Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes
| Autor: | Koji Uchida, Kazuhiro Nishiyama, Yasu-Taka Azuma, Akiyuki Nishimura, Tomohiro Tanaka, Chiemi Toyama, Tomohiro Yamashita, Satoru Koyanagi, Yuko Ibuki, Takuro Numaga-Tomita, Naoya Matsunaga, Yasuyuki Fujimoto, Shigehiro Ohdo, Motohiro Nishida |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cell Survival Pyridines Antineoplastic Agents Ibudilast Pharmacology Cell Line Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine TRPC3 Western blot medicine Animals Humans Myocytes Cardiac Doxorubicin Cytotoxicity TRPC Cation Channels Cardiotoxicity NADPH oxidase medicine.diagnostic_test biology Wasting Syndrome Chemistry Research Papers Mice Inbred C57BL 030104 developmental biology NADPH Oxidase 2 Toxicity biology.protein Tobacco Smoke Pollution Reactive Oxygen Species 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Br J Pharmacol |
| ISSN: | 1476-5381 0007-1188 |
| Popis: | Background and purpose Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin-induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin-induced cytotoxicity, on the TRPC3-Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin-induced systemic tissue wasting in mice. Experimental approach We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT-PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. Key results Ibudilast, an anti-asthmatic drug, attenuated ROS-mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. Conclusions and implications These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking. |
| Databáze: | OpenAIRE |
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