Appari Mahesh, Babu Kamesh R, Kaczorowski Adam, Gross Wolfgang, Herr Ingrid
Molecular Oncosurgery, University Clinic of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University of Heidelberg, Heidelberg, Germany.
Int J Oncol. 2014 Oct;45(4):1391-400. doi: 10.3892/ijo.2014.2539. Epub 2014 Jul 8.
Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all malignancies, and current therapeutic options do not target cancer stem cells (CSCs), which may be the reason for the extreme aggressiveness. The dietary agents sulforaphane and quercetin enriched e.g., in broccoli, and the main and best studied green tea catechin EGCG hold promise as anti-CSC agents in PDA. We examined the efficacy of additional catechins and the combination of these bioactive agents to stem cell features and miRNA signaling. Two established and one primary PDA cell line and non-malignant pancreatic ductal cells were used. Whereas each agent strongly inhibited colony formation, the catechins ECG and CG were more effective than EGCG. A mixture of green tea catechins (GTCs) significantly inhibited viability, migration, expression of MMP-2 and -9, ALDH1 activity, colony and spheroid formation and induced apoptosis, but the combination of GTCs with sulforaphane or quercetin was superior. Following treatment with bioactive agents, the expression of miR-let7-a was specifically induced in cancer cells but not in normal cells and it was associated with K-ras inhibition. These data demonstrate that sulforaphane, quercetin and GTC complement each other in inhibition of PDA progression by induction of miR-let7-a and inhibition of K-ras.
胰腺导管腺癌（PDA）在所有恶性肿瘤中预后最差，目前的治疗方案并未针对癌症干细胞（CSC），而这可能是其极具侵袭性的原因。膳食因子萝卜硫素和槲皮素在西兰花等食物中含量丰富，而主要且研究最多的绿茶儿茶素表没食子儿茶素没食子酸酯（EGCG）有望成为PDA的抗CSC药物。我们研究了其他儿茶素以及这些生物活性药物组合对干细胞特征和miRNA信号传导的影响。使用了两种已建立的和一种原发性PDA细胞系以及非恶性胰腺导管细胞。虽然每种药物都强烈抑制集落形成，但儿茶素表儿茶素（ECG）和儿茶素（CG）比EGCG更有效。绿茶儿茶素混合物（GTCs）显著抑制细胞活力、迁移、基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）的表达、乙醛脱氢酶1（ALDH1）活性、集落和球体形成并诱导凋亡，但GTCs与萝卜硫素或槲皮素的组合效果更佳。在用生物活性药物处理后，miR-let7-a的表达在癌细胞中被特异性诱导，但在正常细胞中未被诱导，并且它与K-ras抑制相关。这些数据表明，萝卜硫素、槲皮素和GTCs通过诱导miR-let7-a和抑制K-ras在抑制PDA进展方面相互补充。
