Molecular targets of dietary agents on cell cycle progression of cancer cells

4.1. Grape seed proanthocyanidins

Although in vitro cell culture models are useful in obtaining mechanistic insights, the observations made using the in vitro systems need to be verified in vivo animal models to establish the relevance of the cellular findings. In an in vivo study, we found that administration of GSPs by oral gavage inhibits the growth of A431 tumor-xenografts in athymic nude mice. The mechanism of inhibition of the growth of tumors by GSPs was further confirmed by the analysis of mRNA levels of proliferating cell nuclear antigen (PCNA) and cyclin D1, as markers of tumor cell proliferation. A reduction in the mRNA expression of cyclin D1 and PCNA was observed in the tumor-xenograft samples of GSP-treated mice as compared to the tumor-xenograft samples of control mice that were not given GSPs by gavage. Further, the inhibition of the growth of tumor xenograft in athymic nude mice by GSPs was associated with the induction of apoptotic cell death of tumor cells [74]. Similar observation were noted when the prostate cancer cells, DU145 and LNCaP, were treated with grape seed extract. These studies indicate that treatment of prostate cancer cells with GSPs results in inhibition of proliferation, induction of apoptosis, G1 phase arrest, increases in Cip1/p21 and decreases in CDK4, CDK2 and cyclin E [75].

4.2. EGCG/green tea polyphenol

EGCG has been identified as a major and most effective constituent of green tea. Therefore most of the in vitro and in vivo studies of the effects of green tea have been conducted using EGCG. EGCG has been shown to induce apoptosis and cell cycle arrest in many cancer cells without affecting normal cells [76]. Treatment of various cancer cells (prostate, lung and skin) with EGCG altered the pattern of cell cycle proteins; specifically the inhibition of CDKs. EGCG also enhances the expression of CDKI proteins, such as Cip1/p21 and Kip1/p27 while reducing the expression of cyclin D1 and the phosphorylation of retinoblastoma protein. EGCG causes cell cycle arrest and promotes apoptosis via a dose- and time-dependent upregulation of Cip1/p21, Kip1/p27, and p16/INK4A and down-regulation of proteins such as cyclin D1, cyclin E, CDK2, and CDK4 [77]. EGCG caused growth arrest at G1 stage of cell cycle through regulation of cyclin D1, CDK4, CDK6, Cip1/p21 and Kip1/p27, and induced apoptosis through generation of reactive oxygen species and activation of caspase-3 and caspase-9 [78]. A comprehensive effect of EGCG has been described on various cell signaling targets in vitro and in vivo systems, which shows the multiple targets of EGCG against malignancies [79, 80].

4.3. Resveratrol

Several reports indicate that resveratrol, a polyphenol found at high concentrations in grapes and red wine, inhibits proliferation of cancer cells by inhibiting cell-cycle progression at different stages of the cell cycle [81–84]. Kuwajerwala et al. [85] have reported that treatment of prostate LNCaP cells with resveratrol induced the cells to enter into S phase, but subsequent progression through S phase was limited by the inhibitory effect of resveratrol on DNA synthesis. This unique ability of resveratrol may be responsible for its apoptotic and antiproliferative effects. Benitez et al. observed that treatment of LNCaP and PC-3 cells with resveratrol induced apoptosis and that this was associated with the reduced levels of expression of cyclins D1 and E and CDK4, as well as a reduction in cyclin D1/CDK4 kinase activity [86]. Resveratrol also reduced proliferation and induced apoptosis in human epidermoid carcinoma A431 cells in a dose- and time-dependent manner. Resveratrol-induced apoptosis in A431 cells was associated with a reduced level of expression of cyclins D1, D2 and E2; a reduction in the levels of CDK2, CDK4 and CDK6; and enhanced levels of Cip1/p21 and Kip1/p27 proteins [82]. Wolter et al. has shown the down-regulation of the cyclin D1/CDK4 complex by resveratrol in colon cancer cell lines [87].

