Overcoming Chemoresistance: Altering pH of Cellular Compartments by Chloroquine and Hydroxychloroquine

Abstract

Resistance to the anti-cancer effects of chemotherapeutic agents (chemoresistance) is a major issue for people living with cancer and their providers. A diverse set of cellular and inter-organellar signaling changes have been implicated in chemoresistance, but it is still unclear what processes lead to chemoresistance and effective strategies to overcome chemoresistance are lacking. The anti-malaria drugs, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are being used for the treatment of various cancers and CQ and HCQ are used in combination with chemotherapeutic drugs to enhance their anti-cancer effects. The widely accepted anti-cancer effect of CQ and HCQ is their ability to inhibit autophagic flux. As diprotic weak bases, CQ and HCQ preferentially accumulate in acidic organelles and neutralize their luminal pH. In addition, CQ and HCQ acidify the cytosolic and extracellular environments; processes implicated in tumorigenesis and cancer. Thus, the anti-cancer effects of CQ and HCQ extend beyond autophagy inhibition. The present review summarizes effects of CQ, HCQ and proton pump inhibitors on pH of various cellular compartments and discuss potential mechanisms underlying their pH-dependent anti-cancer effects. The mechanisms considered here include their ability to de-acidify lysosomes and inhibit autophagosome lysosome fusion, to de-acidify Golgi apparatus and secretory vesicles thus affecting secretion, and to acidify cytoplasm thus disturbing aerobic metabolism. Further, we review the ability of these agents to prevent chemotherapeutic drugs from accumulating in acidic organelles and altering their cytosolic concentrations.

Keywords: Golgi pH; chemoresistance; chloroquine; cytosolic pH; endolysosome pH; hydroxychloroquine.

FIGURE 1

A schematic diagram of CQ pre-treated in overcoming chemoresistance. (A) Beside acidic extracellular microenvironment, tumor cells have a slightly alkaline cytosolic microenvironment, which leads to an increase in aerobic glycolysis. Anti-cancer compounds (many of them are weak bases) tend to accumulate in acidic organelles, like endolysosomes, and increase exocytosis of these compounds back into the extracellular matrix. Thus, the designated effect of these anti-cancer compounds is futile, and the cell becomes resistant to these weak-base anti-cancer compounds. (B) Pre-treatment of CQ acidifies the cytosolic microenvironment and may reverse the increase of aerobic glycolysis as occurs in cancer cells. Pre-treatment of CQ de-acidifies endolysosomes and inhibits autophagic flux. CQ-induced endolysosome de-acidification prevents the accumulation of anti-cancer compounds in endolysosomes and increases their concentration in the cytosol and nucleus, the sites where anti-cancer compounds exert their anti-cancer effects.