The complex relationship between multiple drug resistance and the tumor pH gradient: a review

Abstract

Multiple drug resistance (MDR) is the tumor’s way of escaping the cytotoxic effects of various unrelated chemotherapeutic drugs. It can be either innate or acquired. MDR represents the end of the therapeutic pathway, and it practically leaves no treatment alternatives. Reversing MDR is an unfulfilled goal, despite the important recent advances in cancer research. MDR, the main cause of death in cancer patients, is a multi-factorial development, and most of its known causes have been thoroughly discussed in the literature. However, there is one aspect that has not received adequate consideration - intracellular alkalosis - which is part of wider pH deregulation where the pH gradient is inverted, meaning that extracellular pH is decreased and intracellular pH increased. This situation interacts with MDR and with the proteins involved, such as P-gp, breast cancer resistance protein, and multidrug associated resistance protein 1. However, there are also situations in which these proteins play no role at all, and where pH takes the lead. This is the case in ion trapping. Reversing the pH gradient to normal can be an important contribution to managing MDR. The drugs to manipulate pH exist, and most of them are FDA approved and in clinical use for other purposes. Furthermore, they have low or no toxicity and are inexpensive compared with any chemotherapeutic treatment. Repurposing these drugs and combining them in a reasonable fashion is one of the points proposed in this paper, which discusses the relationship between cancer’s peculiar pH and MDR.

Physicians lectuar abstracts

“…KARDUM FUCAK I. 1 , Mladinović M. 2 1 Opća bolnica "dr. Tomislav Bardek" Koprivnica • Odjel za gastroenterologiju, onkologiju i hematologiju 2 Opća bolnica "dr. Josip Benčević" Slavonski Brod • Odjel za onkologiju i hematologiju ikardum@gmail.com Rak dojke najčešća je maligna bolest u žena u svijetu i većina slučajeva invazivnog raka dojke dijagnosticira se u ranom stadiju. U 70-80% slučajeva radi se o raku dojke s pozitivnim hormonskim receptorima (HR+) i negativnom ekspresijom humanog epidermalnog faktora rasta 2 (HER 2-).…”

“…KARDUM FUCAK I. 1 , Mladinović M. 2 1 General Hospital "dr. Tomislav Bardek" Koprivnica • Department of Gastroenterology, Oncology and Hemathology 2 General Hospital "dr. Josip Benčević" Slavonski Brod…”

“…MLADINOVIĆ M. 1 , Kardum Fucak I. 2 , Silovski T. 3 1 Opća bolnica "dr. Josip Benčević" Slavonski Brod • Odjel za onkologiju i hematologiju 2 Opća bolnica "dr. Tomislav Bardek" Koprivnica • Odjel za gastroenterologiju, onkologiju i hematologiju 3 Klinički bolnički centar Zagreb • Klinika za onkologiju martina.mladinovic@hotmail.com Uvod: Mlade odrasle žene u dobi od 15 do 39 godina najčešće obolijevaju od raka dojke. Invazivni rak dojke u toj populaciji čini 5,6% svih karcinoma dojke kod žena.…”

“…KRIŽIĆ M. 1 , Jazvić M. 2 , Dedić Plavetić N. 1,3 1 Klinički bolnički centar Zagreb • Klinika za onkologiju 2 Klinički bolnički centar Sestre milosrdnice • Klinika za onkologiju i nuklearnu medicinu 3 Sveučilište u Zagrebu • Medicinski fakultet mkrizic13@gmail.com Iako je u posljednje vrijeme ostvaren ogroman napredak u liječenju metastatskog karcinoma dojke, i dalje se smatra neizlječivom bolesti. Hormonski ovisni HER2-negativni metastatski rak dojke je najčešći podtip koji ima povoljniju prognozu u odnosu na ostale podtipove zbog mogućnosti djelovanja na estrogenski receptor.…”

“…KRIŽIĆ M. 1 , Jazvić M. 2 , Dedić Plavetić N. Although tremendous progress has recently been made in treating metastatic breast cancer, it is still considered an incurable disease. Hormone receptor-positive HER2-negative metastatic breast cancer is the most common subtype with a favorable prognosis compared to other subtypes, due to the possibility of acting on estrogen receptors.…”