Tumor acidosis in malignant progression and therapy

Cancer still represents one of the leading causes of death despite the advances achieved during the past years. Improving the outcome of cancer patients requires the identification of more affective therapeutic strategies and a better understanding of the molecular mechanisms involved in the progression of the disease. Recently, the tumor metabolic reprogramming has been included in the hallmarks of cancer and one features associated with tumor metabolism is acidosis, which represents an environmental pressure contributing to the selection of malignant cells. For its contribution to tumor progression and therapy-resistance, the acidic tumor environment is being investigated as a target for cancer therapy.

In this study, we have characterized the catabolic autophagic process as a fundamental survival mechanism acting in cancer cells exposed to acidic conditions in order to adapt to the harsh environment. This finding, coupled to the role of autophagy in drug-resistance, suggests the use of autophagy inhibitors in cancer treatment as a strategy to better target malignant cells localized in a metabolically stressed environment and considered responsible for tumor progression, invasion, chemoresistance and disease relapse. We have observed that the autophagy inhibitor Chloroquine used in clinical studies is not the optimal drug for this purpose since it fails to inhibit the autophagic process and to induce toxicity on cancer cells in acidic conditions. Therefore, we aimed at identifying more effective compounds also active in conditions of acidosis. Salinomycin, also known to specifically kill cancer stem cells showed a preferential cytotoxic activity in cells under acidosis, a phenomenon associated with its ability to inhibit autophagy also at low pH. Finally, we developed a model of drug screening performed on cancer cells chronically adapted to pH 6.8 in order to identify compounds targeting cells in metabolic stress conditions. We identified Verteporfin as a promising new anticancer drug able to target colon carcinoma cells adapted to low pH better than cells in physiological conditions through a mechanism that still need to be further investigated.

We can conclude that a better understanding of the cellular mechanisms involved in the cell adaptation to tumor acidosis is important for the identification of new therapeutic targets and selective anticancer drugs overcoming acidosis-mediated drug-resistance.

List of scientific papers

I. Maria Lucia Marino, Paola Pellegrini, Giuseppe Di Lernia, Mojgan Djavaheri-Mergny, Slavica Brnjic, Xiaonan Zhang, Maria Hägg-Olofsson, Stig Linder, Stefano Fais, Patrice Codogno, Angelo De Milito. Autophagy is a protective mechanism for human melanoma cells under acidic stress. J Biol Chem. 2012 Aug 31;287(36):30664-76.
https://doi.org/10.1074/jbc.M112.339127

II. Paola Pellegrini, Angela Strambi, Chiara Zipoli, Maria Hägg-Olofsson, Maria Buoncervello, Stig Linder, Angelo De Milito. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies. Autophagy. 2014 Apr;10(4):562-71.
https://doi.org/10.4161/auto.27901

III. Paola Pellegrini, Pedram Kharaziha, Francesca Vittoria Sbrana, Maria Karlgren, Maria Buoncervello, Maria Hägg-Olofsson, Ran Ma, Johan Hartman, Svetlana Bajalica-Lagercrantz, Angelo De Milito. Tumor acidosis enhances autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells. [Submitted]

IV. Paola Pellegrini, Thomas Lundbäck, Magdalena Mazurkiewicz, Jason T. Serviss, Iryna Kolosenko, Di Yu, Martin Haraldsson, Dan Grander, Padraig D’Arcy, Stig Linder, Angelo De Milito. [Manuscript]