Co-administration of JQ1, a bromodomain-containing protein 4 inhibitor, enhances the antitumor effect of combretastatin A4, a microtubule inhibitor, while attenuating its cardiotoxicity

被引:4
作者
Orihara, Haruka [1 ]
Ma, Min [1 ]
Nagashima, Yoshiyasu [1 ]
Tochinai, Ryota [1 ,2 ,3 ]
Sekizawa, Shin-ichi [1 ]
Kato, Daiki [4 ]
Shinada, Masahiro [4 ]
Aoki, Susumu [4 ]
Fujita, Naoki [4 ]
Nakagawa, Takayuki [4 ]
Tsuru, Yoshiharu [5 ]
Tatewaki, Yasuko [2 ]
Mutoh, Tatsushi [2 ,3 ]
Taki, Yasuyuki [2 ]
Nishimura, Ryohei [4 ]
Kuwahara, Masayoshi [1 ]
机构
[1] Univ Tokyo, Grad Sch Agr & Life Sci, Dept Vet Pathophysiol & Anim Hlth, 1-1-1 Yayoi,Bunkyo Ku, Tokyo 1138657, Japan
[2] Tohoku Univ, Inst Dev Aging & Canc, Dept Aging Res & Geriatr Med, 4-1 Seiryo cho,Aobaku, Sendai, Miyagi 9808575, Japan
[3] Akita Cerebrospinal & Cardiovasc Ctr, Res Inst Brain & Blood Vessels, 6-10 Sensyu Kubota Machi, Akita, Akita 0100874, Japan
[4] Univ Tokyo, Grad Sch Agr & Life Sci, Lab Vet Surg, 1-1-1 Yayoi,Bunkyo Ku, Tokyo 1138657, Japan
[5] Primetech Corp, Life Sci Lab, 1-1-1 Yayoi,Bunkyo Ku, Tokyo 1138657, Japan
基金
日本学术振兴会;
关键词
CA4; JQ1; BRD4; Cancer; C-Myc; Cardiotoxicity; CELL-LINES; BRD4; CANCER; MYC; PHOSPHATE; SUPPRESSES; TOXICITY; TARGET; AGENTS; DAMAGE;
D O I
10.1016/j.biopha.2023.114353
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Combretastatin A4 (CA4) inhibits microtubule polymerization, and clinical trials of the prodrug, CA4 disodium phosphate (CA4DP), as an anti-cancer agent have been conducted. However, CA4DP has not been marketed to date because the margin between the effective dose and the cardiotoxic dose is insufficient. Meanwhile, bromodomain-containing protein 4 (BRD4) has been reported to be required for recovery from mitotic arrests induced by anti-microtubule drugs. BRD4 has also been reported to be involved in the progression of heart failure. Therefore, we hypothesized that the combined use of CA4DP with BRD4 inhibitors can enhance the antitumor effect and attenuate CA4DP-induced cardiotoxicity. In this study, the antitumor effect and car-diotoxicity caused by the co-administration of CA4DP with JQ1, a BRD4 inhibitor, were evaluated. CA4 or JQ1 alone reduced the viability of cultured canine mammary tumor cells (CHMp-13a). Viability was further reduced by co-administration, through the suppression of c-Myc. BRD4 positivity in CHMp-13a cytoplasm showed a significant increase when treated with CA4 alone, while the increase was not significant following co -administration. In CHMp-13a xenograft-transplanted mice, co-administration of CA4DP and JQ1 suppressed tumor growth significantly.In CA4DP-induced cardiac injury model rats, echocardiography showed a CA4DP-induced decrease in cardiac function and histopathology showed cardiomyocyte necrosis. Meanwhile, these cardiac changes tended to be milder following the co-administration of CA4DP and JQ1.These results suggest that CA4DP-JQ1 co-administration enhances the antitumor effect of CA4DP while attenuating its cardiotoxicity and therefore potentially open the doors to the development of a novel cancer chemotherapy with reduced cardiotoxicity risks.
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页数:8
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