ABSTRACT
Chemoprevention by medicinal plants has evolved as a practical strategy to control the incidence of cancer. Azadirachta indica (neem) containing various bioactive components is a promising candidate for chemoprevention. The present study was undertaken to evaluate the chemopreventive efficacy of the bioactive subfractions ethyl acetate chloroform insoluble fraction (ECIF) and the methanol ethyl acetate insoluble fraction (MEIF) following activity-guided fractionation of neem leaf extract. Analysis of the mechanism of chemoprevention revealed multitargeted mode of action that involved modulation of xenobiotic-metabolizing enzymes, inhibition of cell proliferation, induction of mitochondrial apoptosis, and abrogation of NF-κB signaling. HP-TLC, GC-MS and LC-MS analyses indicated the presence of several polar phytochemical entities in the neem leaf subfractions that might be responsible for their potent chemopreventive efficacy.
Subject(s)
Antineoplastic Agents/pharmacology , Azadirachta/chemistry , Disease Models, Animal , Enzymes/metabolism , Neoplasms/drug therapy , Plant Extracts/pharmacology , Plant Leaves/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Apoptosis/drug effects , Body Weight/drug effects , Cell Proliferation/drug effects , Chemistry, Physical , Chemoprevention , Cricetinae , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Molecular Structure , Neoplasms/pathology , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
BACKGROUND: Chlorophyllin, a water soluble semi-synthetic food-grade derivative is reported to exhibit a wide range of beneficial health effects. We investigated the effect of chlorophyllin supplementation on Wnt/ß-catenin and vascular endothelial growth factor (VEGF) signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model. METHODS AND RESULTS: Hamsters were divided into 4 groups. The right buccal pouches of group 1 and 2 hamsters were painted with 0.5 % DMBA for 14 weeks. Group 2 animals received in addition chlorophyllin (4 mg/kg bw) in the diet. Group 3 animals received chlorophyllin alone and group 4 animals served as control. mRNA and protein expression of components of Wnt, VEGF, and PI3K/Akt signaling pathways were analyzed by RT-PCR and Western blot analysis. Dietary chlorophyllin administration suppressed the development of HBP carcinomas by altering the expression of several components of the Wnt/ß-catenin signaling pathway. This was associated with inhibition of angiogenesis as evidenced by decreased expression of the proangiogenic factors HIF-1α, VEGF, and VEGFR2. Chlorophyllin administration also downregulated the expression of histone deacetylases involved in epigenetic regulation of tumor angiogenesis. CONCLUSION: Dietary chlorophyllin that abrogates Wnt/ß-catenin and VEGF signaling by targeting a multitude of key signaling molecules is an attractive candidate for preventing tumor progression.
