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

Abstract

AIMTo investigate the response to hyperthermia and chemotherapy, analyzing apoptosis, cytotoxicity, and cisplatin concentration in different digestive system cancer cells.METHODSAGS (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.RESULTSAGS 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.CONCLUSIONIn addition to cisplatin, hyperthermia up to 43 °C does not affect the viability of cancer cells in a synergistic manner.

Stimulated upregulation of HO‑1 is associated with inadequate response of gastric and ovarian cancer cell lines to hyperthermia and cisplatin treatment

“…To the best of our knowledge, to date, there has been a lack of evidence regarding the synergy of chemotherapy and hyperthermia. In our previous studies, it was observed that gastrointestinal and ovarian cancer cells responded unpredictably following exposure to cisplatin and hyperthermia (16,31). One of the limits of this response may be the induction of cytoprotective enzymes associated with chemotherapy and/or hyperthermia, in particular HO-1.…”

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Peritoneal Carcinomatosis: Our Initial Experience

“…Future research in the field are dedicated to the improvement of the cytostatic drugs with the help of nanotechnology (55), as well as research in the field of hyperthermia, the standardization of temperature curves and chemotherapeutic concentrations being essential (56,57).…”

Hyperthermic intraperitoneal chemotherapy with cisplatin and mitomycin C for colorectal cancer peritoneal metastases: A systematic review of the literature

“…First, in gastric cancer cell lines, Tang demonstrated a synergistic effect on inhibiting proliferation and induction of cell death via the apoptotic pathway [30]. In 2018, Cesna validated this synergic effect on colon cancer cells [28]. Caco-2 cells (colon cancer cell line) were treated with CDDP.…”

“…In vitro (Table 1) Some experimental studies demonstrated that hyperthermia can affect cell membranes, the cytoskeleton, and the synthesis of macromolecules and can increase drug-induced DNA damage and inhibit the repair of drug-induced DNA damage [28]. CDDP appeared as a drug of choice associated with hyperthermia because hyperthermia provided pharmacokinetic advantages with higher local CDDP concentrations in tissues [29].…”

“…Hyperthermia gradually improved the cytotoxic effect and decreased the viability of cells by one-fourth from 43°C to 45°C. Furthermore, early apoptosis (20% compared to cells treated in normothermia) and an increase in the intracellular CDDP concentration (by 20%) were induced [28]. Some authors have investigated the role of adenosine triphosphate (ATP) in explaining the synergistic effect of chemotherapy and hyperthermia.…”