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

Abstract

We recently demonstrated that AKT activation plays a role in prostate cancer progression and inhibits the pro-apoptotic function of FOXO3a and Par-4. AKT inhibition and Par-4 induction suppressed prostate cancer progression in preclinical models. Here, we investigate the chemopreventive effect of the phytonutrient Withaferin A (WA) on AKT-driven prostate tumorigenesis in a Pten conditional knockout (Pten-KO) mouse model of prostate cancer. Oral WA treatment was carried out at two different doses (3 and 5 mg/kg) and compared to vehicle over 45 weeks. Oral administration of WA for 45 weeks effectively inhibited primary tumor growth in comparison to vehicle controls. Pathological analysis showed the complete absence of metastatic lesions in organs from WA-treated mice, whereas discrete metastasis to the lungs was observed in control tumors. Immunohistochemical analysis revealed the down-regulation of pAKT expression and epithelial-to-mesenchymal transition markers, such as β-catenin and N-cadherin, in WA-treated tumors in comparison to controls. This result corroborates our previous findings from both cell culture and xenograft models of prostate cancer. Our findings demonstrate that the daily administration of a phytonutrient that targets AKT activation provides a safe and effective treatment for prostate cancer in a mouse model with strong potential for translation to human disease.

Withania Somnifera (Ashwagandha) and Withaferin A: Potential in Integrative Oncology

“…Oral administration of WFA with a dose of 3–5 mg/kg inhibited the activation of Akt and facilitated the FOXO3a-(Forkhead box O3a) mediated activation of Par-4 (prostate apoptosis response-4) leading to delayed tumor progression in preclinical prostate cancer models. Thus, WFA has been effective in up-regulating Par-4 and FOXO3a proteins (PI3K/Akt pathway regulated) in Pten -KO mice with a promising outcome for patients with Akt-activating mutations [83,84].…”

Cytoprotective autophagy induction by withaferin A in prostate cancer cells involves GABARAPL1

“…We reported recently that WA treatment suppresses fatty acid metabolism in LNCaP and 22Rv1 cells in vitro and neoplastic cells of the prostate in vivo in Hi‐Myc transgenic mice 20 . Collectively, these studies demonstrate therapeutic as well as chemopreventative potential of WA with no toxicity to normal cells in vitro or in vivo 16‐18 . These studies suggest that it may be worthwhile to investigate the mechanisms underlying anticancer effect of WA.…”

“…Inhibition of prostate cancer cell viability in the presence of WA is also associated with cell cycle arrest 15 . Two studies showed chemoprevention of prostate cancer development in TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) and PTEN‐deleted transgenic mouse models 16,17 . One of the desired characteristics of potential chemopreventive interventions is cancer cell‐selective mechanisms.…”

Withania somnifera root extract inhibits fatty acid synthesis in prostate cancer cells

“…In this context, however, it is important to point out that withaferin A has been shown to inhibit growth of xenografted human prostate cancer cells in immune compromised mice as well as prevent prostate cancer development in transgenic mouse models. 33 , 34 , 35 …”