TY - JOUR AU - Leroy Viana, Pedro Henrique AU - Schvarcz, Csaba András AU - Danics, Lea AU - Besztercei, Balázs AU - Aloss, Kenan AU - Bokhari, Syeda Mahak Zahra AU - Giunashvili, Nino AU - Bócsi, Dániel AU - Koós, Zoltán AU - Benyó, Zoltán AU - Hamar, Péter TI - Heat shock factor 1 inhibition enhances the effects of modulated electro hyperthermia in a triple negative breast cancer mouse model JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 14 PY - 2024 IS - 1 PG - 17 SN - 2045-2322 DO - 10.1038/s41598-024-57659-x UR - https://m2.mtmt.hu/api/publication/34778269 ID - 34778269 AB - Female breast cancer is the most diagnosed cancer worldwide. Triple negative breast cancer (TNBC) is the most aggressive type and there is no existing endocrine or targeted therapy. Modulated electro-hyperthermia (mEHT) is a non-invasive complementary cancer therapy using an electromagnetic field generated by amplitude modulated 13.56 MHz frequency that induces tumor cell destruction. However, we have demonstrated a strong induction of the heat shock response (HSR) by mEHT, which can result in thermotolerance. We hypothesized that inhibition of the heat shock factor 1 (HSF1) can synergize with mEHT and enhance tumor cell-killing. Thus, we either knocked down the HSF1 gene with a CRISPR/Cas9 lentiviral construct or inhibited HSF1 with a specific small molecule inhibitor: KRIBB11 in vivo. Wild type or HSF1-knockdown 4T1 TNBC cells were inoculated into the mammary gland’s fat pad of BALB/c mice. Four mEHT treatments were performed every second day and the tumor growth was followed by ultrasound and caliper. KRIBB11 was administrated intraperitoneally at 50 mg/kg daily for 8 days. HSF1 and Hsp70 expression were assessed. HSF1 knockdown sensitized transduced cancer cells to mEHT and reduced tumor growth. HSF1 mRNA expression was significantly reduced in the KO group when compared to the empty vector group, and consequently mEHT-induced Hsp70 mRNA upregulation diminished in the KO group. Immunohistochemistry (IHC) confirmed the inhibition of Hsp70 upregulation in mEHT HSF1-KO group. Demonstrating the translational potential of HSF1 inhibition, combined therapy of mEHT with KRIBB11 significantly reduced tumor mass compared to either monotherapy. Inhibition of Hsp70 upregulation by mEHT was also supported by qPCR and IHC. In conclusion, we suggest that mEHT-therapy combined with HSF1 inhibition can be a possible new strategy of TNBC treatment with great translational potential. LA - English DB - MTMT ER - TY - JOUR AU - Bokhari, Syeda Mahak Zahra AU - Aloss, Kenan AU - Leroy Viana, Pedro Henrique AU - Schvarcz, Csaba András AU - Besztercei, Balázs AU - Giunashvili, Nino AU - Bocsi, Daniel AU - Koos, Zoltan AU - Balogh, Andrea AU - Benyó, Zoltán AU - Hamar, Péter TI - "Digoxin-Mediated Inhibition of Potential Hypoxia-Related Angiogenic Repair in Modulated Electro-Hyperthermia (mEHT)-Treated Murine Triple-Negative Breast Cancer Model" (vol 7, pg 456, 2024) JF - ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE J2 - ACS PHARMACOL TRANS SCI VL - 7 PY - 2024 IS - 3 SP - 904 EP - 904 PG - 1 SN - 2575-9108 DO - 10.1021/acsptsci.4c00094 UR - https://m2.mtmt.hu/api/publication/34742658 ID - 34742658 LA - English DB - MTMT ER - TY - JOUR AU - Aloss, Kenan AU - Bokhari, Syeda Mahak Zahra AU - Leroy Viana, Pedro Henrique AU - Giunashvili, Nino AU - Schvarcz, Csaba András AU - Szénási, Gábor AU - Bócsi, Dániel