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

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.

Pulmonary toxicity with oxaliplatin and capecitabine/5-Fluorouracil chemotherapy: a case report and review of the literature.

BACKGROUND: Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used in the treatment of colorectal cancer and is rarely associated with pulmonary toxicity. This is the first reported case of oxaliplatin and capecitabine/5-fluorouracil causing pulmonary toxicity in a patient with pre-existing asymptomatic interstitial lung disease. CASE REPORT: We report a case of a man who was treated with oxaliplatin and capecitabine for 1 cycle, then subsequently with oxaliplatin and 5-fluorouracil following a resected Dukes' C colon carcinoma. His preoperative computed tomography scan incidentally showed mild pulmonary interstitial changes for which he was asymptomatic. He developed pulmonary fibrosis during the course of his chemotherapy, and therefore further chemotherapy was stopped. He was treated with high dose steroids and immunosuppressants which initially stabilized his respiratory symptoms. CONCLUSIONS: Pulmonary fibrosis is a rare complication of oxaliplatin and capecitabine/5-fluorouracil. With the widespread use of oxaliplatin combinations in colorectal cancer, active assessment for interstitial lung disease is recommended and caution in its use should be exercised in those with pre-existing interstitial lung disease.