Exploiting the altered bioenergetic metabolism to overcome cancer multidrug resistance

Gao X, Aguanno D and Callaghan R

Department of Biomedical Science and Biochemistry, Research School of Biology, The Australian National University, Canberra, ACT, 0200 Australia.

A major reason for the failure of cancer chemotherapy is the development of multidrug resistance, which may result from many cellular factors. One of the most prevalent factors is the over-expression of the transporter P-glycoprotein (P-gp). This protein mediates the ATP-dependent efflux of drugs from resistant cancer cells against considerable concentration gradients and this activity may impact the cellular ATP pool. Generation of ATP in cancer cells is primarily rely on the catabolism of glucose through the glycolytic pathway, preventing full utilisation of the energy from glucose. This strategy in cancer cells ensures a balance between energy production and sufficient biomass production to sustain proliferation. Does the ATP utilisation caused by active P-gp perturb this balance and initiate a distinct metabolic strategy for resistant cells? The investigation will focus on the metabolic strategy of P-gp over-expressing cells in the presence of drugs stimulating the transport activity of P-gp. We have demonstrated that resistant cells display higher basal levels of ATP, glucose uptake and lactate production, but significantly suppressed mitochondrial respiration. Drug treatment rapidly lowered the cellular ATP levels, causing further enhanced glucose uptake. However, this observation was not associated with an increase in lactate production or glycolytic flux. How do these resistant cells restore the ATP homeostasis? Additionally, we have demonstrated that cellular respiration was elevated to the maximal rate after drug addition, causing a significant increase in ROS levels. In summary, stimulation of P-gp transport activity affected ATP homeostasis, thereby forcing the resistant cells to produce more ATP through mitochondrial oxidative phosphorylation. This adaptive response perturbs ROS homeostasis in cells and may cause apoptosis.