Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Kazuhiro Nishiyama, Takuro Numaga-Tomita, Yasuyuki Fujimoto, Tomohiro Tanaka, Chiemi Toyama, Akiyuki Nishimura, Tomohiro Yamashita, Matsunaga Naoya, Koyanagi Satoru, Yasu Taka Azuma, Yuko Ibuki, Koji Uchida, Shigehiro Ohdo, Motohiro Nishida

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3723-3738
Number of pages16
JournalBritish Journal of Pharmacology
Volume176
Issue number18
DOIs
Publication statusPublished - Sep 1 2019

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NADPH Oxidase
Doxorubicin
Tobacco Smoke Pollution
Proteins
Pharmaceutical Preparations
Anti-Asthmatic Agents
Muscles
Protein Stability
ibudilast
TRPC3 cation channel
Inbred C57BL Mouse
Smoke
Tobacco Products
Antineoplastic Agents
Atrophy
Myocardium
Skeletal Muscle
Western Blotting
Macrophages
Cell Line

All Science Journal Classification (ASJC) codes

  • Pharmacology

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Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes. / Nishiyama, Kazuhiro; Numaga-Tomita, Takuro; Fujimoto, Yasuyuki; Tanaka, Tomohiro; Toyama, Chiemi; Nishimura, Akiyuki; Yamashita, Tomohiro; Naoya, Matsunaga; Satoru, Koyanagi; Azuma, Yasu Taka; Ibuki, Yuko; Uchida, Koji; Ohdo, Shigehiro; Nishida, Motohiro.

In: British Journal of Pharmacology, Vol. 176, No. 18, 01.09.2019, p. 3723-3738.

Research output: Contribution to journalArticle

Nishiyama, Kazuhiro ; Numaga-Tomita, Takuro ; Fujimoto, Yasuyuki ; Tanaka, Tomohiro ; Toyama, Chiemi ; Nishimura, Akiyuki ; Yamashita, Tomohiro ; Naoya, Matsunaga ; Satoru, Koyanagi ; Azuma, Yasu Taka ; Ibuki, Yuko ; Uchida, Koji ; Ohdo, Shigehiro ; Nishida, Motohiro. / Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes. In: British Journal of Pharmacology. 2019 ; Vol. 176, No. 18. pp. 3723-3738.
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AU - Toyama, Chiemi

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AU - Satoru, Koyanagi

AU - Azuma, Yasu Taka

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AU - Ohdo, Shigehiro

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