Ramachandran Cheppail, Rodriguez Sonia, Ramachandran Reshma, Raveendran Nair P K, Fonseca Hugo, Khatib Ziad, Escalon Enrique, Melnick Steven J
Research Institute, Miami Children's Hospital, Miami, FL 33155, USA.
Anticancer Res. 2005 Sep-Oct;25(5):3293-302.
Curcumin (diferuloyl methane), the yellow-colored dietary pigment from the rhizomes of turmeric, has been recognized as a chemopreventive agent because of its antitumor, antioxidant and antiproliferative effects. The cytotoxic, apoptotic and gene regulatory effects of both turmeric and curcumin were investigated in the MCF-7 human breast cancer carcinoma cell line and compared with the effects in MCF-10A human mammary epithelial cells. MCF-7 cells were more sensitive to turmeric and curcumin than MCF-10A cells. MCF-10A cells retained comparatively less curcumin in the medium than MCF- 7 cells after 24 h, thereby reducing the cytotoxic effect. Curcumin induced a significantly higher percentage of apoptosis in MCF-7 than MCF-10A cells at all doses. Microarray hybridization of Clonetech apoptotic arrays with labeled first-strand probes of total RNA was performed to identify and characterize the genes regulated by curcumin in tumor cells. Of the 214 apoptosis-associated genes in the array, the expression of 104 genes was altered by curcumin treatment. The gene expression was altered up to 14-fold levels in MCF-7 as compared to only up to 1.5-fold in the MCF-10A cell line by curcumin. Curcumin up-regulated (>3 fold) 22 genes and down-regulated (<3-fold) 17 genes at both 25 microg/ml and 50 microg/ml doses in the MCF-7 cell line. The up-regulated genes include HIAP1, CRAF1, TRAF6, CASP1, CASP2, CASP3, CASP4, HPRT, GADD45, MCL-1, NIP1, BCL2L2, TRAP3, GSTP1, DAXX, PIG11, UBC, PIG3, PCNA, CDC10, JNK1 and RBP2. The down-regulated genes were TRAIL, TNFR, AP13, IGFBP3, SARP3, PKB, IGFBP, CASP7, CASP9, TNFSF6, TRICK2A, CAS, TRAIL-R2, RATS1, hTRIP, TNFb and TNFRSF5. While a dose-dependent gene expression change was noticed in some genes, opposite regulatory effects were induced by different curcumin doses in three apoptotic genes. These results suggest that curcumin induces apoptosis in breast cancer cells by regulation of multiple signaling pathways, indicating its potential use for prevention and treatment of cancer.
姜黄素（二阿魏酰甲烷）是姜黄根茎中的黄色食用色素，因其具有抗肿瘤、抗氧化和抗增殖作用，已被公认为一种化学预防剂。研究了姜黄和姜黄素对MCF-7人乳腺癌细胞系的细胞毒性、凋亡和基因调控作用，并与MCF-10A人乳腺上皮细胞中的作用进行了比较。MCF-7细胞比MCF-10A细胞对姜黄和姜黄素更敏感。24小时后，MCF-10A细胞在培养基中保留的姜黄素比MCF-7细胞少，从而降低了细胞毒性作用。在所有剂量下，姜黄素诱导MCF-7细胞凋亡的比例均显著高于MCF-10A细胞。利用Clonetech凋亡芯片与总RNA的标记第一链探针进行微阵列杂交，以鉴定和表征姜黄素在肿瘤细胞中调控的基因。在该芯片的214个凋亡相关基因中，104个基因的表达因姜黄素处理而改变。与姜黄素在MCF-10A细胞系中仅上调至1.5倍相比，其在MCF-7细胞中的基因表达上调至14倍水平。在MCF-7细胞系中，25μg/ml和50μg/ml剂量的姜黄素均上调（>3倍）22个基因，下调（<3倍）17个基因。上调的基因包括HIAP1、CRAF1、TRAF6、CASP1、CASP2、CASP3、CASP4、HPRT、GADD45、MCL-1、NIP1、BCL2L2、TRAP3、GSTP1、DAXX、PIG11、UBC、PIG3、PCNA、CDC10、JNK1和RBP2。下调的基因有TRAIL、TNFR、AP13、IGFBP3、SARP3、PKB、IGFBP、CASP7、CASP9、TNFSF6、TRICK2A、CAS、TRAIL-R2、RATS1、hTRIP、TNFb和TNFRSF5。虽然在一些基因中观察到剂量依赖性的基因表达变化，但不同剂量的姜黄素在三个凋亡基因中诱导了相反的调控作用。这些结果表明，姜黄素通过调节多种信号通路诱导乳腺癌细胞凋亡，表明其在癌症预防和治疗中的潜在用途。
