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MitoTam induces ferroptosis and increases radiosensitivity in head and neck cancer cells

FV. Reinema, N. Hudson, GJ. Adema, WJM. Peeters, J. Neuzil, J. Stursa, L. Werner, FCGJ. Sweep, J. Bussink, PN. Span

. 2024 ; 200 (-) : 110503. [pub] 20240824

Jazyk angličtina Země Irsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24018668

BACKGROUND AND PURPOSE: Radiotherapy (RT) is an integral treatment part for patients with head and neck squamous cell carcinoma (HNSCC), but radioresistance remains a major issue. Here, we use MitoTam, a mitochondrially targeted analogue of tamoxifen, which we aim to stimulate ferroptotic cell death with, and sensitize radioresistant cells to RT. MATERIALS AND METHODS: We assessed viability, reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential, and lipid peroxidation in radiosensitive (UT-SCC-40) and radioresistant (UT-SCC-5) HNSCC cells following MitoTam treatment. To assess ferroptosis specificity, we used the ferroptosis inhibitor ferrostatin-1 (fer-1). Also, total antioxidant capacity and sensitivity to tert-butyl hydroperoxide were evaluated to assess ROS-responses. 53BP1 staining was used to assess radiosensitivity after MitoTam treatment. RESULTS: Our data revealed increased ROS, cell death, disruption of mitochondrial membrane potential, and lipid peroxidation following MitoTam treatment in both cell lines. Adverse effects of MitoTam on cell death, membrane potential and lipid peroxidation were prevented by fer-1, indicating induction of ferroptosis. Radioresistant HNSCC cells were less sensitive to the effects of MitoTam due to intrinsic higher antioxidant capacity. MitoTam treatment prior to RT led to superadditive residual DNA damage expressed by 53BP1 foci compared to RT or MitoTam alone. CONCLUSION: MitoTam induced ferroptosis in HNSCC cells, which could be used to overcome the elevated antioxidant capacity of radioresistant cells and sensitize such cells to RT. Treatment with MitoTam followed by RT could therefore present a promising effective therapy of radioresistant cancers. STATEMENT OF SIGNIFICANCE: Radiotherapy is applied in the treatment of a majority of cancer patients. Radioresistance due to elevated antioxidant levels can be overcome by promoting ferroptotic cell death combining ROS-inducing drug MitoTam with radiotherapy.

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$a BACKGROUND AND PURPOSE: Radiotherapy (RT) is an integral treatment part for patients with head and neck squamous cell carcinoma (HNSCC), but radioresistance remains a major issue. Here, we use MitoTam, a mitochondrially targeted analogue of tamoxifen, which we aim to stimulate ferroptotic cell death with, and sensitize radioresistant cells to RT. MATERIALS AND METHODS: We assessed viability, reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential, and lipid peroxidation in radiosensitive (UT-SCC-40) and radioresistant (UT-SCC-5) HNSCC cells following MitoTam treatment. To assess ferroptosis specificity, we used the ferroptosis inhibitor ferrostatin-1 (fer-1). Also, total antioxidant capacity and sensitivity to tert-butyl hydroperoxide were evaluated to assess ROS-responses. 53BP1 staining was used to assess radiosensitivity after MitoTam treatment. RESULTS: Our data revealed increased ROS, cell death, disruption of mitochondrial membrane potential, and lipid peroxidation following MitoTam treatment in both cell lines. Adverse effects of MitoTam on cell death, membrane potential and lipid peroxidation were prevented by fer-1, indicating induction of ferroptosis. Radioresistant HNSCC cells were less sensitive to the effects of MitoTam due to intrinsic higher antioxidant capacity. MitoTam treatment prior to RT led to superadditive residual DNA damage expressed by 53BP1 foci compared to RT or MitoTam alone. CONCLUSION: MitoTam induced ferroptosis in HNSCC cells, which could be used to overcome the elevated antioxidant capacity of radioresistant cells and sensitize such cells to RT. Treatment with MitoTam followed by RT could therefore present a promising effective therapy of radioresistant cancers. STATEMENT OF SIGNIFICANCE: Radiotherapy is applied in the treatment of a majority of cancer patients. Radioresistance due to elevated antioxidant levels can be overcome by promoting ferroptotic cell death combining ROS-inducing drug MitoTam with radiotherapy.
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$a Hudson, N $u Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen the Netherlands
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$a Peeters, W J M $u Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen the Netherlands
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$a Neuzil, J $u School of Pharmacy and Medical Science, Griffith University, Southport, QLD 4222, Australia; Faculty of Science and First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic; Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech Republic
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$a Stursa, J $u Faculty of Science and First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic; Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech Republic
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$a Werner, L $u Faculty of Science and First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic; Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech Republic
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$a Sweep, F C G J $u Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
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$a Bussink, J $u Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen the Netherlands
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