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

Abstract

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.

Corilagin induces apoptosis and inhibits HMBG1/PI3K/AKT signaling pathways in a rat model of gastric carcinogenesis induced by methylnitronitrosoguanidine

“…In the current hypothesis demonstrated that administration of corilagin effectively inhibited the advancement of MNNG‐induced gastric cancer animal models resulting in its anticancer effects toward it as reported in the literatures 31 . The generous loss of weight noted in cancer‐induced rats could be due to the cancer anorexia, malabsorption or cachexia which results to the continuous waste in the adipose tissues and skeletal muscles 23 .…”

“…cancer animal models resulting in its anticancer effects toward it as reported in the literatures. 31 The generous loss of weight noted in cancer-induced rats could be due to the cancer anorexia, malabsorption or cachexia which results to the continuous waste in the adipose tissues and skeletal muscles. 23 The occurred tissue wasting and weight loss is because of the short-living time and poor prognosis.…”

An Overview of the Chemical Characteristics, Bioactivity and Achievements Regarding the Therapeutic Usage of Acetogenins from Annona cherimola Mill.

“…Other research by Roduan et al demonstrated that the application of annonacin at 85 nM significantly reduced tumor incidence as well as volume in a two-stage mouse skin tumorigenesis model. Annonacin also appeared to be non-toxic to liver and kidney, which suggests its potential as a therapeutic compound for the prevention and treatment of skin cancer [ 46 ]. Wang et al administered 10 mg/kg of annonacin orally to in vivo hybrid mice (BDF-1) models and successfully inhibit lung cancer by 57.9% [ 47 ].…”

Current Situation and Perspectives of Fruit Annonaceae in Mexico: Biological and Agronomic Importance and Bioactive Properties

“…Cytotoxic activity has been studied in fruit, leaves, root, and stem bark extracts or isolated acetogenins of some Annona species ( Table 4 ). Annonacin at a very low dose (extracted from A. muricata leaves) decreased the induced-tumors on mice [ 147 , 148 ]; moreover, acetogenins have a potent cytotoxicity against many cancer cell lines (DU-145, A-549, MCF-7, HT-29, A-498, PC-3, HL60, HCT, Caco-2, and HepG-2) [ 88 , 96 , 119 , 137 , 143 , 149 , 150 , 151 , 152 ]. The mechanism of action of acetogenins on cancer cell lines or in vivo cancer models is attributed to inhibition mitochondrial complex I (ubiquinone-linked NADH oxidase) to present in cell membranes; the ATP decrease cause apoptosis [ 123 ].…”