Therapeutic Potential of Gnetin C in Prostate Cancer: A Pre-Clinical Study

Abstract

Natural stilbenes have gained significant attention in the scientific community owing to their potential anticancer effects against prostate cancer. We recently reported that Gnetin C, a resveratrol (Res) dimer, demonstrated more potent inhibition of metastasis-associated protein 1/v-ets avian erythroblastosis virus E26 oncogene homolog 2 (MTA1/ETS2) axis in prostate cancer cell lines than other stilbenes. In this study, we investigated in vivo antitumor effects of Gnetin C in two doses (50 and 25 mg/kg, i.p.) using PC3M-Luc subcutaneous xenografts and compared these to Res and pterostilbene (Pter). We found that while vehicle-treated mice revealed rapid tumor progression, compounds-treated mice showed noticeable delay in tumor growth. Gnetin C in 50 mg/kg dose demonstrated the most potent tumor inhibitory effects. Gnetin C in 25 mg/kg dose exhibited tumor inhibitory effects comparable with Pter in 50 mg/kg dose. Consistent with the effective antitumor effects, Gnetin C-treated tumors showed reduced mitotic activity and angiogenesis and a significant increase in apoptosis compared to all the other groups. The data suggest that Gnetin C is more potent in slowing tumor progression in prostate cancer xenografts than Res or Pter. Taken together, we demonstrated, for the first time, that Gnetin C is a lead compound among stilbenes for effectively blocking prostate cancer progression in vivo.

Dietary stilbenes as modulators of specific miRNAs in prostate cancer

“…The inhibitory effects of resveratrol and pterostilbene on MTA1-mediated angiogenesis involving HIF-1a, VEGF, and IL-1β were also consistently reported (Kai et al, 2011;Li et al, 2013;Dhar et al, 2016;Butt et al, 2017;Hemani et al, 2022). We have also shown the MTA1-mediated and MTA1 independent chemopreventive and therapeutic value of Gnetin C in prostate cancer in vitro and in vivo (Kumar et al, 2019;Gadkari et al, 2020). Importantly, stilbenes can inhibit MTA1-associated oncogenic miRNAs (Figure 3).…”

“…Nutritional interception in intermediate- and high-risk active surveillance patients should target specific molecular pathways. Particularly, our group has shown that natural dietary stilbenes exhibit targeted chemoprotective, interceptive and therapeutic effects against prostate cancer in vitro and in vivo ( Kai et al, 2010 ; Li et al, 2013 ; Dhar et al, 2016 ; Butt et al, 2017 ; Kumar et al, 2019 ; Gadkari et al, 2020 ; Levenson, 2020 ; Hemani et al, 2022 ). This review will focus on the potential of natural stilbenes to protect against prostate cancer through the modulation of specific miRNAs that can conceivably be detected in bloodstream and urine and serve as prognostic and predictive biomarkers for certain populations of prostate cancer patients in the future.…”

“…Moreover, a recent report demonstrated potent anti-angiogenic effect of astringin as well as of resveratrol dimers ε-viniferin, ω-viniferin, and pallidol (C 28 H 22 O 6 ), also concentrated in grapes and red wine ( Fernandez-Cruz et al, 2019 ). Gnetin C (C 28 H 22 O 6 ), a resveratrol dimer found in melinjo ( Gnetum gnemon ) seed extracts that are commonly used in Indonesian cuisine, possesses a broad spectrum of the same pharmacological activities as other stilbenes with the advantage of superior bioavailability and biological efficacy ( Narayanan et al, 2015 ; Kumar et al, 2019 ; Gadkari et al, 2020 ). Chemopreventive effects of dietary stilbenes are mainly due to their anti-inflammatory and antioxidant activity but also direct targeting of multiple signaling pathways involved in carcinogenesis, cancer progression and metastasis.…”

Gnetin C Intercepts MTA1-Associated Neoplastic Progression in Prostate Cancer

“…We have recently reported that a pterostilbene-supplemented diet exerted beneficial effects by diminishing inflammatory pathways and accelerated PIN progression in R26 MTA1 ; Pten +/f mice [ 27 ]. Since we have also previously demonstrated the more potent MTA1-targeted inhibitory activity of gnetin C, a dimer resveratrol ( Figure 1 A), compared to resveratrol and pterostilbene, both in vitro and in prostate cancer xenografts [ 31 , 35 ], we sought to determine the efficacy of gnetin C in an adequate preclinical model of prostate cancer.…”

Molecular Mechanisms and Animal Models of HBV-Related Hepatocellular Carcinoma: With Emphasis on Metastatic Tumor Antigen 1

“…Moreover, MTA1 is gradually perceived to be a new target candidate for cancer drug treatment. Recently, MTA1-targeted chemopreventive agents for cancer therapy have been continuously developed and studied [175][176][177]. For instance, natural compound resveratrol and its analog pterostilbene have been recognized as the potent inhibitors for MTA1 and MTA1-guided signaling [178][179][180].…”