The role of proton dynamics in the development and maintenance of multidrug resistance in cancer

Abstract

With a projected 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm in 2015, improving treatment is an essential focus of cancer research today. Multi-drug resistance (MDR) is the leading cause of chemotherapeutic failure in the treatment of cancer, the term denoting a characteristic of the disease-causing agent to avoid damage by drugs designed to bring about their destruction. MDR is also characterised by a reversal of the pH gradient across cell membranes leading to an acidification of the outer milieu and an alkalinisation of the cytosol that is maintained by the proton pump vacuolar-type ATPase (V-ATPase) and the proton transporters: Na(+)/H(+) exchanger (NHE1), Monocarboxylate Transporters (MCTs), Carbonic anhydrases (CAs) (mainly CA-IX), adenosinetriphosphate synthase, Na(+)/HCO3(-) co-transporter and the Cl(-)/HCO3(-)exchanger. This review aims to give an introduction to MDR. It will begin with an explanation for what MDR actually is and go on to look at the proposed mechanisms by which a state of drug resistance is achieved. The role of proton-pumps in creating an acidic extracellular pH and alkaline cytosol, as well as key biomechanical processes within the cell membrane itself, will be used to explain how drug resistance can be sustained.

The acidic microenvironment as a possible niche of dormant tumor cells

“…Cellular drug uptake and intracellular targeting are key factors for a successful anticancer treatment and both mechanisms are influenced by pH e . Extracellular acidity reduces the intracellular concentration of chemotherapeutic agents, mainly weak base drugs, through a mechanism termed "ion trapping", and based on ion protonation of drugs [99][100][101][102]. Thus, the reversion of this pH gradient may strongly facilitate the successful treatment.…”

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

“…(2) Physicochemical properties of drugs: The tumor microenvironment alters the physicochemical properties of proton transporter 130,131 . Extrusion of protons into the extracellular milieu results in the generation of an acidic pH 1,50 .…”

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

“…In cancer cells, elevated NHE1 activity results in increased H + extrusion that leads to cellular alkalinisation and the establishment of the acidic extracellular tumour microenvironment (13). Over the past decade, experts in the field of pH regulation and homeostasis in tumour cells have realized the potential of targeting the tumour microenvironment pH as an anti-cancer therapy (16)(17)(18)(19). In this review, we present evidence to highlight the role of H + ions as a key carcinogenic signal, regulating both intracellular pH of tumour cells and the extracellular pH of the tumour microenvironment.…”