OXPHOS-targeting drugs in oncology: new perspectives.
Level 5 - mechanism / opinion, no new human data
Narrative review / expert opinion synthesizing preclinical and clinical literature without original human data
PubMed 37736880 · doi:10.1080/14728222.2023.2261631
What was done
This expert opinion article reviewed the preclinical and clinical literature on oxidative phosphorylation (OXPHOS) inhibitors in oncology. The authors evaluated toxicity mechanisms associated with earlier agents (such as IACS-010759) and discussed the therapeutic potential of triphenylphosphonium cation (TPP+)-conjugated molecules, modified natural compounds, and repurposed FDA-approved agents (e.g., MitoQ, metformin, atovaquone, and papaverine) that target mitochondrial respiration.
What was found
The abstract reports no primary experimental metrics or quantitative data. Qualitatively, it highlights that clinical trials of the OXPHOS inhibitor IACS-010759 in acute myeloid leukemia were terminated due to treatment-limiting peripheral neuropathy and lactic acidosis. The authors discuss that TPP+-conjugated agents selectively accumulate in cancer mitochondria due to elevated membrane potential, inhibit respiration (complexes I and III), and show antimetastatic and antiproliferative activity in mice without the dose-limiting neurotoxicity observed with non-targeted inhibitors.
Why it matters
Mitochondrial respiration is a viable cancer target, but clinical translation has been stalled by systemic toxicities. TPP+ conjugation represents a drug-design strategy that may improve the therapeutic index of OXPHOS-targeting therapeutics.
Limits
The paper is a narrative opinion article containing no original clinical data or systematic quantitative synthesis. Evidence for TPP+-based agents in oncology relies predominantly on preclinical rodent models, and their safety and efficacy profiles have not yet been established in dedicated human cancer clinical trials.
Cited by
- supports Certain pharmaceutical drugs produce their effects by downregulating complex I of oxidative phosphorylation.