Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines.
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.
Ramachandran
Cheppail
C
Research Institute, Miami Children's Hospital, Miami, FL 33155, USA. cheppail.ramachandran@mch.com
Rodriguez
Sonia
S
Ramachandran
Reshma
R
Raveendran Nair
P K
PK
Fonseca
Hugo
H
Khatib
Ziad
Z
Escalon
Enrique
E
Melnick
Steven J
SJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D030024:Curcuma; D003474:Curcumin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D008517:Phytotherapy
D000970:Antineoplastic Agents; D003474:Curcumin