Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes
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- Kazuhiro Nishiyama
- Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan
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- Takuro Numaga‐Tomita
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS) Okazaki Japan
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- Yasuyuki Fujimoto
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS) Okazaki Japan
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- Tomohiro Tanaka
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS) Okazaki Japan
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- Chiemi Toyama
- Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan
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- Akiyuki Nishimura
- Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan
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- Tomohiro Yamashita
- Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan
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- Naoya Matsunaga
- Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan
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- Satoru Koyanagi
- Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan
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- Yasu‐Taka Azuma
- Division of Veterinary Science Osaka Prefecture University Graduate School of Life and Environmental Science Osaka Japan
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- Yuko Ibuki
- Graduate Division of Nutritional and Environmental Sciences University of Shizuoka Shizuoka Japan
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- Koji Uchida
- Graduate School of Agricultural and Life Sciences The University of Tokyo Tokyo Japan
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- Shigehiro Ohdo
- Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan
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- Motohiro Nishida
- Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan
抄録
<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Implications</jats:title><jats:p>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.</jats:p></jats:sec>
収録刊行物
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- British Journal of Pharmacology
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British Journal of Pharmacology 176 (18), 3723-3738, 2019-08-06
Wiley
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詳細情報 詳細情報について
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- CRID
- 1360005520486849152
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- ISSN
- 14765381
- 00071188
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- Web Site
- https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fbph.14777
- https://onlinelibrary.wiley.com/doi/pdf/10.1111/bph.14777
- https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bph.14777
- https://onlinelibrary.wiley.com/doi/am-pdf/10.1111%2Fbph.14777
- https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.14777
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- データソース種別
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- Crossref
- KAKEN