Curcumin Downregulates Cyclin D1 Expression

Cyclin D1, a component subunit of cyclin-dependent kinase (Cdk)-4 and Cdk6, is a rate-limiting factor in progression of cells through the first-gap (G1) phase of the cell cycle (67). Cyclin D1 has been shown to be overex-pressed in many cancers including breast, esophagus, head and neck, and prostate (68-73). It is possible that the antiproliferative effects of curcumin are due to inhibition of cyclin D1 expression. We found that curcumin can

Figure 1 Role of curcumin in prevention and therapy of cancer. Curcumin down-regulates multiple pathways involved in tumor growth and metastasis. *Gene expression inhibited by curcumin.

indeed downregulate cyclin D1 expression (32,74,75), and this downregula-tion occurs at the transcriptional and posttranscriptional level.

Overall, numerous mechanisms, as indicated above, could account for the tumor-suppressive effects of curcumin (Fig. 1). Curcumin also has modulatory effects in diseases besides cancer (Fig. 2). These effects are described below.

Wound healing Figure 2 Effect of curcumin on various diseases.

III. EFFECT OF CURCUMIN ON ATHEROSCLEROSIS AND MYOCARDIAL INFARCTION

A. Curcumin Inhibits the Proliferation of Vascular Smooth-Muscle Cells

The proliferation of peripheral blood mononuclear cells (PBMC) and vascular smooth-muscle cells (VSMC) is a hallmark feature of atherosclerosis. Huang et al. investigated the effects of curcumin on the proliferation of PBMC and VSMC (76). Proliferative responses were determined from the uptake of [3H]-thymidine. In human PBMC, curcumin dose-dependently inhibited the response to phytohemagglutinin and the mixed lymphocyte reaction at dose ranges of 1-30 ||M and 3-30 |M, respectively. Curcumin (1-100 |aM) dose-dependently inhibited the proliferation of rabbit VSMC stimulated by fetal calf serum. Curcumin had a greater inhibitory effect on platelet-derived, growth-factor-stimulated proliferation than on serum-stimulated proliferation. Analogs of curcumin (cinnamic acid, coumaric acid, and ferulic acid) were much less effective than curcumin as inhibitors of serum-induced smooth-muscle-cell proliferation. This suggested that curcu-min may be useful for the prevention of the pathological changes associated with atherosclerosis and restenosis.

Chen and Huang examined the possible mechanisms underlying curcumin's antiproliferative and apoptotic effects using the rat VSMC cell line A7r5 (77). Curcumin (1-100 |M) inhibited serum-stimulated [3H]-thymidine incorporation of both A7r5 cells and rabbit cultured VSMC. Cell viability, as determined by the trypan blue dye exclusion method, was unaffected by curcumin at the concentration range 1-10 |M in A7r5 cells. However, the number of viable cells after 100 |M curcumin treatment was less than the basal value. Following curcumin (1-100 |M) treatment, cell cycle analysis revealed a G0/G1 arrest and a reduction in the percentage of cells in S phase. Curcumin at 100 |M also induced cell apoptosis as demonstrated by hematoxylin-eosin staining, TdT-mediated dUTP nick end labeling, DNA laddering, cell shrinkage, chromatin condensation, and DNA fragmentation. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by curcumin (10-100 ||M). On the other hand, phorbol-myristate-acetate-stimulated cytosolic protein kinase C (PKC) activity was reduced by 100 |M curcumin. The level of c-myc mRNA and bcl-2 mRNA was significantly reduced by curcumin but it had little effect on the p53 mRNA level. These results demonstrate that curcumin inhibited cell proliferation, arrested cell cycle progression, and induced cell apoptosis in VSMC. These results may explain how curcumin prevents the pathological changes of atherosclerosis and postangioplasty restenosis.

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