Ym155 localizes to the mitochondria leading to mitochondria dysfunction and activation of AMPK that inhibits BMP signaling in lung cancer cells

Abstract

The imidazolium compound Ym155 was first reported to be a survivin inhibitor. Ym155 potently induces cell death of many types of cancer cells in preclinical studies. However, in phase II clinical trials Ym155 failed to demonstrate a significant benefit. Studies have suggested that the cytotoxic effects of Ym155 in cancer cells are not mediated by the inhibition of survivin. Understanding the mechanism by which Ym155 induces cell death would provide important insight how to improve its efficacy as a cancer therapeutic. We demonstrate a novel mechanism by which Ym155 induces cell death by localizing to the mitochondria causing mitochondrial dysfunction. Our studies suggest that Ym155 binds mitochondrial DNA leading to a decrease in oxidative phosphorylation, decrease in TCA cycle intermediates, and an increase in mitochondrial permeability. Furthermore, we show that mitochondrial stress induced by Ym155 and other mitochondrial inhibitors activates AMP-activated kinase leading to the downregulation to bone morphogenetic protein (BMP) signaling. We provide first evidence that Ym155 initiates cell death by disrupting mitochondrial function.

Toxic Effects of Penetrating Cations

“…The reason for that has started to become clear only recently. It has been shown that, being a penetrating cation, it accumulates in mitochondria and binds to mitochondrial DNA, causing energy depletion in the cells [76]. Ym155 generates ROS in mitochondria, causing DNA damage and inhibiting survivin.…”

Small Molecule Inhibitors Targeting the “Undruggable” Survivin: The Past, Present, and Future from a Medicinal Chemist’s Perspective

“…Indeed, a recent study showed that it accumulates in mitochondria and causes mitochondrial dysfunction, suggesting another potential mechanism of action for compound 1. 115 Compound 1 has a 1,4-benzoquinone containing dual carbonyl groups which is prevalent in both biological molecules and approved drugs. 116 The two carbonyl groups together with the vinyl group can form a conjugated system that appears to be stable.…”

“…Since 1 also contains the (R 3 ) N + (halogen) − motif, it may also accumulate in mitochondria. Indeed, a recent study showed that it accumulates in mitochondria and causes mitochondrial dysfunction, suggesting another potential mechanism of action for compound 1 …”

Toxic Effects of Penetrating Cations

“…The reason for that has started to become clear only recently. It has been shown that, being a penetrating cation, it accumulates in mitochondria, binds to mitochondrial DNA causing energy depletion of the cells [66].…”