Narrow line between benefit and harm: Additivity of hyperthermia to cisplatin cytotoxicity in different gastrointestinal cancer cells

AIM: To investigate the response to hyperthermia and chemotherapy, analyzing apoptosis, cytotoxicity, and cisplatin concentration in different digestive system cancer cells. METHODS: AGS (gastric cancer cell line), Caco-2 (colon cancer cell line) and T3M4 (pancreatic cancer cell line) were treated by cisplatin and different temperature setting (37 °C to 45 °C) either in isolation, or in combination. Treatment lasted for one hour. 48 h after the treatment viability was evaluated by MTT, cell apoptosis by Annexin V-PE and 7ADD flow cytometry. Intracellular cisplatin concentration was measured immediately after the treatment, using mass spectrometry. Isobologram analysis was performed to evaluate the mathematical combined effect of temperature and cisplatin. RESULTS: AGS cells were the most sensitive to isolated application of hyperthermia. Hyperthermia, in addition to cisplatin treatment, did not provoke a synergistic effect at intervals from 37 °C to 41 °C in neither cancer cell line. However, a temperature of 43 °C enhanced cisplatin cytotoxicity for Caco-2 cells. Moreover, isobologram analysis revealed mathematical antagonistic effects of cisplatin and temperature combined treatment in AGS cells; variations between synergistic, additive, and antagonistic effects in Caco-2 cells; and additive and antagonistic effects in T3M4 cells. Combined treatment enhanced initiation of cell apoptosis in AGS, Caco-2, and T3M4 cells by 61%, 20%, and 19% respectively. The increase of intracellular cisplatin concentration was observed at 43 °C by 30%, 20%, and 18% in AGS, Caco-2, and T3M4 cells, respectively. CONCLUSION: In addition to cisplatin, hyperthermia up to 43 °C does not affect the viability of cancer cells in a synergistic manner.