Journal Article

Skin cancer chemopreventive agent, α-santalol, induces apoptotic death of human epidermoid carcinoma A431 cells via caspase activation together with dissipation of mitochondrial membrane potential and cytochrome <i>c</i> release

Manjinder Kaur, Chapla Agarwal, Rana P. Singh, Xiangming Guan, Chandradhar Dwivedi and Rajesh Agarwal

in Carcinogenesis

Volume 26, issue 2, pages 369-380
Published in print February 2005 | ISSN: 0143-3334
Published online February 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh325
Skin cancer chemopreventive agent, α-santalol, induces apoptotic death of human epidermoid carcinoma A431 cells via caspase activation together with dissipation of mitochondrial membrane potential and cytochrome c release

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α-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 α-santalol causes cell growth inhibition and/or cell death by apoptosis. Treatment of cells with α-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 α-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 α-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 α-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 α-santalol-caused apoptosis. Together, this study for the first time identifies the apoptotic effect of α-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.

Keywords: CHX, cycloheximide; DEVD, Asp-Glu-Val-Asp; FACS, fluorescence-activated cell sorting; PARP, poly (ADP-ribose) polymerase; PI, propidium iodide; pNA, p-nitroanilide; Z-IETD.fmk, benzyloxylcarbonyl-Ile-Glu (Ome)-Thr-Asp(Ome)-fluoromethylketone; Z-LEHD.fmk, benzyloxylcarbonyl-Leu-Glu(Ome)-His-Asp(Ome)-fluoromethylketone; Z.VAD.fmk, benzyloxycarbonyl- Val-Ala-Asp-fluoromethylketone

Journal Article.  7434 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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