Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 585, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2020.119465
Keywords
Triphenylphosphonium-Functionalized hyperbranched polymer; Chloroquine; Breast adenocarcinoma; Mitochondria; Ataxia-Telangiectasia Mutated Kinase
Categories
Funding
- Action for the Strategic Development on the Research and Technological Sector - Operational Program Competitiveness, Entrepreneurship and Innovation (NSRF 2014-2020) [MIS 5002567]
- European Union (European Regional Development Fund)
- Italian Ministry of Health [RF-2016-02363460]
- GSRT Greece
- [EE11968]
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Cancer stem cells (CSCs) have garnered increasing attention over the past decade, as they are believed to play a crucial role in tumor progression and drug resistance. Accumulating evidence provides insight into the function of autophagy in maintenance and survival of CSCs. Here, we studied the impact of a mitochondriotropic tri-phenylphosphonium-functionalized dendrimeric nanocarrier on cultured breast cancer cell lines, grown either as adherent cells or as mammospheres that mimic a stem-like phenotype. The nanocarrier manifested a substantial cytotoxicity both alone as well as after encapsulation of chloroquine, a well-known autophagy inhibitor. The cytotoxic e ffects of the nanocarrier could be ascribed to interference with mitochondrial function. Importantly, mammospheres were selectively sensitive to encapsulated chloroquine and this depends on the expression of the gene encoding ATM kinase. Ataxia-telangiectasia mutated (ATM) kinase is an enzyme that functions as an es-sential signaling mediator that enables growth of cancer stem cells through the regulation of autophagy. We noted that this ATM -dependent sensitivity of mammospheres to encapsulated chloroquine was independent of the status of the tumor suppressor gene p53. Our study suggests that breast cancer stem cells, as they are modeled by mammospheres, are sensitive to encapsulated chloroquine, depending on the expression of the ATM kinase, which is thereby characterized as a potential biomarker for sensitivity to this type of treatment.
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