Modulation of cancer signalling pathway(s) in two -stage mouse skin tumorigenesis by annonacin.

BACKGROUND: Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved. METHODS: Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 µL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 µL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin. RESULTS: With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis. CONCLUSIONS: Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.

Annona muricata leaves extracts prevent DMBA/TPA-induced skin tumorigenesis via modulating antioxidants enzymes system in ICR mice.

Annona muricata, locally known as soursop has been reported to exhibit antiproliferative activities against various cancer cell lines. In this current study, we have investigated the antitumor promotion of various fractions of Annona muricata leaves (AML); hexane (AMLH), dichloromethane (AMLD) and methanol (AMLM) fraction respectively on 7, 12-dimethylbenz[α]anthracene (DMBA) induced and 12-0-tetradecaboylphorbol-13-acetate (TPA) promoted skin tumorigenesis in mice via morphological assessment, biochemical analysis and histopathological evaluation. The results of the study revealed significant inhibition in tumor incidence, tumor burden and tumor volume in the groups received AMLH and AMLD, respectively, and suppressive effects in group received AMLM compared with carcinogen control group at week 21. Superoxide dismutase, catalase, and lipid peroxidation levels were returned to near normal by administration of AML to DMBA/TPA-induced mice. The above findings were supported by histopathological studies, in which the extensive epidermal hyperplasia in carcinogen control group was restored to normal in AML treated groups. Whilst, annonacin, a major annaonaceous acetogenin was found to be the highest in AMLH and AMLD. From the present study, it can be inferred that AML supressed DMBA/TPA-induced skin tumor and this antitumor-promoting activity may be linked to the antioxidant/free radical-scavenging constituents of the extract and annonacin contained in the extracts.