AU - Koós, Zoltán AU - Storm, Gert AU - Miklós, Zsuzsanna AU - Benyó, Zoltán AU - Hamar, Péter TI - Modulated Electro-Hyperthermia Accelerates Tumor Delivery and Improves Anticancer Activity of Doxorubicin Encapsulated in Lyso-Thermosensitive Liposomes in 4T1-Tumor-Bearing Mice JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 6 PG - 19 SN - 1661-6596 DO - 10.3390/ijms25063101 UR - https://m2.mtmt.hu/api/publication/34730139 ID - 34730139 N1 - Institute of Translational Medicine, Semmelweis University, Budapest, 1094, Hungary HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, Budapest, 1094, Hungary Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3508, Netherlands Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore117597, Singapore National Korányi Institute for Pulmonology, Budapest, 1122, Hungary Export Date: 9 April 2024 Correspondence Address: Hamar, P.; Institute of Translational Medicine, Hungary; email: hamar.peter@semmelweis.hu AB - Modulated electro-hyperthermia (mEHT) is an adjuvant cancer therapy that enables tumor-selective heating (+2.5 °C). In this study, we investigated whether mEHT accelerates the tumor-specific delivery of doxorubicin (DOX) from lyso-thermosensitive liposomal doxorubicin (LTLD) and improves its anticancer efficacy in mice bearing a triple-negative breast cancer cell line (4T1). The 4T1 cells were orthotopically injected into Balb/C mice, and mEHT was performed on days 9, 12, and 15 after the implantation. DOX, LTLD, or PEGylated liposomal DOX (PLD) were administered for comparison. The tumor size and DOX accumulation in the tumor were measured. The cleaved caspase-3 (cC3) and cell proliferation were evaluated by cC3 or Ki67 immunohistochemistry and Western blot. The LTLD+mEHT combination was more effective at inhibiting tumor growth than the free DOX and PLD, demonstrated by reductions in both the tumor volume and tumor weight. LTLD+mEHT resulted in the highest DOX accumulation in the tumor one hour after treatment. Tumor cell damage was associated with cC3 in the damaged area, and with a reduction in Ki67 in the living area. These changes were significantly the strongest in the LTLD+mEHT-treated tumors. The body weight loss was similar in all mice treated with any DOX formulation, suggesting no difference in toxicity. In conclusion, LTLD combined with mEHT represents a novel approach for DOX delivery into cancer tissue. LA - English DB - MTMT ER - TY - JOUR AU - Bokhari, Syeda Mahak Zahra AU - Aloss, Kenan AU - Leroy Viana, Pedro Henrique AU - Schvarcz, Csaba András AU - Besztercei, Balázs AU - Giunashvili, Nino AU - Bócsi, D. AU - Koós, Z. AU - Balogh, Andrea AU - Benyó, Zoltán AU - Hamar, Péter TI - Digoxin-Mediated Inhibition of Potential Hypoxia-Related Angiogenic Repair in Modulated Electro-Hyperthermia (mEHT)-Treated Murine Triple-Negative Breast Cancer Model JF - ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE J2 - ACS PHARMACOL TRANS SCI VL - 7 PY - 2024 IS - 2 SP - 456 EP - 466 PG - 11 SN - 2575-9108 DO - 10.1021/acsptsci.3c00296 UR - https://m2.mtmt.hu/api/publication/34533207 ID - 34533207 N1 - Institute of Translational Medicine, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary Cerebrovascular and Neurocognitive Disorders Research Group, Eötvös, Loránd Research Network and Semmelweis University (ELKH-SE), Tűzoltó utca 37-47, Budapest, 1094, Hungary Export Date: 9 April 2024 Correspondence Address: