Carcinogenesis Advance Access published online on November 4, 2004
Carcinogenesis, doi:10.1093/carcin/bgh325
© 2004 by Oxford University Press
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1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA
* To whom correspondence should be addressed.
Revised September 25, 2004
Accepted October 26, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Skin cancer chemopreventive agent,
-santalol, induces apoptotic death of human epidermoid carcinoma A431 cells via caspase activation together with dissipation of mitochondrial membrane potential and cytochrome c release
2 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA; University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA
3 Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA
Rajesh Agarwal, E-mail: Rajesh.Agarwal{at}UCHSC.edu
Abstract 
-Santalol, an active component of sandalwood oil, has been studied in detail in recent years for its skin cancer preventive efficacy in murine models of skin carcinogenesis; however, the mechanism of its efficacy is not defined. Two major biological events responsible for the clonal expansion of transformed/initiated cells into tumors are uncontrolled growth and loss of apoptotic death. Accordingly, in the present study, employing human epidermoid carcinoma A431 cells, we assessed whether -santalol causes cell growth inhibition and/or cell death by apoptosis. Treatment of cells with -santalol at 25-75 µM concentrations resulted in a concentration- and a time-dependent decrease in cell number, which was largely due to cell death. FACS analysis of Annexin V-PI stained cells revealed that -santalol induces a strong apoptosis as early as 3 hrs post-treatment, which increases further in a concentration- and a time-dependent manner up to 12 hrs. Mechanistic studies showed an involvement of caspase-3 activation and PARP cleavage through activation of upstream caspase-8 and -9. Further, -santalol treatment of cells also led to disruption of mitochondrial membrane potential and cytochrome-c release into the cytosol, thereby implicating the involvement of mitochondrial pathway. Pretreatment of cells with caspase-8 or -9 inhibitor, pan caspase inhibitor, or cycloheximide totally blocked -santalol-caused caspase-3 activity and cleavage, but only partially reversed apoptotic cell death. This suggests involvement of both caspase-dependent and -independent pathways, at least under caspase inhibiting conditions, in -santalol-caused apoptosis. Together, this study for the first time identifies apoptotic effect of -santalol, and defines the mechanism of apoptotic cascade activated by this agent in A431 cells, which might be contributing to its overall cancer preventive efficacy in mouse skin cancer models.-Santalol; skin cancer; apoptosis; caspases; cancer prevention.
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