Next Article in Journal
FUT9-Driven Programming of Colon Cancer Cells towards a Stem Cell-Like State
Next Article in Special Issue
Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment
Previous Article in Journal
Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages
Previous Article in Special Issue
Cabozantinib Inhibits Photodynamic Therapy-Induced Auto- and Paracrine MET Signaling in Heterotypic Pancreatic Microtumors
Article

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

1
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary
2
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2581; https://doi.org/10.3390/cancers12092581
Received: 5 August 2020 / Revised: 6 September 2020 / Accepted: 7 September 2020 / Published: 10 September 2020
(This article belongs to the Special Issue Combination Therapies in Cancers)
Breast cancer is one of the most frequent cancer types among women worldwide. Triple-negative breast cancer is a highly aggressive breast cancer type with very poor survival due to the lack of targeted therapy. Modulated electro-hyperthermia (mEHT) is a newly emerging form of adjuvant, electromagnetic cancer-treatment. Capacitive energy delivery and frequency modulation enable the application of non-thermal effects. Furthermore, selective energy absorption by the tumor (as demonstrated in our present paper) enables 2.5 °C selective heating of the tumor. In the present study, we demonstrate in an in vivo syngeneic Balb/c TNBC mouse model that mEHT caused a remarkable reduction in the number of viable tumor cells accompanied by significant cleaved caspase-3-related apoptotic tumor tissue destruction and a transitional heat shock response. Furthermore, we demonstrated in vitro that the tumor cell killing effect of mEHT was amplified by inhibitors of the protective heat shock response such as Quercetin and KRIBB11.
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. View Full-Text
Keywords: modulated electro-hyperthermia (mEHT); triple-negative breast cancer (TNBC); isogenic mouse cancer; heat-shock protein-70; BALB/C mouse modulated electro-hyperthermia (mEHT); triple-negative breast cancer (TNBC); isogenic mouse cancer; heat-shock protein-70; BALB/C mouse
Show Figures

Figure 1

MDPI and ACS Style

Danics, L.; Schvarcz, C.A.; Viana, P.; Vancsik, T.; Krenács, T.; Benyó, Z.; Kaucsár, T.; Hamar, P. 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 2020, 12, 2581. https://doi.org/10.3390/cancers12092581

AMA Style

Danics L, Schvarcz CA, Viana P, Vancsik T, Krenács T, Benyó Z, Kaucsár T, Hamar P. 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. 2020; 12(9):2581. https://doi.org/10.3390/cancers12092581

Chicago/Turabian Style

Danics, Lea, Csaba A. Schvarcz, Pedro Viana, Tamás Vancsik, Tibor Krenács, Zoltán Benyó, Tamás Kaucsár, and Péter Hamar. 2020. "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 12, no. 9: 2581. https://doi.org/10.3390/cancers12092581

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop