Electro-hyperthermia up-regulates tumour suppressor Septin 4 to induce apoptotic cell death in hepatocellular carcinoma

Jeon, Taewon; Yang, Hee-Bum; Lee, Chang Geol; Oh, Sang Taek; Seo, Daekwan; Baik, In Hye; Lee, Eun Hye; Yun, Ina; Park, Kyung Ran; Lee, Yun‐Han

doi:10.1080/02656736.2016.1186290

Cited by 32 publications

(28 citation statements)

References 20 publications

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“…In HepG2 hepatocellular carcinoma (hepatoblastoma) carrying wild type TP53 gene (but NRAS p.Gln61Leu c.182A > T mutation), a single shot of mEHT also prompted elevated expression of caspase-3, -8, and -9, leading to a massive apoptosis [ 24 ]. Another group also found strong induction of caspase-mediated apoptosis in HepG2 cells after three repetitions of mEHT treatment of 60 min each, where RNA sequencing revealed the upregulation of the proapoptotic and growth suppressor septin 4 (SEP4) as a potential driver, which was confirmed at the protein level [ 38 ].…”

Section: Meht-induced Apoptosismentioning

confidence: 99%

“…Significant elevation of p21 waf1 levels was consistent with the complete cell cycle arrest indicated by the loss of Ki67 positivity in the damaged central region of the highly proliferating C26 CRC [ 12 ]. Other tumor models where mEHT treatment induced elevated p53 and p21 waf1 levels included HepG2 hepatocellular carcinoma cell cultures [ 38 ] and B16F10 melanoma cells (with Cdkn2a-del, which downregulates Tp53, and Braf mutations), both in culture and mouse xenografts [ 42 ].…”

Section: Meht-induced Dna Double-strand Breaks and P21 Wmentioning

confidence: 99%

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Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models

Krenács

Meggyesházi

Forika

et al. 2020

IJMS

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The benefits of high-fever range hyperthermia have been utilized in medicine from the Ancient Greek culture to the present day. Amplitude-modulated electro-hyperthermia, induced by a 13.56 MHz radiofrequency current (mEHT, or Oncothermia), has been an emerging means of delivering loco-regional clinical hyperthermia as a complementary of radiation-, chemo-, and molecular targeted oncotherapy. This unique treatment exploits the metabolic shift in cancer, resulting in elevated oxidative glycolysis (Warburg effect), ion concentration, and electric conductivity. These promote the enrichment of electric fields and induce heat (controlled at 42 °C), as well as ion fluxes and disequilibrium through tumor cell membrane channels. By now, accumulating preclinical studies using in vitro and in vivo models of different cancer types have revealed details of the mechanism and molecular background of the oncoreductive effects of mEHT monotherapy. These include the induction of DNA double-strand breaks, irreversible heath and cell stress, and programmed cells death; the upregulation of molecular chaperones and damage (DAMP) signaling, which may contribute to a secondary immunogenic tumor cell death. In combination therapies, mEHT proved to be a good chemosensitizer through increasing drug uptake and tumor reductive effects, as well as a good radiosensitizer by downregulating hypoxia-related target genes. Recently, immune stimulation or intratumoral antigen-presenting dendritic cell injection have been able to extend the impact of local mEHT into a systemic “abscopal” effect. The complex network of pathways emerging from the published mEHT experiments has not been overviewed and arranged yet into a framework to reveal links between the pieces of the “puzzle”. In this paper, we review the mEHT-related damage mechanisms published in tumor models, which may allow some geno-/phenotype treatment efficiency correlations to be exploited both in further research and for more rational clinical treatment planning when mEHT is involved in combination therapies.

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Section: Meht-induced Apoptosismentioning

confidence: 99%

Section: Meht-induced Dna Double-strand Breaks and P21 Wmentioning

confidence: 99%

Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models

Krenács

Meggyesházi

Forika

et al. 2020

IJMS

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“…Mice were lightly anaesthetised with tiletamine/zolazepam, and tumours were heated using an experimental Oncothermia unit provided by HOSPICARE Co., Ltd. (Seoul, Korea) (LAB-EHY100, OncoTherm, Budapest, Hungary) equipped for capacitive heating of mouse tumours with amplitude-modulated radiofrequency of 13.56 MHz [47]. Details of Oncothermia heating have been described in previous reports [47][48][49]. Tumour temperatures were measured with an optical thermal probe (Luxtron FOT Lab Kit, LumaSense Technologies, Inc., Santa Clara, CA) inserted into the centre of tumours.…”

Section: Heatingmentioning

confidence: 99%

Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo

Kim

et al. 2017

International Journal of Hyperthermia

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“…mEHT applies lower power than conventional HT, thus interstitially measured average temperature is relatively low, around 39.5 • C. However, the corresponding transmembrane temperature differential across a cell is often quiet high (7). This transmembrane thermal stress destabilizes cell membranes, resulting in necrosis, and also enhanced apoptosis (8)(9)(10)(11). This effect has been shown to enhance the release of heat shock proteins (HSPs), produce damage-associated molecular patterns (DAMP) and leads to increased immunogenicity, thereby mediating immunogenic cell-death (12).…”

Section: Introductionmentioning

confidence: 99%

Putative Abscopal Effect in Three Patients Treated by Combined Radiotherapy and Modulated Electrohyperthermia

Shin

Mehta²,

Yang

et al. 2020

Front. Oncol.

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True abscopal responses from radiation therapy are extremely rare; the combination of immune checkpoint inhibitors with radiation therapy has led to more reports of the abscopal effect, but even in this setting, the genuine magnitude remains unknown and is still considered generally uncommon. We report the occurrence of what appears to be putative, durable abscopal tumor responses with associated auto-immune systemic reactions resulting from the combination of local radiotherapy (RT) and modulated electrohyperthermia (mEHT). Materials and Methods: Data from advanced cancer patients treated palliatively with RT and mEHT between January and December 2017 were collected as part of a post-marketing safety monitoring program of mEHT therapy. We specified a minimum RT dose of 30 Gy and at least four mEHT treatments for reporting toxicities, which was the primary aim of the larger study. Results: Thirty-three patients treated with RT and mEHT, both applied to the same lesion, were included. The median RT dose was 45.5 Gy in 20 fractions (fxs) and the median number of mEHT treatments was 12 (range, 4-20). Most patients had subsequent systemic therapy after one course of RT and mEHT. Three patients (9.1%) developed autoimmune toxicities. Case number 1 received RT and mEHT only; case number 2 had two cycles of concurrent low dose chemotherapy during RT; and case number 3 received concurrent immune checkpoint inhibitors. None of the three patients received any further systemic treatment due to obvious treatment-related autoimmune reactions which occurred rapidly after RT; one had autoimmune hepatitis, one had dermatitis herpetiformis and the third developed severe myasthenia gravis. Interestingly, what we surmise to be long-lasting abscopal responses outside the irradiated area, were noted in all three patients. Conclusion: RT combined with mEHT could putatively result in enhancing immune responsiveness. These preliminary observational findings lead to the generation of a hypothesis that this combination induces both an in-situ, tumor-specific immune reaction Chi et al. RT-mEHT Unleashed Autoimmune-Mediated Abscopal Effect and an anti-self-autoimmune reaction, in at least a small proportion of patients, and of those who experience the auto-immune response, tumor response is a concomitant finding. Mechanisms underlying this phenomenon need to be investigated further.

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Electro-hyperthermia up-regulates tumour suppressor Septin 4 to induce apoptotic cell death in hepatocellular carcinoma

Abstract: These findings suggest that apoptotic cell death induced by mEHT is mediated by the up-regulation of tumour suppressor SEPT4 in human HCC cells.

Cited by 32 publications

References 20 publications

Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models

Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models

Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo

Putative Abscopal Effect in Three Patients Treated by Combined Radiotherapy and Modulated Electrohyperthermia

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