Anticancer efficacy and the mechanism of action of α-santalol, a terpenoid isolated from sandalwood oil, were investigated in human breast cancer cells by using p53 wild-type MCF-7 cells as a model for estrogen receptor(ER)-positive and p53 mutated MDA-MB-231 cells as a model for ER-negative breast cancer. α-Santalol inhibited cell viability and proliferation in a concentration and time-dependent manner in both cells regardless of their ER and/or p53 status. However, α-santalol produced relatively less toxic effect on normal breast epithelial cell line, MCF-10A. It induced G2/M cell cycle arrest and apoptosis in both MCF-7 and MDA-MB-231 cells. Cell cycle arrest induced by α-santalol was associated with changes in the protein levels of BRCA1, Chk1, G2/M regulatory cyclins, Cyclin dependent kinases (CDKs), Cell division cycle 25B (Cdc25B), Cdc25C and Ser-216 phosphorylation of Cdc25C. An up-regulated expression of CDK inhibitor p21 along with suppressed expression of mutated p53 was observed in MDA-MB-231 cells treated with α-santalol. On the contrary, α-santalol did not increase the expression of wild-type p53 and p21 in MCF-7 cells. In addition, α-santalol induced extrinsic and intrinsic pathways of apoptosis in both cells with activation of caspase-8 and caspase-9. It led to the activation of the executioner caspase-6 and caspase-7 in α-santalol-treated MCF-7 cells and caspase-3 and caspase-6 in MDA-MB-231 cells along with strong cleavage of poly(ADP-ribose) polymerase (PARP) in both cells. Taken together, this study for the first time identified strong anti-neoplastic effects of α-santalol against both ER-positive and ER-negative breast cancer cells.

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Anticancer efficacy and the mechanism of action of a-santalol, a terpenoid isolated from sandalwood oil, were investigated in human breast cancer cells by using p53 wild-type MCF-7 cells as a model for estrogen receptor(ER)-positive and p53 mutated MDA-MB-231 cells as a model for ER-negative breast cancer. a-Santalol inhibited cell viability and proliferation in a concentration and time-dependent manner in both cells regardless of their ER and/or p53 status. However, a-santalol produced relatively less toxic effect on normal breast epithelial cell line, MCF-10A. It induced G2/M cell cycle arrest and apoptosis in both MCF-7 and MDA-MB-231 cells. Cell cycle arrest induced by a-santalol was associated with changes in the protein levels of BRCA1, Chk1, G2/M regulatory cyclins, Cyclin dependent kinases (CDKs), Cell division cycle 25B (Cdc25B), Cdc25C and Ser-216 phosphorylation of Cdc25C. An up-regulated expression of CDK inhibitor p21 along with suppressed expression of mutated p53 was observed in MDA-MB-231 cells treated with a-santalol. On the contrary, a-santalol did not increase the expression of wild-type p53 and p21 in MCF-7 cells. In addition, a-santalol induced extrinsic and intrinsic pathways of apoptosis in both cells with activation of caspase-8 and caspase-9. It led to the activation of the executioner caspase-6 and caspase-7 in a-santalol-treated MCF-7 cells and caspase-3 and caspase-6 in MDA-MB-231 cells along with strong cleavage of poly(ADP-ribose) polymerase (PARP) in both cells. Taken together, this study for the first time identified strong anti-neoplastic effects of a-santalol against both ER-positive and ER-negative breast cancer cells.

Alpha-santalol, an active component of sandalwood oil, has been shown to have chemopreventive effects on skin cancer both in vitro and in vivo. However, effects of alpha-santalol on other types of cancer have not been studied. In this study, we examine the effects and mechanisms of action of alpha-santalol on human breast cancer cells using estrogen receptor (ER)- positive (MCF-7) and estrogen receptor- negative (MDA-MB-231) breast cancer cell lines. MTT and BrdU cell proliferation ELISA results showed inhibition of cell viability and proliferation in a time and dose-dependent manner in both cell lines. Alpha-santalol at 25-150 µM concentration decreased cell viability after 12h treatment. In addition, TUNEL assay and flow cytometry results revealed that alpha-santalol significantly induced apoptosis in MCF-7 and MDA-MB-231 cells. Further, immunoblotting and caspase activity assays showed involvement of caspase-3, caspase-8 and caspase-9 in apoptotic cell death. Induction of apoptosis by alpha-santalol was further confirmed by detecting the cleavage of Poly (ADP-ribose) Polymerase (PARP) through western blotting. Cell cycle distribution of alpha-santalol treated MFC-7 and MDA-MB-231 cells were analyzed by fluorescence- activated cell sorting (FACS) analysis of propidium iodide staining. We observed that alpha-santalol treatment arrests cell cycle at G2/M phase at 25µM −75µM concentration in both cell lines. Taken together, our studies reveal a potential mechanism for the chemopreventive effect of alpha-santalol on ER- positive and ER- negative breast cancer cells through induction of apoptosis and cell cycle arrest at G2/M phase. Alpha-santalol could be effective for the prevention and treatment of breast cancer. (Supported by Translational Cancer Research Center funded by South Dakota, Governors Office of Economic Development) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 574. doi:1538-7445.AM2012-574

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