Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells
Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells
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DOI：
10.1007/s10637-008-9183-7
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发表时间：
2009-10-01
影响因子：
3.4
通讯作者：
Szekeres, Thomas
中科院分区：
文献类型：
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作者：
Bernhaus, Astrid;Ozsvar-Kozma, Maria;Szekeres, Thomas
由于缺乏早期诊断和肿瘤细胞对化疗的耐药性，胰腺癌是一种侵袭性很强的恶性疾病。有明确的证据表明，食物来源的多酚对包括胰腺癌在内的多种癌症的发展具有化学预防作用。白藜芦醇是在葡萄皮和其他具有已知抗癌活性的水果中发现的酚类化合物之一。各种多甲氧基化白藜芦醇衍生物在肿瘤细胞系中表现出比白藜芦醇更强的抗增殖作用。我们研究的目的是评估新合成的多甲氧基化白藜芦醇类似物 N-羟基-N'-(3,4,5-三甲氧基苯基)-3,4,5-三甲氧基苯甲脒 (KITC) 在两种人胰腺癌细胞系中的细胞毒性和生化作用。使用人胰腺癌细胞系 AsPC-1 和 BxPC-3 来测试白藜芦醇衍生物对细胞增殖的潜在抑制作用及其潜在机制。孵育7天后，KITC抑制AsPC-1和BxPC-3细胞的生长，IC50值分别为9.6和8.7μM。 KITC (40 μM) 将细胞阻滞于细胞周期的 G0/G1 期，并耗尽细胞周期的 S 期细胞（分别为对照的-105% 和 -35%）。 KITC 在两种胰腺癌细胞系中诱导剂量依赖性细胞凋亡，并被发现显着降低核糖核苷酸还原酶（DNA 合成的关键酶）的原位活性。采用生长抑制测定，KITC 与吉西他滨在两种细胞系中均发挥协同作用。总之，我们发现 KITC 对人类胰腺癌细胞具有相当大的抗肿瘤活性，并且可能成为进一步研究建立新化疗方案的有希望的候选者。
Pancreatic cancer is a very aggressive malignant disease due to lack of early diagnosis and chemotherapeutic resistance of the tumor cells. There is distinct evidence that food derived polyphenols possess chemopreventive effects in the development of several cancers including pancreatic carcinoma. Resveratrol is one of those phenolic compounds found in grape skins and other fruits with known anticancer activity. Various polymethoxylated resveratrol derivatives showed stronger antiproliferative effects than resveratrol in tumor cell lines. The aim of our study was to evaluate the cytotoxic and biochemical effects of a newly synthesized polymethoxylated resveratrol analogue, N-hydroxy-N'-(3,4,5-trimethoxphenyl)-3,4,5-trimethoxy-benzamidine (KITC) in two human pancreatic cancer cell lines. The human pancreatic cancer cell lines, AsPC-1 and BxPC-3 were used to test the potential inhibitory effect of the resveratrol derivative on cell proliferation and the underlying mechanisms of this effect. After 7 days of incubation, KITC inhibited the growth of AsPC-1 and BxPC-3 cells with IC50 values of 9.6 and 8.7 mu M, respectively. KITC (40 mu M) arrested cells in the G0/G1 phase and depleted cells in the S phase of the cell cycle (-105% and -35% of control, respectively). KITC induced dose-dependent apoptosis in both pancreatic cancer cell lines and was found to significantly reduce the in situ activity of ribonucleotide reductase, the key enzyme of DNA synthesis. Employing growth inhibition assays, KITC acted synergistically with gemcitabine in both cell lines. In summary, we found that KITC exerted considerable antitumor activity against human pancreatic cancer cells and could be a promising candidate for further investigations to establish a new chemotherapeutic regimen.