salinomycin and Acidosis

Sustained autophagy contributes to the metabolic adaptation of cancer cells to hypoxic and acidic microenvironments. Since cells in such environments are resistant to conventional cytotoxic drugs, inhibition of autophagy represents a promising therapeutic strategy in clinical oncology. We previously reported that the efficacy of hydroxychloroquine (HCQ), an autophagy inhibitor under clinical investigation is strongly impaired in acidic tumor environments, due to poor uptake of the drug, a phenomenon widely associated with drug resistance towards many weak bases. In this study we identified salinomycin (SAL) as a potent inhibitor of autophagy and cytotoxic agent effective on several cancer cell lines under conditions of transient and chronic acidosis. Since SAL has been reported to specifically target cancer-stem cells (CSC), we used an established model of breast CSC and CSC derived from breast cancer patients to examine whether this specificity may be associated with autophagy inhibition. We indeed found that CSC-like cells are more sensitive to autophagy inhibition compared to cells not expressing CSC markers. We also report that the ability of SAL to inhibit mammosphere formation from CSC-like cells was dramatically enhanced in acidic conditions. We propose that the development and use of clinically suitable SAL derivatives may result in improved autophagy inhibition in cancer cells and CSC in the acidic tumor microenvironment and lead to clinical benefits.

Topics: Acidosis; Antineoplastic Agents; Autophagy; Biopsy; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Female; Humans; Neoplastic Stem Cells; Pyrans; Spheroids, Cellular; Tumor Microenvironment; Tumor Stem Cell Assay

Salinomycin, a new ionophore antibiotic, was tested and compared with lasalocid and monensin for preventing experimentally induced lactic acidosis. Five rumen-fistulated adult cattle were used in a 5 X 5 Latin square design, and the treatments were as follows: no treatment (control), 0.11 mg of salinomycin/kg of body weight (S1), 0.22 mg of salinomycin/kg (S2), 0.66 of lasalocid/kg, and 0.66 mg of monensin/kg. Acidosis was induced by intraruminal administration of a ground corn-corn starch mixture (50:50, 12.5 g/kg) once a day for up to 4 days. Antibiotics were administered along with grain-starch mixture. Rumen and blood samples were obtained before and at 6, 12, and 24 hours after each carbohydrate-antibiotic dosing to monitor acid-base status. Control and S1-treated cattle became ruminally acidotic within 54 hours, whereas cattle treated with S2, lasalocid, and monensin resisted acidosis for up to 78 hours after dosing. Cattle treated with S2, lasalocid, or monensin had higher rumen pH and lower L(+)- and D(-)-lactate concentrations than did control or S1-treated cattle. Rumen pH decrease to below 5.0 in S2-, lasalocid-, and monensin-treated cattle was not due to lactic acid, but to increased production of volatile fatty acids. Rumen propionate proportion increased initially in antibiotic-treated cattle, but after 48 hours, butyrate proportion increased significantly. Despite low rumen pH and high lactate concentration, lacticacidemia was not evident, and the systemic acid-base disturbance was mild in control cattle.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acidosis; Animal Feed; Animals; Cattle; Cattle Diseases; Food Additives; Hydrogen-Ion Concentration; Lactates; Lasalocid; Monensin; Pyrans; Rumen