Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Carcinogenesis. 2011 Jan;32(1):93-101. doi: 10.1093/carcin/bgq230. Epub 2010 Nov 2.
The chemopreventive potential of resveratrol is marred by its low bioavailability. Studies of modified resveratrol may reveal features that affect its bioefficacy and bioavailability. We compared the anti-proliferative and gene regulatory activities of resveratrol with trimethoxy-resveratrol and triacetyl-resveratrol using cultured human prostate cancer (CaP) cells. LNCaP cells were incubated with resveratrol and its analogues. Changes in proliferation, colony formation, cell cycle, apoptosis and prostate specific antigen (PSA) PSA were determined. DNA damage was assayed by phosphorylated-histone H2AX changes. Expression of total and serine-15-phosphorylated p53 and p53-inducible cell cycle regulatory protein p21 and ribonucleotide reductase subunit p53R2 involved in DNA repair were measured by immunobloting and reverse transcription-polymerase chain reaction. Exposure to resveratrol or triacetyl-resveratrol activated p53, increased p21 and p53R2 and decreased PSA expression in LNCaP cells. These changes were attenuated by the p53 inhibitor pifithrin-α. However, LNCaP cells exposed to trimethoxy-resveratrol showed induction of apoptosis, reduction in G₁ and prolongation of the SG₂M phases. Resveratrol and analogues were also studied in CWR22Rv1 (containing mutated p53) and p53-null PC-3 cells. CWR22Rv1 cells exposed to resveratrol and triacetyl-resveratrol showed a G₁S block, concomitant with increased p53 and p21 expression; however, identically treated PC-3 cells showed attenuated progression through the SG₂M phases. Trimethoxy-resveratrol did not affect CWR22Rv1 cell cycle but reduced and expanded PC-3 cells in the G₁ and SG₂M phases, respectively. These results suggest that triacetyl-resveratrol and trimethoxy-resveratrol are active against different stage CaP cells, using overlapping and distinct mechanisms.
白藜芦醇的化学预防潜力因其生物利用度低而受到影响。对修饰后的白藜芦醇的研究可能会揭示影响其生物功效和生物利用度的特征。我们使用培养的人前列腺癌细胞 (CaP) 比较了白藜芦醇及其类似物的抗增殖和基因调控活性。用白藜芦醇及其类似物孵育 LNCaP 细胞。测定增殖、集落形成、细胞周期、细胞凋亡和前列腺特异性抗原 (PSA) PSA 的变化。通过磷酸化组蛋白 H2AX 的变化测定 DNA 损伤。通过免疫印迹和逆转录-聚合酶链反应测量总和丝氨酸 15 磷酸化 p53 以及 p53 诱导的细胞周期调节蛋白 p21 和参与 DNA 修复的核苷酸还原酶亚基 p53R2 的表达。用 p53 抑制剂 pifithrin-α 处理后，白藜芦醇或三乙酰基白藜芦醇激活了 LNCaP 细胞中的 p53，增加了 p21 和 p53R2，并降低了 PSA 的表达。这些变化被 p53 抑制剂 pifithrin-α 减弱。然而，用三甲氧基白藜芦醇处理的 LNCaP 细胞显示出凋亡诱导、G₁ 减少和 SG₂M 期延长。还研究了白藜芦醇及其类似物在含有突变型 p53 的 CWR22Rv1 和 p53 缺失的 PC-3 细胞中的作用。用白藜芦醇和三乙酰基白藜芦醇处理 CWR22Rv1 细胞可导致 G₁S 阻滞，同时增加 p53 和 p21 的表达；然而，相同处理的 PC-3 细胞显示出 SG₂M 期进展减弱。三甲氧基白藜芦醇不会影响 CWR22Rv1 细胞周期，但会分别减少和扩大 G₁ 和 SG₂M 期的 PC-3 细胞。这些结果表明，三乙酰基白藜芦醇和三甲氧基白藜芦醇对不同阶段的 CaP 细胞具有活性，使用重叠和不同的机制。
