Exploiting the metabolic energy demands of drug efflux pumps provides a strategy to overcome multidrug resistance in cancer

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 8; p. 129915
• Main Authors: Gao, Xuexin, Aguanno, Doriane, Board, Mary, Callaghan, Richard
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2021
• Subjects: ABC transporter; Cancer; cell death; cell viability; Collateral sensitivity; energy; glycolysis; homeostasis; hypersensitivity; Metabolism; Multidrug resistance; multiple drug resistance; oxidative phosphorylation; P-glycoprotein; P-glycoproteins; phenotype; reactive oxygen species; verapamil; P-glycoprotein; Collateral sensitivity; Metabolism; ABC transporter; Multidrug resistance; Cancer
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2021.129915

P-glycoprotein (P-gp) is a prevalent resistance mediator and it requires considerable cellular energy to ensure ATP dependent efflux of anticancer drugs. The glycolytic pathway generates the majority of catabolic energy in cancer cells; however, the high rates of P-gp activity places added strain on its inherently limited capacity to generate ATP. This is particularly relevant for compounds such as verapamil that are believed to trap P-gp in a futile transport process that requires continuing ATP consumption. Ultimately, this leads to cell death and the hypersensitivity of resistant cells to verapamil is termed collateral sensitivity. We show that the addition of verapamil to resistant cells produces a prominent reduction in ATP levels that supports the idea of disrupted energy homeostasis. Even in the absence of verapamil, P-gp expressing cells display near maximal rates of glycolysis and oxidative phosphorylation, which prevents an adequate response to the demand for ATP to sustain transport activity. Moreover, the near perpetually maximal rate of oxidative phosphorylation in the presence of verapamil resulted in elevated levels of reactive oxygen species that affect cell survival and underscore collateral sensitivity. Our results demonstrate that the strained metabolic profiles of P-gp expressing resistant cancer cells can be overwhelmed by additional ATP demands. Consequently, collateral sensitising drugs may overcome the resistant phenotype by exploiting, rather than inhibiting, the energy demanding activity of pumps such as P-gp. [Display omitted] •Resistant cancer cells have an added energy burden to evade chemotherapy.•Resistance caused by drug pumps such as P-glycoprotein is energetically demanding.•Resistant cells expressing P-glycoprotein are hyper-sensitive to verapamil.•Verapamil traps P-glycoprotein in a futile transport cycle using high amounts of ATP.•Verapamil can overwhelm the metabolic balance of P-glycoprotein expressing cells.