Why cancer cells have a more hyperpolarised mitochondrial membrane potential and emergent prospects for therapy

BioRxiv : the Preprint Server for Biology
Michael D Forrest

Abstract

Cancer cells have a more hyperpolarised mitochondrial membrane potential (Ψ) than normal cells. Ψ = ~-220 mV in cancer cells as compared to ~-140 mV in normal cells. Until now it has not been known why. This paper explains this disparity, in a mathematical framework, and identifies molecular targets and operations unique to cancer cells. These are thence prospective cancer drug targets. BMS-199264 is proposed as an anti-cancer drug. It inhibits the reverse, proton-pumping mode of ATP synthase, which this paper identifies as crucial to cancer cells but not to healthy, normal adult cells. In the cancer cell model, the adenine nucleotide exchanger (ANT) is inversely orientated in the mitochondrial inner membrane as compared to normal cells. This predicts it to have a different drug interaction profile, which can be leveraged for cancer therapy. Uncouplers, which dissipate the proton motive force, are proposed as anti-cancer medicines e.g. 2,4-dinitrophenol.

Related Concepts

Dinitrophenols
Antineoplastic Agents
Proton Therapy
Normal Cell
2,4-Dinitrophenol
ATP Synthase
Adenine Nucleotide Translocase
Mitochondrial Membranes
Cancer Treatment
Uncouplers [MoA]

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