Hamar, P.; Institute of Translational Medicine, Üllői út 26, Hungary; email: hamar.peter@semmelweis.hu Chemicals/CAS: digoxin, 20830-75-5, 57285-89-9; haptoglobin, 9087-69-8; isoflurane, 26675-46-7; pimonidazole, 70132-51-3, 82204-64-6; vasculotropin D, 193363-12-1 Funding details: STIA-OTKA-2022 Funding details: 2021-1.2.4-TÉT-2021-00060, ÚNKP-22-4 Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA, NVKP 16-1-2016-0042 Funding details: Innovációs és Technológiai Minisztérium, ÚNKP-22-4-I-SE-15 Funding text 1: The authors wish to thank Éva Mátrainé Balogh, Zsuzsanna Forgács, and Rita Uzseka for their expert technical assistance with the preparation of samples for immunohistochemistry. They also thank Oncotherm Ltd. (Budapest, Hungary) for making the LabEHY-200 device available, together with its accessories, and for maintenance. Semmelweis Science and Innovation Fund: Semmelweis NKFIH-OTKA Átsegítő Támogatás (STIA-OTKA-2022) for Péter Hamar. Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund, NVKP (National Competitiveness and Excellency Program), Improving the efficiency and market introduction of electromagnetic cancer therapy equipment, (NVKP 16-1-2016-0042), Tempus Foundation: Stipendium Hungaricum scholarship, Semmelweis Excellence 250+ Scholarship EFOP-3.6.3-VEKOP-16-2017-00009 Ministry for Innovation and Technology, Hungary (National Research, Development and Innovation Fund): Bilateral Science and Technology (S&T) cooperation (Brazil relation), (2021-1.2.4-TÉT-2021-00060), ÚNKP-22-4 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund (ÚNKP-22-4-I-SE-15) Funding text 2: Semmelweis Science and Innovation Fund: Semmelweis NKFIH-OTKA Átsegítő Támogatás (STIA-OTKA-2022) for Péter Hamar. Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund, NVKP (National Competitiveness and Excellency Program), Improving the efficiency and market introduction of electromagnetic cancer therapy equipment, (NVKP 16-1-2016-0042), Tempus Foundation: Stipendium Hungaricum scholarship, Semmelweis Excellence 250+ Scholarship EFOP-3.6.3-VEKOP-16-2017-00009 Ministry for Innovation and Technology, Hungary (National Research, Development and Innovation Fund): Bilateral Science and Technology (S&T) cooperation (Brazil relation), (2021-1.2.4-TÉT-2021-00060), ÚNKP-22-4 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund (ÚNKP-22-4-I-SE-15) AB - Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer type with no targeted therapy and hence limited treatment options. Modulated electrohyperthermia (mEHT) is a novel complementary therapy where a 13.56 MHz radiofrequency current targets cancer cells selectively, inducing tumor damage by thermal and electromagnetic effects. We observed severe vascular damage in mEHT-treated tumors and investigated the potential synergism between mEHT and inhibition of tumor vasculature recovery in our TNBC mouse model. 4T1/4T07 isografts were orthotopically inoculated and treated three to five times with mEHT. mEHT induced vascular damage 4-12 h after treatment, leading to tissue hypoxia detected at 24 h. Hypoxia in treated tumors induced an angiogenic recovery 24 h after the last treatment. Administration of the cardiac glycoside digoxin with the potential hypoxia-inducible factor 1-α (HIF1-α) and angiogenesis inhibitory effects could synergistically augment mEHT-mediated tumor damage and reduce tissue hypoxia signaling and consequent vascular recovery in