Research Papers: Autophagy and Cell Death:

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

Paola Pellegrini, Matheus Dyczynski, Francesca Vittoria Sbrana, Maria Karlgren, Maria Buoncervello, Maria Hägg-Olofsson, Ran Ma, Johan Hartman, Svetlana Bajalica-Lagercrantz, Dan Grander, Pedram Kharaziha and Angelo De Milito _

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Oncotarget. 2016; 7:35703-35723. https://doi.org/10.18632/oncotarget.9601

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Paola Pellegrini1, Matheus Dyczynski1, Francesca Vittoria Sbrana2, Maria Karlgren3, Maria Buoncervello4, Maria Hägg-Olofsson1, Ran Ma1, Johan Hartman1, Svetlana Bajalica-Lagercrantz1, Dan Grander1, Pedram Kharaziha1 and Angelo De Milito1

1 Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden

2 Istituto Ortopedico Rizzoli, Bologna, Italy

3 Department of Pharmacy and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP) - Science for Life Laboratory, Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, Sweden

4 Istituto Superiore di Sanità, Rome, Italy

Correspondence to:

Angelo De Milito, email:

Keywords: Autophagy, chloroquine, tumor acidosis, cancer therapy, pH

Received: January 15, 2016 Accepted: April 20, 2016 Published: May 27, 2016


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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