8-Amino-adenosine activates p53-independent cell death of metastatic breast cancers

• Published in: Molecular cancer therapeutics 2012-11, Vol.11 (11), p.2495-2504
• Main Authors: Polotskaia, Alla, Hoffman, Sandy, Krett, Nancy L, Shanmugam, Mala, Rosen, Steven T, Bargonetti, Jill
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Antineoplastic Agents - pharmacology; Autophagy - drug effects; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Caspase Inhibitors - pharmacology; Cell Death - drug effects; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Doxycycline - chemistry; Doxycycline - pharmacology; Female; Humans; Mutant Proteins - metabolism; Neoplasm Metastasis; Oligopeptides - pharmacology; Receptors, Estrogen - metabolism; Signal Transduction - drug effects; Transcription, Genetic - drug effects; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-12-0085

8-Amino-adenosine (8-NH(2)-Ado) is a ribose sugar nucleoside analogue that reduces cellular ATP levels and inhibits mRNA synthesis. Estrogen receptor-negative (ER-) metastatic breast cancers often contain mutant p53; therefore, we asked if 8-NH(2)-Ado could kill breast cancer cells without activating the p53-pathway. Regardless of the breast cancer subtype tested or the p53 status of the cells, 8-NH(2)-Ado was more cytotoxic than either gemcitabine or etoposide. 8-NH(2)-Ado treatment inhibited cell proliferation, activated cell death, and did not activate transcription of the p53 target gene p21 or increase protein levels of either p53 or p21. This occurred in the estrogen receptor-positive (ER+) MCF-7 cells that express wild-type p53, the ER+ T47-D cells that express mutant p53, and the ER- MDA-MB-468 cells or MDA-MB-231 cells that both express mutant p53. 8-NH(2)-Ado induced apoptotic death of MCF-7 cells and apoptosis was not inhibited by knockdown of functional p53. Moreover, the pan-caspase inhibitor Z-VAD blocked the 8-NH(2)-Ado-induced MCF-7 cell death. Interestingly, 8-NH(2)-Ado caused the MDA-MB-231 cells to detach from the plate with only limited evidence of apoptotic cell death markers and the cell death was not inhibited by Z-VAD. Inhibition of MDA-MB-231 cell autophagy, by reduction of ATG7 or 3-methyladenine treatment, did not block this 8-NH(2)-Ado-mediated cytotoxicity. Importantly 8-NH(2)-Ado was highly cytotoxic to triple-negative breast cancer cells and worked through a pathway that did not require wild-type p53 for cytoxicity. Therefore, 8-NH(2)-Ado should be considered for the treatment of triple-negative breast cancers that are chemotherapy resistant.