Division of Pharmacy Practice and Administration, College of Phamacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210-1291, USA.
Anticancer Res. 2012 Jul;32(7):2415-21.
(5Z)-7-Oxozeaenol was studied to reveal the path through which it exerts its effects on triple-negative MDA-MB-231 breast cancer cells.
The apoptotic effect of (5Z)-7-oxozeaenol on MDA-MB-231 cancer cells was analyzed by cell flow cytometry. The effects of (5Z)-7-oxozeaenol on the expression of the nuclear factor kappa B (NF-κB) p65, p50, IκB kinase (IKKα), IKKβ and caspase-7 were analyzed by western blot. The expression of intracellular reactive oxygen species (ROS) and effects on cell adhesion were also assessed. Cell viability was determined using the 3[4,5-dimethylthiazol-2-yl-]2,5-diphenyl tetrazolium bromide (MTT) assay.
(5Z)-7-Oxozeaenol down-regulated NF-κB in a dose-dependent manner. Intracellular levels of ROS increased in a dose-dependent manner when treated with (5Z)-7-oxozeaenol and potentiated in the presence of H(2)O(2), when compared to paclitaxel which was used as positive control. Treatment with (5Z)-7-oxozeaenol resulted in G1-phase arrest of treated cells and inhibition of cell proliferation. Cell adhesion was notably affected in treated cells. (5Z)-7-Oxozeaenol also significantly enhanced apoptosis of treated cells, through the activation of caspase-7.
Our findings suggest that (5Z)-7-oxozeaenol is a potent up-stream inhibitor of the NF-κB pathway, enhances the sensitivity of treated cells to apoptosis induced by ROS, and affects cell adhesion of MDA-MB-231 breast cancer cells. Thus, (5Z)-7-oxozeaenol is a potential new lead for breast cancer drug development since it might, in combination therapy, enhance the efficacy of current treatments and reduce resistance to chemotherapy of triple negative breast cancer.
研究（5Z）-7-氧代玉米赤霉醇，揭示其对三阴性 MDA-MB-231 乳腺癌细胞发挥作用的途径。
通过细胞流式细胞术分析（5Z）-7-氧代玉米赤霉醇对 MDA-MB-231 癌细胞的凋亡作用。通过 Western blot 分析（5Z）-7-氧代玉米赤霉醇对核因子 kappa B（NF-κB）p65、p50、IκB 激酶（IKKα）、IKKβ 和 caspase-7 的表达的影响。还评估了细胞内活性氧（ROS）的表达和对细胞黏附的影响。使用 3[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴化物（MTT）测定法测定细胞活力。
（5Z）-7-氧代玉米赤霉醇呈剂量依赖性地下调 NF-κB。当用（5Z）-7-氧代玉米赤霉醇处理时，细胞内 ROS 水平呈剂量依赖性增加，并且在存在 H（2）O（2）时，与用作阳性对照的紫杉醇相比，增加更为明显。用（5Z）-7-氧代玉米赤霉醇处理导致处理细胞的 G1 期阻滞和细胞增殖抑制。处理细胞的细胞黏附明显受到影响。（5Z）-7-氧代玉米赤霉醇还通过激活 caspase-7 显著增强了处理细胞的凋亡。
我们的研究结果表明，（5Z）-7-氧代玉米赤霉醇是 NF-κB 途径的有效上游抑制剂，增强了处理细胞对 ROS 诱导的凋亡的敏感性，并影响 MDA-MB-231 乳腺癌细胞的细胞黏附。因此，（5Z）-7-氧代玉米赤霉醇是一种有潜力的新型乳腺癌药物开发新先导化合物，因为它可能与联合治疗相结合，增强当前治疗的疗效，并降低三阴性乳腺癌对化疗的耐药性。
