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
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 i...
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| Format: | Article |
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MDPI AG
2020-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/9/2581 |
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| author | Lea Danics Csaba András Schvarcz Pedro Viana Tamás Vancsik Tibor Krenács Zoltán Benyó Tamás Kaucsár Péter Hamar |
| author_facet | Lea Danics Csaba András Schvarcz Pedro Viana Tamás Vancsik Tibor Krenács Zoltán Benyó Tamás Kaucsár Péter Hamar |
| author_sort | Lea Danics |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T16:26:11Z |
| format | Article |
| id | doaj.art-2546528074014aba80b530ecbff14230 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T16:26:11Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2546528074014aba80b530ecbff142302023-11-20T13:13:04ZengMDPI AGCancers2072-66942020-09-01129258110.3390/cancers12092581Exhaustion of Protective Heat Shock Response Induces Significant Tumor Damage by Apoptosis after Modulated Electro-Hyperthermia Treatment of Triple Negative Breast Cancer Isografts in MiceLea Danics0Csaba András Schvarcz1Pedro Viana2Tamás Vancsik3Tibor Krenács4Zoltán Benyó5Tamás Kaucsár6Péter Hamar7Institute of Translational Medicine, Semmelweis University, 1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, 1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, 1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, 1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, 1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, 1094 Budapest, HungaryModulated 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.https://www.mdpi.com/2072-6694/12/9/2581modulated electro-hyperthermia (mEHT)triple-negative breast cancer (TNBC)isogenic mouse cancerheat-shock protein-70BALB/C mouse |
| spellingShingle | Lea Danics Csaba András Schvarcz Pedro Viana Tamás Vancsik Tibor Krenács Zoltán Benyó Tamás Kaucsár Péter Hamar 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 Cancers modulated electro-hyperthermia (mEHT) triple-negative breast cancer (TNBC) isogenic mouse cancer heat-shock protein-70 BALB/C mouse |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | modulated electro-hyperthermia (mEHT) triple-negative breast cancer (TNBC) isogenic mouse cancer heat-shock protein-70 BALB/C mouse |
| url | https://www.mdpi.com/2072-6694/12/9/2581 |
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