Tumor acidosis enhances cytotoxic effects and autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells

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...

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Vydáno v:Oncotarget Ročník 7; číslo 24; s. 35703 - 35723
Hlavní autoři: Pellegrini, Paola, Dyczynski, Matheus, Sbrana, Francesca Vittoria, Karlgren, Maria, Buoncervello, Maria, Hägg-Olofsson, Maria, Ma, Ran, Hartman, Johan, Bajalica-Lagercrantz, Svetlana, Grander, Dan, Kharaziha, Pedram, De Milito, Angelo
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 14.06.2016
Témata:
Acidosis - physiopathology
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Autophagy - drug effects
Biopsy
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Breast Neoplasms - physiopathology
Cell Line, Tumor
Cell Survival
Female
Humans
Neoplastic Stem Cells - drug effects
Pyrans - pharmacology
Pyrans - therapeutic use
Spheroids, Cellular - drug effects
Spheroids, Cellular - physiology
Tumor Microenvironment - physiology
Tumor Stem Cell Assay
chloroquine
pH
cancer therapy
tumor acidosis
Autophagy
ISSN:1949-2553
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Shrnutí: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.
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content type line 23
ISSN:1949-2553
DOI:10.18632/oncotarget.9601