Procyanidin B2 3,3^″-di-O-gallate, a Biologically Active Constituent of Grape Seed Extract, Induces Apoptosis in Human Prostate Cancer Cells Via Targeting NF-κB, Stat3, and AP1 Transcription Factors

Abstract

Recently, we identified procyanidin B2 3,3″-di-O-gallate (B2G2) as most active constituent of grape seed extract (GSE) for efficacy against prostate cancer (PCa). Isolating large quantities of B2G2 from total GSE is labor intensive and expensive, thereby limiting both efficacy and mechanistic studies with this novel anti-cancer agent. Accordingly, here we synthesized gram-scale quantities of B2G2, compared it with B2G2 isolated from GSE for possible equivalent biological activity, and conducted mechanistic studies. Both B2G2 preparations inhibited cell growth, decreased clonogenicity, and induced cell cycle arrest and apoptotic death, comparable to each other, in various human PCa cell lines. Mechanistic studies focusing on transcription factors involved in apoptotic and survival pathways revealed that B2G2 significantly inhibits NF-κB and AP1 transcriptional activity and nuclear translocation of Stat3 in PCa cell lines, irrespective of their functional androgen receptor status. B2G2 also decreased survivin expression which is regulated by NF-κB, AP1 and Stat3, and increased cleaved PARP level. In summary, we report B2G2 chemical synthesis at gram-quantity with equivalent biological efficacy against human PCa cell lines and same molecular targeting profiles at key transcription factors level. The synthetic B2G2 will stimulate more research on prostate and possibly other malignancies in preclinical models and clinical translation.

Protective effects of a grape-supplemented diet in a mouse model of retinal degeneration

“…Specific polyphenol compounds found in grapes, including quercetin, procyanidin B2, resveratrol and epicatechin are bioactive, and can regulate apoptotic, oxidative stress and inflammatory pathways [23]. Molecular targets of grape-derived compounds include key pro-survival molecules, such as glycogen synthase kinase 3β (GSK3β) [24] and the transcription factor STAT3 [25], among many others. Interestingly, modulating both GSK3β and STAT3 has been shown to improve photoreceptor survival [26].…”

GATA4 promotes hepatoblastoma cell proliferation by altering expression of miR125b and DKK3

“…This deregulation of TFs contributes to tumor development by promoting the expression of oncogenic proteins and inhibiting tumor suppressor genes [9]. Many TFs, including STAT family members, serum response factors, NF-kB, and AP1, contribute to the development of various human cancers in this way, while the expression of many tumor suppressor proteins, such as GATA4 and Dickkopf-related proteins, is inhibited during carcinogenesis [10-12]. Despite recent progress in identifying the cellular events and mechanisms underlying the development of various liver cancers, the molecular mechanisms of HB development and progression have not been fully explored.…”

Procyanidin B2 3,3″-di-O-gallate Inhibits Endothelial Cells Growth and Motility by Targeting VEGFR2 and Integrin Signaling Pathways

“…Matrigel were procured from BD Biosciences (San Jose, CA). B2G2 was synthesized according to the method published recently [32]. B2G2 stock solution was prepared in DMSO and stored at −80°C.…”

“…In the present study, we evaluated the potential anti-angiogenic efficacy of one such phytochemical namely Procyanidin B2 3,3″-di-O-gallate (B2G2) (Fig 1A) in various established angiogenesis-related cell culture models. B2G2 has been identified by our laboratory as the most active constituent of grape seed extract (GSE), a naturally occurring dietary agent with proven potential against various malignancies including PCA [30–32]. Earlier, we have shown that B2G2 is effective against various PCA cells such as LNCaP, C4-2B, DU145 and PC-3 by causing growth inhibition and inducing apoptosis in these cells; however, its anti-angiogenic activity is still unknown [31, 32].…”

“…B2G2 has been identified by our laboratory as the most active constituent of grape seed extract (GSE), a naturally occurring dietary agent with proven potential against various malignancies including PCA [30–32]. Earlier, we have shown that B2G2 is effective against various PCA cells such as LNCaP, C4-2B, DU145 and PC-3 by causing growth inhibition and inducing apoptosis in these cells; however, its anti-angiogenic activity is still unknown [31, 32]. Our results suggest that B2G2 inhibits proliferation, capillary tube formation, motility and invasiveness of endothelial cells by inducing cell cycle arrest and apoptosis and by targeting VEGFR2/PI3K/Akt and Integrin signaling pathways, which indicate towards its strong and promising anti-angiogenic activity.…”