Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF.
Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF.
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DOI：
10.1158/0008-5472.can-09-4598
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Sarkar FH
中科院分区：
文献类型：
--
作者：
Ali S;Ahmad A;Banerjee S;Padhye S;Dominiak K;Schaffert JM;Wang Z;Philip PA;Sarkar FH
姜黄素在体外诱导肿瘤细胞生长停滞和凋亡，但其体内生物利用度低，限制了其抗肿瘤疗效。我们之前已经评估了姜黄素的新型类似物与姜黄素相比的生物利用度，我们发现类似物CDF表现出更大的全身和胰腺组织生物利用度。在这项研究中，我们评估了CDF或姜黄素单独或与吉西他滨联合对吉西他滨敏感和吉西他滨耐药胰腺癌（PC）细胞系的细胞活力和凋亡的影响。机制研究显示，与姜黄素处理的细胞相比，CDF处理的细胞活力显著降低，这也与诱导凋亡有关，这些结果与Akt、环氧合酶-2、前列腺素E2、血管内皮生长因子和NF-κB DNA结合活性的下调一致。我们还记录了相对于吉西他滨敏感细胞，吉西他滨耐药细胞中miR-200表达减弱和miR-21表达增加（肿瘤侵袭性的标志）。有趣的是，CDF处理上调miR-200的表达，下调miR-21的表达，并且miR-21的下调导致PTEN的诱导。这些结果促使人们进一步关注CDF作为一种药物形式，以改善诊断为PC的患者的治疗结果，因为它在胰腺组织中具有更高的生物利用度。
Curcumin induces cancer cell growth arrest and apoptosis in vitro, but its poor bioavailability in vivo limits its antitumor efficacy. We have previously evaluated the bioavailability of novel analogues of curcumin compared with curcumin, and we found that the analogue CDF exhibited greater systemic and pancreatic tissue bioavailability. In this study, we evaluated the effects of CDF or curcumin alone or in combination with gemcitabine on cell viability and apoptosis in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer (PC) cell lines. Mechanistic investigations revealed a significant reduction in cell viability in CDF-treated cells compared with curcumin-treated cells, which were also associated with the induction of apoptosis, and these results were consistent with the downregulation of Akt, cyclooxygenase-2, prostaglandin E2, vascular endothelial growth factor, and NF-κB DNA binding activity. We have also documented attenuated expression of miR-200 and increased expression of miR-21 (a signature of tumor aggressiveness) in gemcitabine-resistant cells relative to gemcitabine-sensitive cells. Interestingly, CDF treatment upregulated miR-200 expression and downregulated the expression of miR-21, and the downregulation of miR-21 resulted in the induction of PTEN. These results prompt further interest in CDF as a drug modality to improve treatment outcome of patients diagnosed with PC as a result of its greater bioavailability in pancreatic tissue.