Xanthocillin X Dimethyl Ether Exhibits Anti-Proliferative Effect on Triple-Negative Breast Cancer by Depletion of Mitochondrial Heme

TL;DR

Xanthocillin X dimethyl ether fights triple-negative breast cancer by reducing mitochondrial heme, disrupting energy production in cancer cells.

Contribution

XanDME's novel anti-cancer mechanism involves mitochondrial heme depletion and disruption of the electron transport chain in TNBC.

Findings

XanDME binds to hemin and depletes regulatory heme in cells.

XanDME enters mitochondria and interacts with cytochromes, disrupting the electron transport chain.

Mitochondrial respiration is inhibited, leading to anti-proliferative effects in TNBC both in vitro and in vivo.

Abstract

Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to the absence of specific targeted treatments. In this study, we explored the therapeutic potential of xanthocillin X dimethyl ether (XanDME), a naturally occurring isocyanide isolated from the marine fungus Scedosporium apiospermum, on TNBC. To elucidate the underlying mechanism, we initially demonstrated that XanDME directly binds to hemin, the oxidized form of heme, in vitro, corroborating previous reports. This interaction led to the depletion of intracellular regulatory heme. We further established that XanDME translocates into the mitochondria, where it interacts with crucial hemoproteins, namely cytochromes. The binding of XanDME with mitochondrial cytochromes disrupts the electron transport chain (ETC), inhibits the activity of mitochondrial complexes, and inactivates mitochondrial respiration. The inhibitory activity of XanDME on mitochondrial function significantly contributes to its anti-TNBC effects, as observed both in vitro and in vivo. Our study underscores the potential of XanDME against TNBC, warranting further investigations.

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