Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells

• Published in: International journal of oncology Vol. 41; no. 3; pp. 1101 - 1109
• Main Authors: WANG, JING, KIM, TAE HYUNG, AHN, MEE YOUNG, LEE, JAEWON, JUNG, JEE H, CHOI, WAHN SOO, LEE, BYUNG MU, YOON, KYUING SIL, YOON, SUNGPIL, KIM, HYUNG SIK
• Format: Journal Article
• Language: English
• Published: Athens D.A. Spandidos 01-09-2012; Editorial Academy of the International Journal of Oncology; Spandidos Publications UK Ltd
• Subjects: Acetylation; Adenine - analogs & derivatives; Adenine - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; bcl-2 Homologous Antagonist-Killer Protein - biosynthesis; bcl-2-Associated X Protein - biosynthesis; Benzamides - pharmacology; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cytochrome; Cytochromes c - biosynthesis; Cytochromes c - secretion; Down-Regulation; Female; G1 Phase Cell Cycle Checkpoints - drug effects; Gene expression; Gynecology. Andrology. Obstetrics; histone deacetylase inhibitor; Histone Deacetylase Inhibitors - pharmacology; Humans; Mammary gland diseases; Medical sciences; Microtubule-Associated Proteins - biosynthesis; Naphthols - pharmacology; Proteins; sirtinol; sirtuin; Sirtuins - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism; Tumors; Up-Regulation; United States > US; Human; Histone deacetylase; Breast disease; Breast cancer; Malignant tumor; sirtinol; Autophagy; Sirtuin; Mammary gland diseases; Histone deacetylase inhibitor; Cancerology; Cell death; Established cell line; Tumor cell; Cancer; Apoptosis
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2012.1534

Sirtuins (SIRTs), NAD+-dependent class III histone deacetylases (HDACs), play an important role in the regulation of cell division, survival and senescence. Although a number of effective SIRT inhibitors have been developed, little is known about the specific mechanisms of their anticancer activity. In this study, we investigated the anticancer effects of sirtinol, a SIRT inhibitor, on MCF-7 human breast cancer cells. Apoptotic and autophagic cell death were measured. Sirtinol significantly inhibited the proliferation of MCF-7 cells in a concentration-dependent manner. The IC50 values of sirtinol were 48.6 μM (24 h) and 43.5 μM (48 h) in MCF-7 cells. As expected, sirtinol significantly increased the acetylation of p53, which has been reported to be a target of SIRT1/2. Flow cytometry analysis revealed that sirtinol significantly increased the G1 phase of the cell cycle. The upregulation of Bax, downregulation of Bcl-2 and cytochrome c release into the cytoplasm, which are considered as mechanisms of apoptotic cell death, were observed in the MCF-7 cells treated with sirtinol. The Annexin V-FITC assay was used to confirm sirtinol-induced apoptotic cell death. Furthermore, the expression of LC3-II, an autophagy-related molecule, was significantly increased in MCF-7 cells after sirtinol treatment. Autophagic cell death was confirmed by acridine orange and monodansylcadaverine (MDC) staining. Of note, pre-treatment with 3-methyladenine (3-MA) increased the sirtinol-induced MCF-7 cell cytotoxicity, which is associated with blocking autophagic cell death and increasing apoptotic cell death. Based on our results, the downregulation of SIRT1/2 expression may play an important role in the regulation of breast cancer cell death; thus, SIRT1/2 may be a novel molecular target for cancer therapy and these findings may provide a molecular basis for targeting SIRT1/2 in future cancer therapy.