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. Key words γ-ray; radiosensitizer; transient receptor potential vanilloid type 1 channelRadiation therapy plays an important role in treatment of numerous cancers, 1) because ionizing radiation induces potentially lethal DNA damage, such as DNA double-strand breaks (DSBs). Although DSBs cause cell death or genomic instability, 2,3) they can be repaired by mechanisms such as non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ rejoins the DNA ends without requiring sequence homologies, and is mediated by a DNA-dependent protein kinase holoenzyme. On the other hand, HR processes use undamaged homologous DNA sequences (sister chromatid or the homologous chromosome) to ensure the fidelity of the repair process. [4][5][6] The DNA damage response pathways protect genomic integrity and act as a barrier against cancer, 7) and are important for recovery of irradiated normal cells. However, overexpression of DNA repair proteins is involved in radioresistance of cancer cells, [8][9][10] and therefore these mechanisms also decrease the efficiency of radiation therapy.Since ionizing radiation does not discriminate between cancer cells and normal cells, damage to normal tissues is usually a dose-limiting factor in radiation therapy. In addition, many solid ...

A Novel Mechanism of γ-Irradiation-Induced IL-6 Production Mediated by P2Y11 Receptor in Epidermal Keratinocytes

“…Considering the cell cycle arrest in irradiated cells, the cell proliferation could be decreased in irradiated cells. Cellular DNA damages are usually repaired in a few hours, 46,47) but in this study DNA damage response and repair factors were still not disappeared at 48 h after γ-irradiation. Previously, a phenomenon called senescencelike growth arrest (SLGA) was reported as a growth arrest reaction induced by radiation, 48) in which ATM and γH2AX were continuously activated.…”

Involvement of TRPV1 and TRPV4 Channels in Enhancement of Metastatic Ability Induced by γ-Irradiation in Human Lung Cancer A549 Cells

“…These results are consistent with the γ-irradiation-induced decrease of cell viability due to irreversible cell damage. 36) Based on the results in Fig. 1A, we chose a dose of 2.0 Gy for subsequent experiments using A549 cells.…”

“…[47][48][49][50][51] In addition, we have recently reported that a TRPV1 channel inhibitor suppressed DNA repair after irradiation, 32) suggesting that TRPV1 inhibitors might increase the radiosensitivity of cancer cells. 36) Therefore, administration of TRPV channel inhibitors concomitantly with radiotherapy might reduce the risk of metastasis, as well as amplifying the cytotoxic effect of radiation.…”

Anticancer Activity of Natural and Synthetic Capsaicin Analogs

“…Capsazepine was also found to be an inhibitor of Janus kinase/STAT3 signaling in prostate cancer cells (Huang et al, 2006). Capsazepine also sensitized A549 lung cancer cells to radiation therapy (Nishino et al, 2016). Thomas et al (2007Thomas et al ( , 2011Thomas et al ( , 2012 synthesized the capsaicin analog nonivamide (Fig.…”