Silibinin inhibits hypoxia‐induced HIF‐1α‐mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics

Abstract

Hypoxia is associated with aggressive phenotype and poor prognosis in prostate cancer (PCa) patients suggesting that PCa growth and progression could be controlled via targeting hypoxia-induced signaling and biological effects. Here, we analyzed silibinin (a natural flavonoid) efficacy to target cell growth, angiogenesis and metabolic changes in human PCa, LNCaP and 22Rv1 cells under hypoxic condition. Silibinin treatment inhibited the proliferation, clonogenicity and endothelial cells tube formation by hypoxic (1% O2) PCa cells. Interestingly, hypoxia promoted a lipogenic phenotype in PCa cells via activating acetyl-Co A carboxylase (ACC) and fatty acid synthase (FASN) that was inhibited by silibinin treatment. Importantly, silibinin treatment strongly decreased hypoxia-induced HIF-1α expression in PCa cells together with a strong reduction in hypoxia-induced NADPH oxidase (NOX) activity. HIF-1α overexpression in LNCaP cells significantly increased the lipid accumulation and NOX activity; however, silibinin treatment reduced HIF-1α expression, lipid levels, clonogenicity and NOX activity even in HIF-1α overexpressing LNCaP cells. In vivo, silibinin feeding (200 mg/kg body weight) to male nude mice with 22Rv1 tumors, specifically inhibited tumor vascularity (measured by dynamic contrast-enhanced MRI) resulting in tumor growth inhibition without directly inducing necrosis (as revealed by diffusion-weighted MRI). Silibinin feeding did not significantly affect tumor glucose uptake measured by FDG-PET; however, reduced the lipid synthesis measured by quantitative 1H-NMR metabolomics. IHC analyses of tumor tissues confirmed that silibinin feeding decreased proliferation and angiogenesis as well as reduced HIF-1α, FASN and ACC levels. Together, these findings further support silibinin usefulness against PCa through inhibiting hypoxia-induced signaling.

Apparent diffusion coefficients in prostate cancer: correlation with molecular markers Ki‐67, HIF‐1α and VEGF

“…High HIF‐1α expression has been shown to be associated with metastasis, resistance to radiotherapy, castration resistance, chemoresistance and biochemical recurrence in patients with PCa . Many HIF‐1α inhibitors have been developed and used to improve treatment success . To date, there are no non‐invasive methods to assess the expression of HIF‐1α in PCa, and no data investigating the relationship between HIF‐1α expression and GS.…”

“…In comparison with these biomarkers, nuclcar‐associated antigen Ki‐67 (Ki‐67), hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) can reflect the biological activity of certain tumor cells in specific regions. Recently, Ki‐67, HIF‐1α and VEGF have been used as prognostic biomarkers for the prediction of aggressiveness, prognosis and overall survival rate in patients with PCa . Previous studies have shown that Ki‐67 and/or VEGF are associated with the grade of tumor in PCa, astrocytomas and oligodendrogliomas, and osteosarcoma …”

“…In PCa, it has been demonstrated that a high level of HIF‐1α is associated with poor patient prognosis and an aggressive tumor phenotype . HIF‐1α inhibitors have been identified and have been shown to have anti‐cancer effects in PCa . Angiogenesis is essential in tumor growth and is one of the hallmarks of cancer, and the VEGF family plays a vital role in promoting tumor angiogenesis .…”

Silymarin antiproliferative and apoptotic effects: Insights into its clinical impact in various types of cancer

“…In an in vivo study, an oral treatment with silibinin in male nude mice with 22Rv1 tumors inhibited tumor vascularity and, thus, tumor growth without directly inducing necrosis. In addition, feeding with silibinin resulted in a reduction of proliferation and angiogenesis and on the levels of HIF‐1α, fatty acid synthase, and acetyl‐Co A carboxylase (Deep et al, ).…”

Developing a High-Performance Liquid Chromatography Fast and Accurate Method for Quantification of Silibinin In-Vitro

“…In some investigations, Silibinin decreases micro-vessel density in prostate carcinoma tumors by decreasing VEGF expression. Others found that Silibinin targeted the onset of angiogenesis in prostate cancer and inhibited signaling originated by HIF-1α (13,14). In terms of colorectal cancers, Silibinin also inhibited angiogenesis through a decrease in expression and production of VEGF, HIF-1α، COX2, and iNOS (15).…”