Human Disease and Membrane Transport Laboratory, Division of Biomedical Science & Biochemistry, Research School of Biology and Medical School, The Australian National University, Canberra 2601, Australia.
St. Hilda's College, University of Oxford, Oxford OX4 1DY, UK.
Biochim Biophys Acta Gen Subj. 2021 Aug;1865(8):129915. doi: 10.1016/j.bbagen.2021.129915. Epub 2021 May 12.
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.
P-糖蛋白（P-gp）是一种普遍的耐药介质，它需要大量的细胞能量来确保 ATP 依赖性抗癌药物的外排。糖酵解途径是癌细胞中产生大部分分解代谢能量的途径；然而，P-gp 活性的高比率对其固有的有限产生 ATP 的能力造成了额外的压力。这对于维拉帕米等被认为会将 P-gp 困在需要持续消耗 ATP 的无效转运过程中的化合物尤其相关。最终，这导致细胞死亡，并且耐药细胞对维拉帕米的超敏性被称为旁系敏感性。
我们表明，维拉帕米的加入会使耐药细胞中的 ATP 水平明显降低，这支持了能量平衡失调的观点。即使没有维拉帕米，表达 P-gp 的细胞也显示出接近最大的糖酵解和氧化磷酸化速率，这阻止了对维持转运活性所需 ATP 的需求做出充分反应。此外，在存在维拉帕米的情况下，氧化磷酸化的近永久最大速率导致活性氧水平升高，影响细胞存活并强调旁系敏感性。
我们的结果表明，表达 P-gp 的耐药癌细胞的紧张代谢特征可以被额外的 ATP 需求所克服。
因此，旁系增敏药物可以通过利用而不是抑制泵（如 P-gp）的能量需求活性来克服耐药表型。
