Singh Chandra K, Chhabra Gagan, Ndiaye Mary A, Siddiqui Imtiaz A, Panackal Jennifer E, Mintie Charlotte A, Ahmad Nihal
Department of Dermatology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
William S. Middleton VA Medical Center, Madison, WI 53705, USA.
Cancers (Basel). 2020 Aug 2;12(8):2141. doi: 10.3390/cancers12082141.
Prostate Cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men. Therefore, novel mechanistically-driven approaches are needed for PCa management. Here, we determined the effects of grape antioxidants quercetin and/or resveratrol (60 and 600 mg/kg, respectively, in diet) against PCa in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP)-model in prevention and intervention settings. We found resveratrol alone and in combination significantly inhibited prostate tumorigenesis in prevention setting, while the same was seen only in combination after intervention. The observed effects were associated with marked inhibition in proliferation, oxidative stress, and tumor survival markers, and induced apoptosis markers. Utilizing PCa PCR array analysis with prevention tumor tissues, we identified that quercetin-resveratrol modulates genes involved in promoter methylation, cell cycle, apoptosis, fatty acid metabolism, transcription factors, androgen response, PI3K/AKT and PTEN signaling. Ingenuity Pathway Analysis (IPA) identified IGF1 and BCL2 as central players in two gene networks. Functional annotation predicted increased apoptosis and inhibited cell viability/proliferation, hyperplasia, vasculogenesis, and angiogenesis with dual treatment. Furthermore, IPA predicted upstream inhibition of major PCa signaling VEGF, Ca, PI3K, CSF2, PTH). Based on PCR array, we identified decreased levels of EGFR, EGR3, and IL6, and increased levels of IGFBP7 and NKX3.1, overall supporting anti-PCa effects of quercetin-resveratrol.
前列腺癌（PCa）是男性癌症相关发病和死亡的主要原因。因此，需要新的基于机制的方法来管理前列腺癌。在此，我们在预防和干预环境下，确定了葡萄抗氧化剂槲皮素和/或白藜芦醇（分别在饮食中为60和600mg/kg）对小鼠前列腺转基因腺癌（TRAMP）模型中前列腺癌的影响。我们发现，单独使用白藜芦醇及其组合在预防环境中显著抑制前列腺肿瘤发生，而在干预后仅在组合中观察到相同效果。观察到的效果与增殖、氧化应激和肿瘤存活标志物的显著抑制以及凋亡标志物的诱导有关。利用预防肿瘤组织进行前列腺癌PCR阵列分析，我们确定槲皮素-白藜芦醇调节参与启动子甲基化、细胞周期、凋亡、脂肪酸代谢、转录因子、雄激素反应、PI3K/AKT和PTEN信号传导的基因。 Ingenuity通路分析（IPA）确定IGF1和BCL2是两个基因网络中的核心参与者。功能注释预测双重治疗可增加凋亡并抑制细胞活力/增殖、增生、血管生成和血管发生。此外，IPA预测对主要前列腺癌信号VEGF、Ca、PI3K、CSF2、PTH的上游抑制。基于PCR阵列，我们确定EGFR、EGR3和IL6水平降低，IGFBP7和NKX3.1水平升高，总体上支持槲皮素-白藜芦醇的抗前列腺癌作用。
