Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs – an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research

Abstract

In recent years an increasing number of publications have emphasized the growing importance of hydrogen ion dynamics in modern cancer research, from etiopathogenesis and treatment. A proton [H+]-related mechanism underlying the initiation and progression of the neoplastic process has been recently described by different research groups as a new paradigm in which all cancer cells and tissues, regardless of their origin and genetic background, have a pivotal energetic and homeostatic disturbance of their metabolism that is completely different from all normal tissues: an aberrant regulation of hydrogen ion dynamics leading to a reversal of the pH gradient in cancer cells and tissues (↑pHi/↓pHe, or “proton reversal”). Tumor cells survive their hostile microenvironment due to membrane-bound proton pumps and transporters, and their main defensive strategy is to never allow internal acidification because that could lead to their death through apoptosis. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na+/H+ exchanger isoform 1 (NHE1). An elevated NHE1 activity can be correlated with both an increase in cell pH and a decrease in the extracellular pH of tumors, and such proton reversal is associated with the origin, local growth, activation and further progression of the metastatic process. Consequently, NHE1 pharmaceutical inhibition by new and potent NHE1 inhibitors represents a potential and highly selective target in anticancer therapy. Cariporide, being one of the better studied specific and powerful NHE1 inhibitors, has proven to be well tolerated by humans in the cardiological context, however some side-effects, mainly related to drug accumulation and cerebrovascular complications were reported. Thus, cariporide could become a new, slightly toxic and effective anticancer agent in different human malignancies.

KR-33028, a potent inhibitor of the Na+/H+ exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells

“…4a. When MDA-MB-231, MDA-MB-468 and Hs578T TNBC cells were treated with 2.5 μM KR-33028, rates of 13 cell migration were greatly reduced ( # P<0.05, + P>0.01, *P<0.001, N=3; Fig. 4b).…”

“…However, neither type of NHE1 inhibitor has been developed as successful anticancer agents in humans. The use of amiloride in cancer therapy in animal models and clinical trials was recently reviewed [12], as was cariporide and other novel NHE1 inhibitors [13]. In this study, we focused on a new, potent and selective small molecule NHE1 inhibitor, KR-33028 (4-cyano (benzo[b]thiophene-2-carbonyl)guanidine) [14,15].…”

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

“…The use of pharmacological inhibitors of NHE1 as anti-cancer therapies was recently reviewed (39,85); in summary, they comprise of two main chemical classes: amiloride and its derivatives, and benzoyl (acyl) guanidines. Amiloride, a potassium-sparing diuretic, was the earliest developed NHE1 inhibitor, and the only drug clinically used in humans.…”

“…Other compounds also have promising potential. Some are well absorbed by the gastrointestinal tract and can be given orally such as compound 9t (85,87).…”

Rethinking therapeutic strategies in cancer: Wars, fields, anomalies and monsters

“…A number of chemicals that are used to treat other conditions have shown promising results in the field of cancer. These chemicals can be divided in two groups known as: (i) proton pump inhibitors and, (ii) pH-buffers (Harguindey et al, 2013;De Milito et al, 2012;Spugnini et al, 2015;Fais et al, 2014). In (i) one finds (ia) amiloride-derivatives that are potassium-sparing diuretic agents usually used to treat congestive heart failure and hypertension; (i-b) omeprazole-derivatives used to treat gastric acid reflux.…”