Ciftci Kadriye, Su Jiangfeng, Trovitch Peter B
Temple University, School of Pharmacy, Department of Pharmaceutical Sciences, 3307 N. Broad Street, Philadelphia, PA 19140, USA.
J Pharm Pharmacol. 2003 Aug;55(8):1135-41. doi: 10.1211/002235703322277177.
A variety of molecules including growth factors are involved in the metastasis of breast cancer cells to bone. We have investigated the effects of osteoblast derived growth factors, such as insulin-like growth factor-1 (IGF-1) and transforming growth factor beta-1 (TGF-beta1), on doxorubicin (adriamycin)-induced apoptosis and growth arrest of estrogen receptor positive (ER+) (MCF-7) and negative (ER-) (MDA-MB-435) breast cancer cell lines. Human breast normal epithelial (MCF-10A), breast cancer (MCF-7) and metastatic breast cancer (MDA-MB-435) cell lines were exposed to different doses of doxorubicin (0.1, 1 or 10 microM) at various exposure times (12, 24 or 48 h). The doxorubicin cytotoxicity was found to be higher in cancer cell lines (MDA-MB-435 and MCF-7) compared with normal breast epithelial cells (MCF-10A cells). Doxorubicin appeared to exert a blockade of MCF-7 and MDA-MB-435 cells at the G2/M phase, and induced apoptosis in MDA-MB-435 (29 +/- 4.2% vs 3.4 +/- 1.9% control) as assessed by flow cytometry, DNA fragmentation and terminal deoxynucleotidyl-transferase mediated deoxyuridine 5-triphosphate and biotin nick-end labelling (TUNEL) assays. Estradiol (E2) stimulated the growth of MCF-7 cells and increased the distribution of the cells at the G2/M and S phases. Exogenous IGF-1 partially neutralized the doxorubicin cytotoxicity in both cancer cell lines (MCF-7 and MDA-MB-435). Similarly, TGF-beta1 partially neutralized the doxorubicin cytotoxicity in MDA-MB-435 cells by reducing the number of cells at the <G1 phase (from 29% to 6.4%) and enhanced the doxorubicin blockade of MCF-7 (E2-) at the G0/G1 phase. Results showed that the osteoblast-derived growth factors could affect the chemotherapy response of breast cancer cells, thereby allowing for the possibility of chemotherapeutic modulation.
包括生长因子在内的多种分子参与了乳腺癌细胞向骨的转移。我们研究了成骨细胞衍生的生长因子，如胰岛素样生长因子-1（IGF-1）和转化生长因子β-1（TGF-β1），对阿霉素（ Adriamycin）诱导的雌激素受体阳性（ER+）（MCF-7）和阴性（ER-）（MDA-MB-435）乳腺癌细胞系凋亡和生长停滞的影响。将人乳腺正常上皮细胞（MCF-10A）、乳腺癌细胞（MCF-7）和转移性乳腺癌细胞（MDA-MB-435）在不同暴露时间（12、24或48小时）下暴露于不同剂量的阿霉素（0.1、1或10 microM）。发现与正常乳腺上皮细胞（MCF-10A细胞）相比，阿霉素对癌细胞系（MDA-MB-435和MCF-7）的细胞毒性更高。阿霉素似乎使MCF-7和MDA-MB-435细胞在G2/M期受到阻滞，并通过流式细胞术、DNA片段化和末端脱氧核苷酸转移酶介导的脱氧尿苷5-三磷酸和生物素缺口末端标记（TUNEL）分析评估，诱导MDA-MB-435细胞凋亡（29±4.2%对3.4±1.9%对照）。雌二醇（E2）刺激MCF-7细胞生长，并增加细胞在G2/M期和S期的分布。外源性IGF-1部分中和了两种癌细胞系（MCF-7和MDA-MB-435）中阿霉素的细胞毒性。同样，TGF-β1通过减少处于<G1期的细胞数量（从29%降至6.4%）部分中和了MDA-MB-435细胞中阿霉素的细胞毒性，并增强了MCF-7（E2-）在G0/G1期对阿霉素的阻滞作用。结果表明，成骨细胞衍生的生长因子可影响乳腺癌细胞的化疗反应，从而为化疗调节提供了可能性。
