580 South Preston Street, Delia Baxter II, Room 304E, University of Louisville, Louisville, KY 40202.
Cancer Prev Res (Phila). 2014 Apr;7(4):456-65. doi: 10.1158/1940-6207.CAPR-13-0248. Epub 2014 Feb 5.
Curcumin is widely known for its antioxidant, anti-inflammatory, and antiproliferative activities in cell-culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvent oral bioavailability issues, and tested their potential against 17β-estradiol (E2)-mediated mammary tumorigenesis. Female Augustus Copenhagen Irish (ACI) rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2 cm; 200 mg each; 20% drug load) 4 days before grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Curcumin implants were changed after 4.5 months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months, and after the tumor incidence reached >80% (~6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2 ± 1 vs. 5 ± 3; P = 0.001) and tumor volume (184 ± 198 mm(3) vs. 280 ± 141 mm(3); P = 0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity, whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in the presence of E2. Because CYP1A and CYP3A4 metabolize most of the E2 to its noncarcinogenic 2-OH metabolite, and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by high-performance liquid chromatography showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered.
姜黄素在细胞培养研究中因其抗氧化、抗炎和抗增殖活性而广为人知。然而，较差的口服生物利用度限制了其在动物和临床研究中的疗效。最近，我们开发了聚合物姜黄素植入物，以规避口服生物利用度问题，并测试其对 17β-雌二醇（E2）介导的乳腺肿瘤发生的潜在作用。雌性奥古斯都哥本哈根爱尔兰（ACI）大鼠在皮下植入 E2 硅酮植入物（1.2 cm，9 mg E2）前 4 天通过饮食（1000 ppm）或聚合物姜黄素植入物（两个 2 cm；200 mg 各；20%药物负荷）给予姜黄素。在可触及肿瘤出现后 4.5 个月更换姜黄素植入物，以提供更高的姜黄素剂量。在对照动物的肿瘤发病率达到>80%（约 6 个月）后，动物被安乐死。植入物给予的姜黄素导致肿瘤多发性（2±1 与 5±3；P=0.001）和肿瘤体积（184±198 mm3 与 280±141 mm3；P=0.0283）均显著减少；然而，饮食中的姜黄素无效。饮食中的姜黄素增加了肝 CYP1A 和 CYP1B1 的活性，而对 CYP3A4 活性没有影响，而姜黄素植入物在存在 E2 的情况下增加了 CYP1A 和 CYP3A4 的活性，但降低了 CYP1B1 的活性。因为 CYP1A 和 CYP3A4 将大部分 E2 代谢为其非致癌的 2-OH 代谢物，而 CYP1B1 产生潜在致癌的 4-OH 代谢物，通过系统给予姜黄素对这些 CYP 的有利调节可能是潜在机制之一。高效液相色谱法对血浆和肝脏的分析表明，尽管给予的剂量明显较高，但通过植入物给药的姜黄素水平明显高于饮食途径。