mEHT-treated TNBC tumors. Conclusively, repeated mEHT induced vascular damage and hypoxic stress in TNBC that promoted vascular recovery. Inhibiting this hypoxic stress signaling enhanced the effectiveness of mEHT and may potentially enhance other forms of cancer treatment. © 2024 The Authors. Published by American Chemical Society. LA - English DB - MTMT ER - TY - JOUR AU - Giunashvili, Nino AU - Thomas, Mbuotidem Jeremiah AU - Schvarcz, Csaba András AU - Leroy Viana, Pedro Henrique AU - Aloss, Kenan AU - Bokhari, Syeda Mahak Zahra AU - Koós, Zoltán AU - Bócsi, Dániel AU - Major, Enikő AU - Balogh, Andrea AU - Benyó, Zoltán AU - Hamar, Péter TI - Enhancing therapeutic efficacy in triple-negative breast cancer and melanoma: synergistic effects of modulated electro-hyperthermia (mEHT) with NSAIDs especially COX-2 inhibition in in vivo models JF - MOLECULAR ONCOLOGY J2 - MOL ONCOL VL - 18 PY - 2024 IS - 4 SP - 1012 EP - 1030 PG - 18 SN - 1574-7891 DO - 10.1002/1878-0261.13585 UR - https://m2.mtmt.hu/api/publication/34506551 ID - 34506551 N1 - Institute of Translational Medicine, Semmelweis University, Budapest, Hungary HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, Budapest, Hungary Export Date: 30 January 2024 Correspondence Address: Hamar, P.; Institute of Translational Medicine, Üllői út 26., Hungary; email: hamar.peter@semmelweis.hu Funding details: EFOP‐3.6.3‐VEKOP‐16‐2017‐00009 Funding details: Innovációs és Technológiai Minisztérium, OTKA_ANN 110810, OTKA_SNN 114619, ÚNKP‐23‐3‐II‐SE‐45, ÚNKP‐23‐4‐I‐SE‐22 Funding details: National Research, Development and Innovation Office, OTKA_K 145998 Funding text 1: The authors wish to thank Éva Mátrainé Balogh, Zsuzsanna Forgács, and Rita Uzseka for their expert technical assistance with the preparation of samples for immunohistochemistry. We also would like to thank Oncotherm Ltd. (Budapest, Hungary) for making the LabEHY‐200 device available, together with its accessories, and for maintenance. The authors thank the financial support provided by: Semmelweis Science and Innovation Fund: Semmelweis NKFIH‐OTKA Átsegítő Támogatás (STIA‐OTKA‐2022) for Péter Hamar; National Research, Development, and Innovation Office (OTKA_K 145998); Tempus Foundation: Stipendium Hungaricum scholarship; Semmelweis Excellence 250+ Scholarship (EFOP‐3.6.3‐VEKOP‐16‐2017‐00009); New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development, and Innovation Office (ÚNKP‐23‐4‐I‐SE‐22); New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development, and Innovation Office (ÚNKP‐23‐3‐II‐SE‐45); National Research, Development, and Innovation Office (OTKA_SNN 114619); National Research, Development, and Innovation Office (OTKA_ANN 110810). AB - Triple‐negative breast cancer (TNBC) is a leading cause of cancer mortality and lacks modern therapy options. Modulated electro‐hyperthermia (mEHT) is an adjuvant therapy with demonstrated clinical efficacy for the treatment of various cancer types. In this study, we report that mEHT monotherapy stimulated interleukin‐1 beta (IL‐1β) and interleukin‐6 (IL‐6) expression, and consequently cyclooxygenase 2 (COX‐2), which may favor a cancer‐promoting tumor microenvironment. Thus, we combined mEHT with nonsteroid anti‐inflammatory drugs (NSAIDs): a nonselective aspirin, or the selective COX‐2 inhibitor SC236, in vivo . We demonstrate that NSAIDs synergistically increased the effect of mEHT in the 4T1 TNBC