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.
Highlights
Three of the most challenging cancers are renal cell carcinoma, triple negative breast cancer and Ewing’s sarcoma [1,2,3,4]
The data confirm the existence of adverse reaction to Englerin A (EA) in mice and suggest that it depends on a combination of TRPC4 and TRPC5 which overlaps partially with TRPC4-dependent cancer cell cytotoxicity
EA activates TRPC5 channels [8] but it has been suggested that this channel might only rarely be relevant to cancer cell cytotoxicity [7], the topic is worthy of further investigation because of the suggested importance of TRPC5 in chemotherapy-resistant breast cancer [11]
Summary
Three of the most challenging cancers are renal cell carcinoma, triple negative breast cancer and Ewing’s sarcoma [1,2,3,4]. EA was found to be a remarkably efficacious agonist of the TRPC4 and TRPC5 ion channels [7, 8, 10]. It has nanomolar potency at these channels and is apparently directly-acting and specific [7, 8]. EA activates TRPC5 channels [8] but it has been suggested that this channel might only rarely be relevant to cancer cell cytotoxicity [7], the topic is worthy of further investigation because of the suggested importance of TRPC5 in chemotherapy-resistant breast cancer [11]. Whether the PKCθ mechanism is related to TRPC4 channels is unknown
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