Carcinogenesis Advance Access originally published online on November 4, 2004
Carcinogenesis 2005 26(2):369-380; doi:10.1093/carcin/bgh325
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis vol.26 no.2 © Oxford University Press 2005; all rights reserved.
ARTICLE |
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
1 Department of Pharmaceutical Sciences, School of Pharmacy, 2 University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA and 3 Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA
* To whom correspondence should be addressed Email: rajesh.agarwal{at}uchsc.edu
-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 concentrations of 25–75 µM resulted in a concentration- and a time-dependent decrease in cell number, which was largely due to cell death. Fluorescence-activated cell sorting analysis of Annexin V/propidium iodide (PI) stained cells revealed that -santalol induces a strong apoptosis as early as 3 h post-treatment, which increases further in a concentration- and a time-dependent manner up to 12 h. Mechanistic studies showed an involvement of caspase-3 activation and poly(ADP-ribose) polymerase cleavage through activation of upstream caspase-8 and -9. Further, the treatment of cells with -santalol also led to disruption of the mitochondrial membrane potential and cytochrome c release into the cytosol, thereby implicating the involvement of the mitochondrial pathway. Pre-treatment 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 the 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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Dwivedi, H. B. Valluri, X. Guan, and R. Agarwal Chemopreventive effects of {alpha}-santalol on ultraviolet B radiation-induced skin tumor development in SKH-1 hairless mice Carcinogenesis, September 1, 2006; 27(9): 1917 - 1922. [Abstract] [Full Text] [PDF]
|
|