model. Moreover, the strongest tumor destruction ratio was observed in the combination SC236 + mEHT groups. Tumor damage was accompanied by a significant increase in cleaved caspase‐3, suggesting that apoptosis played an important role. IL‐1β and COX‐2 expression were significantly reduced by the combination therapies. In addition, a custom‐made nanostring panel demonstrated significant upregulation of genes participating in the formation of the extracellular matrix. Similarly, in the B16F10 melanoma model, mEHT and aspirin synergistically reduced the number of melanoma nodules in the lungs. In conclusion, mEHT combined with a selective COX‐2 inhibitor may offer a new therapeutic option in TNBC. LA - English DB - MTMT ER - TY - JOUR AU - Hamar, Péter AU - Schvarcz, Csaba András AU - Danics, Lea AU - Krenács, Tibor AU - Leroy Viana, Pedro Henrique AU - Nagy, Á. AU - Szász, A. AU - Benyó, Zoltán TI - Mutiplex Analysis of Modulated Electro-Hyperthermia-Induced Local Acute Phase Protein Production in Mouse TNBC Model JF - MOLECULAR ONCOLOGY J2 - MOL ONCOL VL - 17 PY - 2023 IS - S1 SP - 468 EP - 469 PG - 2 SN - 1574-7891 UR - https://m2.mtmt.hu/api/publication/34726330 ID - 34726330 LA - English DB - MTMT ER - TY - JOUR AU - Aloss, Kenan AU - Schvarcz, Csaba András AU - Leroy Viana, Pedro Henrique AU - Bokhari, Syeda Mahak Zahra AU - Guinasvilli, N. AU - Bocsi, D. AU - Koós, Z. AU - Hamar, Péter TI - Modulated Electro Hyperthermia Enhances the Delivery and Antitumor Effects of Doxorubicin Encapsulated in Lyso-thermosensitive Liposome in 4T1 Mouse Model JF - MOLECULAR ONCOLOGY J2 - MOL ONCOL VL - 17 PY - 2023 IS - S1 SP - 467 EP - 468 PG - 2 SN - 1574-7891 UR - https://m2.mtmt.hu/api/publication/34726322 ID - 34726322 LA - English DB - MTMT ER - TY - JOUR AU - Giunashvili, Nino AU - Thomas, Mbuotidem Jeremiah AU - Leroy Viana, Pedro Henrique AU - Aloss, Kenan AU - Bokhari, Syeda Mahak Zahra AU - Koós, Z. AU - Dániel, B. AU - Benyó, Zoltán AU - Schvarcz, Csaba András AU - Hamar, Péter TI - Non-steroid anti-inflammatory treatment enhances the efficacy of modulated electro hyperthermia on triple negative breast cancer and melanoma cancer models in vivo JF - MOLECULAR ONCOLOGY J2 - MOL ONCOL VL - 17 PY - 2023 IS - S1 SP - 461 EP - 461 PG - 1 SN - 1574-7891 UR - https://m2.mtmt.hu/api/publication/34726312 ID - 34726312 LA - English DB - MTMT ER - TY - JOUR AU - Leroy Viana, Pedro Henrique AU - Schvarcz, Csaba András AU - Danics, Lea AU - Besztercei, Balázs AU - Aloss, Kenan AU - Bokhari, Syeda Mahak Zahra AU - Giunashvili, Nino AU - Benyó, Zoltán AU - Hamar, Péter TI - Inhibition of Triple-Negative Breast Cancer Growth in a Mouse Model –Enhancement of Modulated Electro-Hyperthermia (mEHT) Effects by Heat Shock Factor 1 Inhibition JF - MOLECULAR ONCOLOGY J2 - MOL ONCOL VL - 17 PY - 2023 IS - S1 SP - 460 EP - 461 PG - 2 SN - 1574-7891 UR - https://m2.mtmt.hu/api/publication/34726279 ID - 34726279 LA - English DB - MTMT ER - TY - JOUR AU - Schvarcz, Csaba András AU - Danics, Lea AU - Forika, Gertrud AU - Leroy Viana, Pedro Henrique AU - Krenács, Tibor AU - Benyó, Zoltán AU - Vancsik, Tamás AU - Hamar, Péter TI - Synergism between methotrexate and modulated electro-hyperthermia is mediated by H19 lnc-RNA JF - MOLECULAR ONCOLOGY J2 - MOL ONCOL VL - 17 PY - 2023 IS - (S1) SP - 459 EP - 460 PG - 2 SN - 1574-7891 UR - https://m2.mtmt.hu/api/publication/34725681 ID - 34725681 LA - English DB - MTMT ER -