Li Y, Bhuiyan M, Alhasan S, Senderowicz A M, Sarkar F H
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Clin Cancer Res. 2000 Jan;6(1):223-9.
Flavopiridol is a flavone that inhibits several cyclin-dependent kinases and exhibits potent growth-inhibitory activity against a number of human tumor cell lines, both in vitro and when grown as xenografts in mice. It is presently being investigated as a novel antineoplastic agent in the primary screen conducted by the Developmental Therapeutics Program, National Cancer Institute. Because breast cancer is the most common cancer and second leading cause of cancer-related deaths in women in the United States, we investigated whether flavopiridol could be an effective agent against a series of isogenic breast- cancer cell lines having different levels of erbB-2 expression and differential invasion and metastatic characteristics. Flavopiridol was found to inhibit the growth of MDA-MB-435 (parental) and 435.eB (stable transfectants) cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. Induction of apoptosis was also observed in these cell lines when treated with flavopiridol, as measured by DNA laddering, PARP, and CPP32 cleavages. We also found modest up-regulation of Bax and down-regulation of Bcl-2, but there was a significant down-regulation of c-erbB-2 in flavopiridol-treated cells. Gelatin zymography showed that flavopiridol inhibits the secretion of matrix metalloproteinase (MMP; MMPs 2 and 9) in the breast cancer cells and that the inhibition of c-erbB-2 and MMPs may be responsible for the inhibition of cell invasion observed in flavopiridol-treated cells. Collectively, these molecular effects of flavopiridol, however, were found to be independent of c-erbB-2 overexpression, suggesting that flavopiridol may be effective in all breast cancer. From these results, we conclude that flavopiridol inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and inhibits invasion and, thus, may inhibit metastasis of breast cancer cells. These findings suggest that flavopiridol may be an effective chemotherapeutic or preventive agent against breast cancer.
黄酮哌啶醇是一种黄酮类化合物，它能抑制多种细胞周期蛋白依赖性激酶，在体外以及在小鼠体内作为异种移植瘤生长时，对多种人类肿瘤细胞系均表现出强大的生长抑制活性。目前，它正在作为一种新型抗肿瘤药物，在美国国立癌症研究所的发展治疗学项目进行的初步筛选中接受研究。由于乳腺癌是美国女性中最常见的癌症，也是癌症相关死亡的第二大主要原因，我们研究了黄酮哌啶醇是否能有效对抗一系列具有不同erbB-2表达水平以及不同侵袭和转移特征的同基因乳腺癌细胞系。研究发现，黄酮哌啶醇能抑制通过将c-erbB-2 cDNA转染到MDA-MB-435细胞中而建立的MDA-MB-435（亲代）和435.eB（稳定转染子）细胞的生长。在用黄酮哌啶醇处理这些细胞系时，还观察到了凋亡的诱导，这通过DNA梯状条带、PARP和CPP32切割来测量。我们还发现Bax有适度上调，Bcl-2有下调，但在黄酮哌啶醇处理的细胞中c-erbB-2有显著下调。明胶酶谱分析表明，黄酮哌啶醇能抑制乳腺癌细胞中基质金属蛋白酶（MMP；MMPs 2和9）的分泌，并且对c-erbB-2和MMPs的抑制可能是黄酮哌啶醇处理的细胞中观察到的细胞侵袭抑制的原因。然而，黄酮哌啶醇的这些分子效应被发现与c-erbB-2过表达无关，这表明黄酮哌啶醇可能对所有乳腺癌都有效。从这些结果中，我们得出结论，黄酮哌啶醇能抑制MDA-MB-435乳腺癌细胞的生长，诱导凋亡，调节基因表达，并抑制侵袭，因此可能抑制乳腺癌细胞的转移。这些发现表明，黄酮哌啶醇可能是一种有效的乳腺癌化疗或预防药物。
