Purpose: Modulated electro-hyperthermia (mEHT), known as oncothermia, is an anticancer therapy that induces radiofrequency thermal damage to the cancer tissues. This study aimed to evaluate the potential effectiveness of mEHT as a therapeutic tool in ovarian and cervical cancer. Materials and methods: We used both tumor-bearing mice and ovarian and cervical OVCAR-3, SK-OV-3, HeLa and SNU-17 cancer cell lines to investigate the effects of mEHT in vivo and in vitro, respectively, and determine whether it was enhanced by cotreatment with an autophagy inhibitor. Results: We discovered that phosphorylation of p38, a stress-dependent kinase, was induced at the Thr180/Tyr182 residue in cancer cells exposed to mEHT. Apoptotic markers such as cleaved caspase-3 and poly-ADP ribose polymerase (PARP) were increased in OVCAR-3 and SNU-17 cells. Fluorescence-activated cell sorting (FACS) analysis showed a significant increase in the population of sub-G1 mEHT-exposed cells, which are dying and apoptotic cells. mEHT also reduced both weight and volume of xenograft tumors in mice transplanted with ovarian and cervical cancer cells and patient-derived cancer tissues. We determined that mEHT-induced cellular damage recovery was mediated by autophagy and, therefore, expectedly, cotreatment with mEHT and 3-methyladenine (3-MA), an autophagy inhibitor, more effectively inhibited cancer cell growth than individual treatment did. Conclusions: mEHT treatment alone was sufficient to inhibit cancer growth, while a combined treatment with mEHT and an autophagy inhibitor amplified this inhibition effect.
Bibliographical noteFunding Information:
All animal experiments were approved by the Institutional Animal Care and Use Committee of Yonsei University in the Republic of Korea (IACUC Approval No. 2014–0346). Before this study commenced, approval was obtained from the Institutional Review Board (IRB) of Gangnam Severance Hospital (IRB No. 3–2014-0184), written informed consent to participate in the study was obtained from each patient, and all experiments were performed in accordance with relevant guidelines and regulations. Tissue samples of patients with cancer were provided by the Korea Gynecologic Cancer Bank [KGCB] through the Bio and Medical Technology Development Program of the Ministry of Education, Science and Technology, Korea.
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1A2B2008505 and NRF-2017R1D1A1A09000576).
All Science Journal Classification (ASJC) codes
- Physiology (medical)
- Cancer Research