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

Abstract

Cancer cells have a more hyperpolarised mitochondrial membrane potential (Ψ IM ) than normal cells. Ψ IM = ~-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.

Cancer cells have distinct electrical properties that predict a susceptibility to lipophilic anions; a new cancer drug paradigm

“…Peak anion accumulation in the IMS (or cytoplasm), over and above that of a normal cell, is when ΨPM is depolarised and ΨIM is hyperpolarised. The latter aligns with the reality of cancer cells, which have a depolarised ΨPM [4][5][6][7][8][9][10] and a hyperpolarised ΨIM [11][12][13][14][15][16][17][18][19][20][21][22][23]. So, the model indicates that lipophilic anions, rather than cations, are better as anti-cancer medicines.…”

“…The more invasive and dangerous the cancer, the more hyperpolarised its ΨIM is observed to be [17][18][19]. In a prior paper, I used biophysical modelling to show how and why aerobic glycolysis produces a more hyperpolarised ΨIM [23]. Here I explain why it produces a depolarised ΨPM also.…”

“…In a normal cell, ΨIM flickers between -108 and -159 mV: with a mean value of -139 mV [45][46]. Cancer cells have a more hyperpolarised ΨIM than normal cells [11][12][13][14][15][16][17][18][19][20][21][22][23]. The more invasive and dangerous the cancer, the more hyperpolarised its ΨIM is observed to be [17][18][19].…”

“…They reflect the delimited diversity in ΨPM and ΨIM between different cancers. Cancers, as compared to normal cells, consistently have a depolarised ΨPM [4][5][6][7][8][9][10] and hyperpolarised ΨIM [11][12][13][14][15][16][17][18][19][20][21][22][23] but the actual 7 values involved within this trend can vary among different cancers. We capture some of this diversity by having two alternative cancer models, which differ in the degree of their ΨPM depolarisation and ΨIM hyperpolarisation: Models V1 and V2.…”

“…The ΨIM hyperpolarisation in cancer cells can even be double that of normal cells [22]. In a prior paper, I provided a quantitative, biophysical explanation of why ΨIM is more hyperpolarized in cancer cells [23].…”