ME-344 is a second-generation
isoflavone with unusual cytotoxic properties that is in clinical testing in
cancer. To identify targets that contribute to its anticancer activity and therapeutic index, we used
lung cancer cell lines that are naturally sensitive or resistant to
ME-344. Drug-induced apoptosis was linked with enhanced levels of
reactive oxygen species and this initiated a nuclear erythroid factor 2-like 2 signaling response, downstream of which,
heme oxygenase 1 (HO-1) was also found to be time-dependently inhibited by
ME-344.
ME-344 specifically bound to, and altered, HO-1 structure and increased HO-1 translocation from the rough endoplasmic reticulum to mitochondria, but only in drug-sensitive cells. These effects did not occur in either drug-resistant or primary lung fibroblasts with lower HO-1 basal levels. HO-1 was confirmed as a drug target by using surface plasmon resonance technology and through interaction with a clickable
ME-344 compound (M2F) and subsequent proteomic analyses, showing direct binding of
ME-344 with HO-1. Proteomic analysis showed that clusters of
mitochondrial proteins, including
voltage-dependent anion-selective channels, were also impacted by
ME-344. Human
lung cancer biopsies expressed higher levels of Nrf2 and HO-1 compared with normal tissues. Overall, our data show that
ME-344 inhibits HO-1 and impacts its mitochondrial translocation. Other
mitochondrial proteins are also affected, resulting in interference in
tumor cell redox homeostasis and mitochondrial function. These factors contribute to a beneficial therapeutic index and support continued clinical development of
ME-344. SIGNIFICANCE: A novel cytotoxic
isoflavone is shown to inhibit
heme oxygenase, a desirable yet elusive target that disrupts redox homeostasis causing cell death.