rehmannic-acid and Skin-Neoplasms

The C-2 arylidene analog (compound 3) of pentacyclic triterpenoid Lantadene A (compound 1) was synthesized and evaluated by the National Cancer Institute, USA, for in vitro cytotoxicity against a panel of melanoma cancer cell lines: LOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257 UACC-62 and B16F10. Compound 3 showed enhanced cytotoxicity compared with compound 1 and the standard drug cisplatin. At the same time, compound 3 showed selective toxicity toward cancer cells and was inactive (i.e., nontoxic) against normal cells (VERO). Compound 3 induced sub-G1 cell cycle arrest and apoptosis in B16F10 cells by down-regulating NF-κB, c-jun, Bcl-2, and by activating caspase-3 and Bax expression. Compound 3 also demonstrated beneficial effects in a clinically relevant B16F10 allograft mice model, with significant reduction of tumor growth/tumor weight in vivo. Compound 3 improved the survival rate in comparison to the control group and the cisplatin group. At the same time, compound 3 had a better safety profile than cisplatin in terms of hematological parameters and liver enzyme levels.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Cycle; Cell Line, Tumor; Cells, Cultured; Chlorocebus aethiops; Disease Models, Animal; DNA Fragmentation; In Vitro Techniques; Male; Melanoma; Mice; Mice, Inbred C57BL; NF-kappa B; Oleanolic Acid; Pentacyclic Triterpenes; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-jun; Skin Neoplasms; Survival Rate; Transplantation, Homologous; Vero Cells

Lantadenes are pentacyclic triterpenoids isolated from leaves of Lantana camara L. and have antitumor activity. Lantadene A (LA) and methyl ester of LA (LAM) were earlier studied in the author's lab for their chemopreventive effect on 7,12-dimethylbenz(a)anthracene (DMBA) followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) induced squamous cell carcinoma incidence in Swiss albino mice. The present study was specially designed to initiate the involvement of the molecular targets in chemopreventive activity of these compounds. Skin lesions were induced by twice-weekly topical application of DMBA (100 nmol/100 microl of acetone) for 2 weeks followed by TPA (1.7 nmol/100 microl of acetone) on depilated back of mice for 20 weeks. LA and LAM were administered orally at a dose of 50 mg/kg body weight twice weekly, 1 week before DMBA application and continued for 20 weeks thereafter. A significant decrease in the incidence of number of lesions in mice was obtained in LA/LAM treated groups as compared to DMBA/TPA alone. Significant increase in the protein levels of c-jun, p65, and p53 by ELISA were observed in DMBA/TPA treated mice tumors whereas less expression was observed in LA and LAM treated tumors. Further immunohistochemical localization of transcription factors was studied which also showed less localization of c-jun, p65, and p53 in LA and LAM treated tumors as compared to localization in DMBA/TPA treated tumors. It can be inferred that LA and LAM chemopreventive activity may be linked to the deregulation of above molecular targets which warrants further studies in that direction.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Carcinogens; Cell Transformation, Neoplastic; Cytoprotection; Enzyme-Linked Immunosorbent Assay; Esters; Female; Immunohistochemistry; Mice; NF-kappa B; Oleanolic Acid; Papilloma; Skin Neoplasms; Tissue Distribution; Transcription Factor AP-1; Tumor Suppressor Protein p53