TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A.
TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A.
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DOI：
10.18632/oncotarget.25659
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发表时间：
2018-07-03
期刊：
影响因子：
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通讯作者：
Vasudev NS
中科院分区：
文献类型：
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作者：
Cheung SY;Henrot M;Al-Saad M;Baumann M;Muller H;Unger A;Rubaiy HN;Mathar I;Dinkel K;Nussbaumer P;Klebl B;Freichel M;Rode B;Trainor S;Clapcote SJ;Christmann M;Waldmann H;Abbas SK;Beech DJ;Vasudev NS
（-）-Englerin A（EA）是一种天然产物，对肾细胞癌细胞和其他类型的癌细胞具有强的细胞毒作用，但对非癌细胞没有作用。尽管对癌细胞具有选择性细胞毒性，但已表明在小鼠和大鼠中存在不良反应。EA是由瞬时受体电位典型4和5蛋白（TRPC 4和TRPC 5）形成的离子通道的非常有效的激活剂，并且TRPC 4对于EA介导的癌细胞毒性是必需的。在此，我们专门研究了TRPC 4和TRPC 5与不良反应的相关性。腹腔注射EA（2 mg·kg-1）不利地影响小鼠约1小时，表现为运动活动的显著减少，之后它们完全恢复。TRPC 4和TRPC 5单敲除小鼠被部分保护，双敲除小鼠被完全保护。TRPC 4/TRPC 5双敲除小鼠也受到保护免于静脉内注射EA。TRPC 4/TRPC 5通道的重要性进一步通过预先施用化合物31（Pico 145）来表明，化合物31是TRPC 4/TRPC 5通道的有效和选择性小分子抑制剂，其本身不引起不良反应，但防止对EA的不良反应。在血浆中检测到EA，但在大脑中未检测到，因此涉及外周机制，但未确定。这些数据证实了小鼠中存在对EA的不良反应，并表明其依赖于TRPC 4和TRPC 5的组合，因此与TRPC 4依赖性癌细胞毒性部分重叠。作为TRPC 4/TRPC 5通道激活的结果，观察到的对EA的不良反应的潜在性质仍不清楚，需要进一步研究。
(-)-Englerin A (EA) is a natural product which has potent cytotoxic effects on renal cell carcinoma cells and other types of cancer cell but not non-cancer cells. Although selectively cytotoxic to cancer cells, adverse reaction in mice and rats has been suggested. EA is a remarkably potent activator of ion channels formed by Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) and TRPC4 is essential for EA-mediated cancer cell cytotoxicity. Here we specifically investigated the relevance of TRPC4 and TRPC5 to the adverse reaction. Injection of EA (2 mg.kg-1 i.p.) adversely affected mice for about 1 hour, manifesting as a marked reduction in locomotor activity, after which they fully recovered. TRPC4 and TRPC5 single knockout mice were partially protected and double knockout mice fully protected. TRPC4/TRPC5 double knockout mice were also protected against intravenous injection of EA. Importance of TRPC4/TRPC5 channels was further suggested by pre-administration of Compound 31 (Pico145), a potent and selective small-molecule inhibitor of TRPC4/TRPC5 channels which did not cause adverse reaction itself but prevented adverse reaction to EA. EA was detected in the plasma but not the brain and so peripheral mechanisms were implicated but not identified. The data confirm the existence of adverse reaction to EA in mice and suggest that it depends on a combination of TRPC4 and TRPC5 which therefore overlaps partially with TRPC4-dependent cancer cell cytotoxicity. The underlying nature of the observed adverse reaction to EA, as a consequence of TRPC4/TRPC5 channel activation, remains unclear and warrants further investigation.