Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: a paradigm of synergistic molecular targeting treatment for ovarian cancer.
Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: a paradigm of synergistic molecular targeting treatment for ovarian cancer.
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DOI：
10.1186/1756-9966-29-102
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发表时间：
2010-07-30
期刊：
影响因子：
--
通讯作者：
Uslu R
中科院分区：
文献类型：
--
作者：
Karabulut B;Karaca B;Varol U;Muslu U;Cakar B;Atmaca H;Kisim A;Uzunoglu S;Uslu R
卵巢癌是世界上最致命的妇科恶性肿瘤。虽然铂类药物治疗被广泛使用，但该疾病在两年内变得难治，应寻找新的治疗方案。全反式维甲酸（ATRA）诱导某些类型的癌细胞的生长停滞、分化和细胞死亡，并且其与各种抗癌剂的组合导致增强的细胞毒性。唑来膦酸是一种常见的双膦酸盐，其抗癌作用超出了目前用于治疗癌症引起的骨病的范围。我们的目的是研究两种药物在OVCAR-3和MDAH-2774卵巢癌细胞系中可能的相加/协同效应，因为两种药物在不良事件方面均显示出优于常规细胞毒性药物的优势。XTT细胞增殖试验用于显示细胞毒性。为了验证细胞凋亡，使用通过ELISA测定的DNA片段化和半胱天冬酶3/7活性测量。由112个凋亡相关基因组成的OligoGeArray®用于阐明癌细胞内的遗传变化。为了验证我们的寡核苷酸阵列结果，对四个选择的基因进行定量实时PCR，这些基因受联合治疗的影响最大：光敏素β受体（LTBR），髓样细胞白血病-1（MCL-1），肿瘤坏死因子受体超家族成员1A（TNFRSF 1A），TNFRSF 1A相关死亡结构域蛋白（TRADD）。我们证明了ATRA和唑来膦酸的新组合是两种卵巢癌细胞中凋亡相关细胞死亡的强诱导剂。虽然联合治疗显著诱导促凋亡基因如肿瘤坏死因子受体超家族（TNFRSF）、TRADD和半胱天冬酶4，但一些抗凋亡基因如MCL-1、LTBR、BAG 3和Bcl-2家族成员被抑制。这些是ATRA和唑来膦酸的新型联合治疗的初步分子结果，与传统的细胞毒性药物相比，副作用更少。通过额外的实验分析，它可能是治疗难治性和老年卵巢癌患者的一个很好的选择，对他们来说，治疗选择非常有限。
Ovarian cancer is the most fatal gynecologic malignancies in the world. Although, platinum based treatments are widely used, the disease becomes treatment refractory within two years, and novel treatment options should be searched. All- trans retinoic acid (ATRA) induces growth arrest, differentiation and cell death in some types of cancer cells and its combination with various anticancer agents results in enhanced cytotoxicity. Zoledronic acid is a common bisphosphonate known for its anticancer effects beyond its current use in the treatment of cancer-induced bone disease. We aimed to investigate the possible additive/synergistic effect of both agents in OVCAR-3 and MDAH-2774 ovarian cancer cell lines, since both agents show superiority to conventional cytotoxics in terms of adverse events. XTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. OligoGeArray® which consists of 112 apoptosis related genes was used to elucidate the genetic changes within cancer cells. To validate our oligoarray results, quantitative real-time PCR was performed on four selected genes that were maximally effected by the combination treatment: lymphotoxin beta receptor (LTBR), myeloid cell leukemia-1 (MCL-1), tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), TNFRSF1A-associated death domain protein (TRADD). We demonstrated that a novel combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in both ovarian cancer cells. While the combination therapy significantly induced proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), TRADD and caspase 4, some of the antiapoptotic genes such as members of MCL-1, LTBR, BAG3 and Bcl-2 family members were inhibited. These are the preliminary molecular results of a novel combination treatment of ATRA and zoledronic acid, with fewer side effects as compared to conventional cytotoxic agents. With additional experimental analysis, it may serve as a good option for the treatment of refractory and elderly ovarian cancer patients, for whom there exists very limited choice of treatment.
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