Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis.
OBJECTIVE
To unravel the molecular mechanisms underlying the chemopreventive potential of [6]-gingerol, a pungent ingredient of ginger rhizome (Zingiber officinale Roscoe, Zingiberaceae), against benzo[a]pyrene (B[a]P)-induced mouse skin tumorigenesis.


METHODS
Topical treatment of [6]-gingerol (2.5 muM/animal) was given to the animals 30 min prior and post to B[a]P (5 mug/animal) for 32 weeks. At the end of the study period, the skin tumors/tissues were dissected out and examined histopathologically. Flow cytometry was employed for cell cycle analysis. Further immunohistochemical localization of p53 and regulation of related apoptogenic proteins were determined by Western blotting.


RESULTS
Chemopreventive properties of [6]-gingerol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Cell cycle analysis revealed that the appearance of sub-G1 peak was significantly elevated in [6]-gingerol treated animals with post treatment showing higher efficacy in preventing tumorigenesis induced by B[a]P. Moreover, elevated apoptotic propensity was observed in tumor tissues than the corresponding non-tumor tissues. Western blot analysis also showed the same pattern of chemoprevention with [6]-gingerol treatment increasing the B[a]P suppressed p53 levels, also evident by immunohistochemistry, and Bax while decreasing the expression of Bcl-2 and Survivin. Further, [6]-gingerol treatment resulted in release of Cytochrome c, Caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction.


CONCLUSIONS
On the basis of the results we conclude that [6]-gingerol possesses apoptotic potential in mouse skin tumors as mechanism of chemoprevention hence deserves further investigation.
Nigam
Nidhi
N
Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR), M.G. Marg, P.O. Box 80, Lucknow 226001, India.
George
Jasmine
J
Srivastava
Smita
S
Roy
Preeti
P
Bhui
Kulpreet
K
Singh
Madhulika
M
Shukla
Yogeshwer
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001564:Benzo(a)pyrene; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D005233:Fatty Alcohols / Q000494:pharmacology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000077022:Survivin; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; C117749:Birc5 protein, mouse; D002396:Catechols; D005233:Fatty Alcohols; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D001564:Benzo(a)pyrene; D045304:Cytochromes c; C007845:gingerol; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases