title: Radiosensitizing Effect of TRPV1 Channel Inhibitors in Cancer Cells.
abstract: Radiosensitizers are used in cancer therapy to increase the γ-irradiation susceptibility of cancer cells, including radioresistant hypoxic cancer cells within solid tumors, so that radiotherapy can be applied at doses sufficiently low to minimize damage to adjacent normal tissues. Radiation-induced DNA damage is repaired by multiple repair systems, and therefore these systems are potential targets for radiosensitizers. We recently reported that the transient receptor potential vanilloid type 1 (TRPV1) channel is involved in early responses to DNA damage after γ-irradiation of human lung adenocarcinoma A549 cells. Therefore, we hypothesized that TRPV1 channel inhibitors would have a radiosensitizing effect by blocking repair of radiation-induced cell damage. Here, we show that pretreatment of A549 cells with the TRPV1 channel inhibitors capsazepine, AMG9810, SB366791 and BCTC suppressed the γ-ray-induced activation of early DNA damage responses, i.e., activation of the protein kinase ataxia-telangiectasia mutated (ATM) and accumulation of p53-binding protein 1 (53BP1). Further, the decrease of survival fraction at one week after γ-irradiation (2.0 Gy) was enhanced by pretreatment of cells with these inhibitors. On the other hand, inhibitor pretreatment did not affect cell viability, the number of apoptotic or necrotic cells, or DNA synthesis at 24 h after irradiation. These results suggest that inhibition of DNA repair by TRPV1 channel inhibitors in irradiated A549 cells caused gradual loss of proliferative ability, rather than acute facilitation of apoptosis or necrosis. TRPV1 channel inhibitors could be novel candidates for radiosensitizers to improve the efficacy of radiation therapy, either alone or in combination with other types of radiosensitizers.
authors.affiliation: Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nishino
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tanamachi
authors.forename: Yuto
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Shunta
authors.initials: S
authors.lastname: Ide
authors.forename: Shuji
authors.initials: S
authors.lastname: Kojima
authors.forename: Sei-Ichi
authors.initials: S
authors.lastname: Tanuma
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Tsukimoto
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002934:Cinnamates / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D009336:Necrosis / Q000139:chemically induced; D009369:Neoplasms / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000178:Acrylamides; D000813:Anilides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D011719:Pyrazines; D011725:Pyridines; D011838:Radiation-Sensitizing Agents; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C071423:capsazepine; D002211:Capsaicin