Sharma Girish, Tyagi Anil K, Singh Rana P, Chan Daniel C F, Agarwal Rajesh
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Breast Cancer Res Treat. 2004 May;85(1):1-12. doi: 10.1023/B:BREA.0000020991.55659.59.
With an approach to enhance the efficacy of chemotherapy agents against breast cancer treatment, here, we investigated the anti-cancer effects of grape seed extract (GSE) and doxorubicin (Dox), either alone or in combination, in estrogen receptor-positive MCF-7 and receptor-negative MDA-MB468 human breast carcinoma cells. GSE (25-200 micro g/ml) treatment of cells resulted in 16-72% growth inhibition and 9-33% cell death, in a dose- and a time-dependent manner. In other studies, Dox (10-100 nM) treatment showed 23-96% growth inhibition and 10-55% cell death. Based on these results, several combinations of GSE (25-100 micro g/ml) with Dox (10-75 nM) were next assessed for their synergistic, additive and/or antagonistic efficacy towards cell growth inhibition and death. In both MCF-7 and MDA-MB468 cells, a combination of 100 micro g/ml GSE with 25-75 nM Dox treatment for 48 h showed a strong synergistic effect [combination index (CI) < 0.5] in cell growth inhibition, but mostly an additive effect (CI approximately 1) in cell death. In cell-cycle progression studies, GSE plus Dox combination resulted in a moderate increase in G1 arrest in MCF-7 cells compared to each agent alone. GSE plus Dox combination showed a very strong and significant G1 arrest in MDA-MB468 cells when compared with Dox alone, however, it was less than that observed with GSE alone. In quantitative apoptosis studies, GSE and Dox alone and in combination showed comparable apoptotic death of MCF-7 cells, however, a combination of the two was inhibitory to Dox induced apoptosis in MDA-MB468 cells. This was further confirmed in another estrogen receptor-negative MDA-MB231 cell line, in which GSE and Dox combination strongly inhibited cell growth but did not show any increase in apoptotic cell death caused by Dox. Together, these results suggest a strong possibility of synergistic efficacy of GSE and Dox combination for breast cancer treatment, independent of estrogen receptor status of the cancer cell.
为了提高化疗药物对乳腺癌治疗的疗效，在此，我们研究了葡萄籽提取物（GSE）和阿霉素（Dox）单独或联合使用对雌激素受体阳性的MCF-7和受体阴性的MDA-MB468人乳腺癌细胞的抗癌作用。用GSE（25 - 200微克/毫升）处理细胞会导致16 - 72%的生长抑制和9 - 33%的细胞死亡，呈剂量和时间依赖性。在其他研究中，用Dox（10 - 100纳摩尔）处理显示出23 - 96%的生长抑制和10 - 55%的细胞死亡。基于这些结果，接下来评估了几种GSE（25 - 100微克/毫升）与Dox（10 - 75纳摩尔）组合对细胞生长抑制和死亡的协同、相加和/或拮抗作用。在MCF-7和MDA-MB468细胞中，100微克/毫升GSE与25 - 75纳摩尔Dox联合处理48小时在细胞生长抑制方面显示出强烈的协同作用[联合指数（CI）< 0.5]，但在细胞死亡方面大多为相加作用（CI约为1）。在细胞周期进程研究中，与单独使用每种药物相比，GSE加Dox组合使MCF-7细胞中G1期阻滞适度增加。与单独使用Dox相比，GSE加Dox组合在MDA-MB468细胞中显示出非常强烈且显著的G1期阻滞，然而，其程度低于单独使用GSE时观察到的情况。在定量凋亡研究中，单独和联合使用GSE和Dox在MCF-7细胞中显示出相当的凋亡死亡，然而，两者的组合对Dox诱导的MDA-MB468细胞凋亡具有抑制作用。这在另一种雌激素受体阴性的MDA-MB231细胞系中得到进一步证实，在该细胞系中，GSE和Dox组合强烈抑制细胞生长，但未显示出由Dox引起的凋亡细胞死亡有任何增加。总之，这些结果表明GSE和Dox联合使用对乳腺癌治疗具有协同疗效的可能性很大，且与癌细胞的雌激素受体状态无关。
