Intracellular Hyper-Acidification Potentiated by Hydrogen Sulfide Mediates Invasive and Therapy Resistant Cancer Cell Death

Abstract

Slow and continuous release of H2S by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death. The present study investigated the potency of H2S released by GYY4137 against invasive and radio- as well as chemo-resistant cancers, known to be glycolytically active. We characterized and utilized cancer cell line pairs of various organ origins, based on their aggressive behaviors, and assessed their response to GYY4137. We compared glycolytic activity, via lactate production, and intracellular pH of each cancer cell line pair after exposure to H2S. Invasive and therapy resistant cancers, collectively termed aggressive cancers, are receptive to H2S-mediated cytotoxicity, albeit at a higher concentration of GYY4137 donor. While lactate production was enhanced, intracellular pH of aggressive cancers was only modestly decreased. Inherently, the magnitude of intracellular pH decrease is a key determinant for cancer cell sensitivity to H2S. We demonstrated the utility of coupling GYY4137 with either simvastatin, known to inhibit monocarboxylate transporter 4 (MCT4), or metformin, to further boost glycolysis, in bringing about cell death for aggressive cancers. Simvastatin inhibiting lactate extrusion thence contained excess lactate induced by GYY4137 within intracellular compartment. In contrast, the combined exposure to both GYY4137 and metformin overwhelms cancer cells with lactate over-production exceeding its expulsion rate. Together, GYY4137 and simvastatin or metformin synergize to induce intracellular hyper-acidification-mediated cancer cell death.

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs

“…Further, Szabo and Papapetropoulos rightly point out that not only H 2 S-poor diseases can be corrected by H 2 S supplementation, since ''there are also several indications where endogenous H 2 S levels are not suppressed, and yet H 2 S donation may be beneficial or warranted.'' Additional evidence, obtained mainly after the list just cited was compiled, supports considering therapeutic application of H 2 S prodrugs in cancer (148), psoriasis (12), multiple viral infections (24,25), colitis (180), autoimmune pathologies (42), systemic sclerosis (2), multiple sclerosis (245), Parkinson's disease (PD) (111), intracerebral hemorrhage (288), Duchenne muscular dystrophy/cardiomyopathy (44), allergic diseases (173), fibrotic disorders (229), osteoarthritis (164), osteoporosis (281), sarcopenia (32), pulmonary hypertension (287), ocular hypertension (225), kidney diseases (15), hearing loss (152), lens opacification (190), testicular dysfunction (262), male subfertility (178), erectile dysfunction (64), and periodontitis (89) as well.…”

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…Since extracellular acidification also increases the activity of P-gp, in this way inducing MDR in different cancer cells and tissues [ 125 , 128 , 132 ], it becomes logical to associate PPI with PTI, not only to improve the effect of chemotherapy in metastatic BC, but also to overcome MDR. The clinical use of such a combination is considered a fundamental therapeutic measure in any integrated clinical protocol in the treatment of BC [ 4 , 10 , 30 , 31 , 64 , 67 , 68 , 71 , 72 , 73 , 78 , 101 , 122 , 124 , 139 , 140 , 165 , 167 , 174 , 175 , 180 , 188 , 189 , 190 , 195 , 196 , 197 , 202 , 208 , 233 , 307 , 308 , 309 , 310 , 311 ]. The integral pH-related approach to MDR has shown that the therapeutic failure in inducing the acidification of the cytoplasm and/or reverse CPR is the main factor underlying MDR.…”

Functional and molecular mechanism of intracellular pH regulation in human inducible pluripotent stem cells

“…Therefore, intracellular acid extruders, such as NHE and MCT, are activated to maintain pH i homeostasis. The overactivation and/or overexpression of the acid extrusion mechanism results in an increased pH i that further promotes proliferation and prevents apoptosis in cancer cells[24,26,28,29]. Furthermore, accompanying extracellular acidification causes restructuring of the extracellular matrix and further promotes malicious metastasis and invasion[26,30,31].…”