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TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A
Sin Ying Cheung1, Matthias Henrot2, Mohammad Al-Saad3
1School of Medicine, University of Leeds, Leeds, LS2 9JT, England, UK.
Abstract:
(-)-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.
Insights
(-)-Englerin A (EA) causes adverse reactions in mice by activating TRPC4/TRPC5 ion channels. Blocking these channels prevents side effects, suggesting a therapeutic target for cancer drug development.
Area of Science:
- Pharmacology
- Neuroscience
- Oncology
Background:
- (-)-Englerin A (EA) is a natural product with potent, selective cytotoxicity against cancer cells.
- EA activates Transient Receptor Potential Canonical 4 and 5 (TRPC4/TRPC5) ion channels, with TRPC4 crucial for its anti-cancer effects.
- Adverse reactions to EA have been observed in preclinical models, necessitating investigation into their underlying mechanisms.
Purpose of the Study:
- To investigate the role of TRPC4 and TRPC5 ion channels in mediating the adverse reactions induced by (-)-Englerin A.
- To determine if TRPC4/TRPC5 channel activity is essential for EA-induced side effects in mice.
Main Methods:
- Administration of EA to wild-type and TRPC4/TRPC5 knockout mice.
- Assessment of behavioral changes, specifically locomotor activity, following EA injection.
- Evaluation of the protective effects of a TRPC4/TRPC5 inhibitor (Compound 31/Pico145) against EA-induced adverse reactions.
Main Results:
- EA injection caused transient but marked reduction in locomotor activity in mice.
- TRPC4 and TRPC5 single knockout mice showed partial protection, while double knockout mice were fully protected against EA's adverse effects.
- Pre-treatment with Compound 31 prevented EA-induced adverse reactions without causing side effects itself.
Conclusions:
- The adverse reaction to (-)-Englerin A in mice is dependent on the activation of TRPC4 and TRPC5 ion channels.
- TRPC4/TRPC5 channels represent a potential target for mitigating EA's side effects, partially overlapping with the channels involved in its anti-cancer activity.
- The precise molecular mechanisms underlying EA-induced TRPC4/TRPC5 channel activation and subsequent adverse reactions require further elucidation.
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