Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2018; 24(10): 1072-1083
Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1072
Narrow line between benefit and harm: Additivity of hyperthermia to cisplatin cytotoxicity in different gastrointestinal cancer cells
Vaidotas Cesna, Arturas Sukovas, Aldona Jasukaitiene, Rima Naginiene, Giedrius Barauskas, Zilvinas Dambrauskas, Saulius Paskauskas, Antanas Gulbinas
Vaidotas Cesna, Giedrius Barauskas, Department of Surgery, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
Arturas Sukovas, Saulius Paskauskas, Department of Obstetrics and Gynecology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
Aldona Jasukaitiene, Zilvinas Dambrauskas, Antanas Gulbinas, Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
Rima Naginiene, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
Author contributions: Cesna V, Sukovas A analyzed the data and drafted the manuscript; Jasukaitiene A performed most of experiments; intracellular cisplatin concentration analysis was performed by Naginiene R; Barauskas G, Paskauskas S and Gulbinas A designed and coordinated the research; Gulbinas A and Dambrauskas Z revised the manuscript for important intellectual content; all authors have read and approved the final version to be published.
Supported by the Research Council of Lithuania, No. SEN-01/2015.
Institutional review board statement: The study was reviewed and approved by the Kaunas Regional Biomedical Research Ethics Committee.
Conflict-of-interest statement: All authors have nothing to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Zilvinas Dambrauskas, MD, PhD, Lecturer, Professor, Surgeon, Lithuanian University of Health Sciences, Institute for Digestive Research, Eiveniu str., 4, Kaunas LT-50161, Lithuania.
Telephone: +370-68-669255 Fax: +370-37-326179
Received: December 2, 2017
Peer-review started: December 2, 2017
First decision: December 27, 2017
Revised: January 2, 2018
Accepted: January 16, 2018
Article in press: January 16, 2018
Published online: March 14, 2018

To investigate the response to hyperthermia and chemotherapy, analyzing apoptosis, cytotoxicity, and cisplatin concentration in different digestive system cancer cells.


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.


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.


In addition to cisplatin, hyperthermia up to 43 °C does not affect the viability of cancer cells in a synergistic manner.

Keywords: Hyperthermal intraperitoneal chemotherapy, Cisplatin, Hyperthermia, Isobolograms, Gastric cancer, Pancreatic cancer, Colon cancer

Core tip: Hyperthermal intraperitoneal chemotherapy is widely used as a standard treatment option for peritoneum invading gastrointestinal cancer. Our in vitro results suggest that optimal temperature has to be taken into consideration for achieving optimal therapeutic effect. In addition to cisplatin, hyperthermia up to 43 °C does not affect the viability of AGS, Caco-2, and T3M4 cells in a synergistic manner. However, some regimens of hyperthermia and cisplatin treatment are beneficial regarding an increase in intracellular cisplatin concentration and enhancement apoptosis of gastrointestinal cancer cells.