Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model

Abstract

We previously reported that withaferin A (WA), a natural compound, deters prostate cancer by inhibiting AKT while inducing apoptosis. In the current study, we examined its chemopreventive efficacy against carcinogenesis in the prostate using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Two distinct sets of experiments were conducted. To determine whether WA delays tumor progression, it was given before cancer onset, at week 6, and until week 44. To determine its effect after the onset of prostate cancer, it was given from weeks 12 to 35. In both strategies, oral administration of WA effectively suppressed tumor burden when compared to vehicle-treated animals. No toxicity was seen in treated animals at gross pathological examination. Western blot analysis and immunohistochemistry of tumor sections revealed that in TRAMP controls, AKT and pAKT were highly expressed while nuclear FOXO3a and Par-4 were downregulated. On the contrary, treated mice showed inhibition of AKT signaling and activation of FOX03a-Par-4-induced cell death. They also displayed inhibition of mesenchymal markers such as β-catenin, vimentin, and snail as well as upregulation of E-cadherin. Because expressions of the angiogenic markers factor VIII and retic were downregulated, an anti-angiogenic role of WA is suggested. Overall, our results suggest that WA could be a promising anti-cancer agent that effectively inhibits carcinogenesis of the prostate.

Withaferin A Inhibits Prostate Carcinogenesis in a PTEN-deficient Mouse Model of Prostate Cancer

“…Recent studies in our laboratory demonstrated the therapeutic efficacy of WA against CaP in mouse models of the disease [39], [40], [41]. In the present study, our objective was to evaluate the efficacy of WA chemoprevention in the Pten conditional knockout mouse Pten-loxp/loxp:PB-Cre4 + (Pten-KO) model, since AKT serves as the primary target for PTEN-mediated signaling.…”

Peptidyl‐prolyl cis/trans isomerase Pin1 regulates withaferin A‐mediated cell cycle arrest in human breast cancer cells

“…Cancer chemopreventive effect of WA has been demonstrated in preclinical rodent models of breast and other cancers . For example, the incidence of 7,12‐dimethylbenz[ a ]anthracene‐induced oral cancer in hamsters was completely inhibited by oral administration of 20 mg WA/kg body for 14 weeks .…”

“…For example, the incidence of 7,12‐dimethylbenz[ a ]anthracene‐induced oral cancer in hamsters was completely inhibited by oral administration of 20 mg WA/kg body for 14 weeks . Oral administration of WA (3 and 5 mg/kg body weight) was also effective for prevention of prostate cancer development in a transgenic mouse model . Experimental evidence for chemopreventive efficacy of WA against breast cancer was provided by our research group .…”

Withaferin a synergistically enhances the effects of paclitaxel against lung cancer.

“…The Gupta lab group at the University of Louisville, among other projects, is focused on developing WFA into a useful therapeutic agent for the management of lung cancer. Building on hypotheses based on previous findings in this and other laboratories, WFA has shown excellent efficacy and potency against various cancers -lung [32][33][34], cervical [35], prostate [36], breast [37][38][39], ovarian [40] and pancreatic in vitro and in vivo. In the present study, a simple but effective strategy of combining WFA with paclitaxel against the proliferation, migration, and invasion of two human NSCLC cells was explored.…”

“…Similarly, another independent study in WFA [3 or 5 mg/kg] was administered orally to transgenic mice for 39 weeks, there was significant inhibition of tumorigenesis and metastasis of prostate adenocarcinoma [36]. In cervical cancer, data from in vitro and in vivo experiments indicates the inhibition of human papillomavirus oncogenes E6/E7 coupled with induction of p53, the tumor suppressor protein [34].…”