjunct to hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis are warranted.
Table 1. Cancer-specific synergistic cytotoxicity between roscovitine and hyperthermic oxaliplatin