Title:Determinants of Anti-Cancer Effect of Mitochondrial Electron Transport Chain Inhibitors: Bioenergetic Profile and Metabolic Flexibility of Cancer Cells
Volume: 22
Issue: 39
Author(s): Félix A. Urra, Boris Weiss-López and Ramiro Araya-Maturana
Affiliation:
Keywords:
Respiratory complexes, oxidative phosphorylation, glutamine metabolism, slow-cycling cancer cells, reductive carboxylation,
metabolic remodeling, anti-cancer agents, mitochondrial impairment.
Abstract: Recent evidence highlights that energy requirements of cancer cells vary greatly
from normal cells and they exhibit different metabolic phenotypes with variable participation
of both glycolysis and oxidative phosphorylation (OXPHOS). Interestingly, mitochondrial
electron transport chain (ETC) has been identified as an essential component in bioenergetics,
biosynthesis and redox control during proliferation and metastasis of cancer cells. This
dependence converts ETC of cancer cells in a promising target to design small molecules
with anti-cancer actions. Several small molecules have been described as ETC inhibitors
with different consequences on mitochondrial bioenergetics, viability and proliferation of
cancer cells, when the substrate availability is controlled to favor either the glycolytic or
OXPHOS pathway. These ETC inhibitors can be grouped as 1) inhibitors of a respiratory
complex (e.g. rotenoids, vanilloids, alkaloids, biguanides and polyphenols), 2) inhibitors of
several respiratory complexes (e.g. capsaicin, ME-344 and epigallocatechin-3 gallate) and 3)
inhibitors of ETC activity (e.g. elesclomol and VLX600). Although pharmacological ETC inhibition may produce
cell death and a decrease of proliferation of cancer cells, factors such as degree of inhibition of ETC activity by
small molecules, bioenergetic profile and metabolic flexibility of different cancer types or subpopulations of cells
in a particular cancer type, can affect the impact of the anti-cancer actions. Particularly interesting are the adaptive
mechanisms induced by ETC inhibition, such as induction of glutamine-dependent reductive carboxylation,
which may offer a strategy to sensitize cancer cells to inhibitors of glutamine metabolism.
