Department of Immunology, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
Oncol Rep. 2012 Apr;27(4):1245-50. doi: 10.3892/or.2012.1639. Epub 2012 Jan 16.
Sulindac, a non-steroidal anti-inflammatory drug, suppresses carcinogenesis and inhibits growth of tumor cells. Pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, has been also identified as a potential anti-neoplastic agent. We hypothesized that combination of sulindac and PDTC could result in augmentation of cytotoxicity against ovarian cancer cells. The effect of sulindac and PDTC was examined on several ovarian cancer lines. Tumor cell viability was assessed using the MTT assay. Annexin-V/PI staining was used to detect apoptosis, cell cycle distribution was analyzed in FACS, and expression of cellular proteins was detected by western blotting. Incubation of OVA-14, OVP-10 and CAOV-1 ovarian cancer cells with sulindac and PDTC resulted in significantly greater inhibition of cell viability compared to either compound alone. In a model of OVA-14 cells it was evident that this effect was not related to the expression of COX enzymes since both active (sulindac sulfide) and inactive (sulindac) in vitro compounds affected the growth of tumor cells to a similar extent and synergized in cytotoxicity with PDTC. Combination of sulindac and PDTC lead to G0 arrest and massive apoptosis in co-treated cultures. Western blotting analysis argued for induction of the mitochondrial apoptotic pathway. These data demonstrate the synergistic cytotoxic effect of sulindac and PDTC on ovarian cancer cells through apoptosis and cell cycle arrest and prompt to test the efficacy of this combination in animal models.
舒林酸是一种非甾体抗炎药，可抑制致癌作用并抑制肿瘤细胞生长。吡咯烷二硫代氨基甲酸盐（PDTC）是一种有效的 NF-κB 抑制剂，也被鉴定为一种有潜力的抗肿瘤药物。我们假设舒林酸和 PDTC 的联合使用可能会导致对卵巢癌细胞的细胞毒性增强。我们研究了舒林酸和 PDTC 对几种卵巢癌细胞系的影响。使用 MTT 测定法评估肿瘤细胞活力。通过 Annexin-V/PI 染色检测细胞凋亡，通过 FACS 分析细胞周期分布，通过 Western blot 检测细胞内蛋白的表达。用舒林酸和 PDTC 孵育 OVA-14、OVP-10 和 CAOV-1 卵巢癌细胞导致细胞活力的抑制明显大于任一化合物单独作用。在 OVA-14 细胞模型中，这一效应与 COX 酶的表达无关，因为体外的活性（舒林酸亚砜）和非活性（舒林酸）化合物对肿瘤细胞的生长有相似程度的影响，并与 PDTC 协同发挥细胞毒性。舒林酸和 PDTC 的联合使用导致共同处理培养物中的 G0 期停滞和大量细胞凋亡。Western blot 分析表明诱导了线粒体凋亡途径。这些数据表明舒林酸和 PDTC 对卵巢癌细胞具有协同的细胞毒性作用，通过细胞凋亡和细胞周期停滞来实现，并促使在动物模型中测试这种联合治疗的疗效。
