Exhaustion of Protective Heat Shock Response Induces Significant Tumor Damage by Apoptosis after Modulated Electro-Hyperthermia Treatment of Triple Negative Breast Cancer Isografts in Mice
| Autor: | Tamás Kaucsár, Tamás Vancsik, Pedro Viana, Péter Hamar, Csaba András Schvarcz, Lea Danics, Tibor Krenács, Zoltán Benyó |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Chemistry Isograft Hyperthermia Treatment lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens lcsh:RC254-282 Article triple-negative breast cancer (TNBC) Hsp70 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology Downregulation and upregulation In vivo Apoptosis 030220 oncology & carcinogenesis Cancer research heat-shock protein-70 Heat shock modulated electro-hyperthermia (mEHT) BALB/C mouse Triple-negative breast cancer isogenic mouse cancer |
| Zdroj: | Cancers, Vol 12, Iss 2581, p 2581 (2020) Cancers Volume 12 Issue 9 |
| ISSN: | 2072-6694 |
| Popis: | Modulated electro-hyperthermia (mEHT) is a complementary antitumor therapy applying capacitive radiofrequency at 13.56 MHz. Here we tested the efficiency of mEHT treatment in a BALB/c mouse isograft model using the firefly luciferase-transfected triple-negative breast cancer cell line, 4T1. Tumors inoculated orthotopically were treated twice using a novel ergonomic pole electrode and an improved mEHT device (LabEHY 200) at 0.7 ± 0.3 W for 30 min. Tumors were treated one, two, or three times every 48 h. Tumor growth was followed by IVIS, caliper, and ultrasound. Tumor destruction histology and molecular changes using immunohistochemistry and RT-qPCR were also revealed. In vivo, mEHT treatment transitionally elevated Hsp70 expression in surviving cells indicating heat shock-related cell stress, while IVIS fluorescence showed a significant reduction of viable tumor cell numbers. Treated tumor centers displayed significant microscopic tumor damage with prominent signs of apoptosis, and major upregulation of cleaved/activated caspase-3-positive tumor cells. Serial sampling demonstrated substantial elevation of heat shock (Hsp70) response twelve hours after the treatment which was exhausted by twenty-four hours after treatment. Heat shock inhibitors Quercetin or KRIBB11 could synergistically amplify mEHT-induced tumor apoptosis in vitro. In conclusion, modulated electro-hyperthermia exerted a protective heat shock response as a clear sign of tumor cell stress. Exhaustion of the HSR manifested in caspase-dependent apoptotic tumor cell death and tissue damage of triple-negative breast cancer after mEHT monotherapy. Inhibiting the HSR synergistically increased the effect of mEHT. This finding has great translational potential. |
| Databáze: | OpenAIRE |
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