4.4. Genistein/Apigenin

Genistein has been found to induce apoptosis and G2 arrest and inhibited proliferation in a variety of cancer cell lines, regardless of p53 status [88]. The dietary flavonoid apigenin, which is abundantly present in fruits and vegetables, induces G2/M phase arrest in two p53-mutant cancer cell lines, HT-29 and MG63, and simultaneously enhances the levels of Cip1/p21, a CDK inhibitory protein [89]. Oral administration of apigenin by gavage has been found to inhibit the growth of prostate tumor xenograft in athymic nude mice through the down-modulation of cyclins D1, D2 and E; CDK2, CDK4, and CDK6, and enhancement of the levels of Cip1/p21 and Kip1/p27 proteins [90]. Treatment of PC-3 and LNCaP cells with apigenin caused a marked reduction in the levels of cyclin D1 protein and decreases in CDK2, CDK4 and CDK6, which leads to G0/G1 phase arrest of the cell cycle and induction of apoptosis [91]. Apigenin induced G2/M phase cell cycle arrest and reduced the levels of cyclin A, cyclin B, phosphorylated forms of cdc2 and cdc25 in pancreatic cancer cell lines [92]. It was shown that the apoptosis induced by apigenin in Hep G2 cells was possibly mediated through the p53-dependent pathway and the induction of Cip1/p21 expression, which was probably associated with the cell cycle arrest in G2/M phase [93]. Treatment with apigenin resulted in growth-inhibition and G2/M phase arrest in two p53-mutant cancer cell lines, HT-29 and MG63. These effects were associated with a marked increase in the protein expression of Cip1/p21. These results suggest that there is a p53-independent pathway for apigenin in p53-mutant cell lines, which induces Cip1/p21 expression and growth-inhibition, and that apigenin may be a useful chemopreventive agent not only in wild-type p53 status, but also in cancer with mutant p53 [94].

4.5. Silymarin/silibinin

Treatment of prostate cancer cells with silibinin, an active constituent of silymarin, a plant flavonoid from milk thistle, induced apoptosis, which was associated with G1 phase arrest, inhibition of cyclin dependent kinases (CDK2, CDK4 and CDK6), and a reduction in the levels of cyclin D1 [Reviewed in 95]. In the same set of experiments, silibinin was found to increase the levels of CDKI (Cip1/p21 and Kip1/p27) proteins, suggesting their mechanistic involvement. Dietary agents also can synergize with chemotherapeutic drugs, thereby reducing the toxicity of these drugs. Silibinin has been found to synergize the growth-inhibitory effect of doxorubicin on prostate carcinoma DU145 cells, and this was associated with a significant G2/M arrest. The underlying mechanism of G2/M arrest indicated an inhibitory effect on Cdc25c, Cdc2 and cyclin B1 protein expression and Cdc2/p34 kinase activity [95]. Treatment of human malignant melanoma cells, A375-S2, with silymarin results in increased G(2)/M phase arrest, possibly providing a prolonged time for DNA repair. Consequently, silymarin protected A375-S2 cell against UV-induced apoptosis was partially through SIRT1 pathway and modulation of the cell cycle distribution [96]. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder), and this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, Cip1/p21 and Kip1/p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis and metastasis [97].

4.6. Curcumin

Curcumin (Curcuma longa) is a common spice that is used commonly in the preparation of food in most Indian house-holds and in several Asian countries. Curcumin inhibits cell cycle progression of immortalized human umbilical vein endothelial cells by up-regulating the cyclin-dependent kinase inhibitors, Cip1/p21, Kip1/p27 and p53 [98]. In neuroblastoma cells, both curcumin and resveratrol upregulate p53 expression and induce nuclear translocation of p53, followed by induction of Cip1/p21 and Bax expression [99]. Treatment of Lovo cells and HCT-116 cells with curcumin resulted in an accumulation of the cells in the G2/M phase and prevented cells from entering the next cell cycle [100–102]. Curcumin inhibited the growth of glioma U251 cells in a dose-dependent manner, with the low dose of curcumin inducing G2/M cell cycle arrest. The high dose of curcumin not only enhanced G2/M cell cycle arrest, but also induced S phase arrest. Curcumin induces the expression of p53 and up-regulates the levels of Cip1/p21 and ING4 in glioma U251 cells [103]. Aggarwal et al. [104] have demonstrated a dose-and time-dependent down-regulation of expression of cyclin E by curcumin that correlates with a reduction in the proliferation of human prostate and breast cancer cells. The suppression of cyclin E expression was not cell-type dependent as down-regulation occurred in estrogen-positive and -negative breast cancer cells, androgen-dependent and -independent prostate cancer cells, leukemia and lymphoma cells, head and neck carcinoma cells, and lung cancer cells. This study indicated that curcumin enhanced the expression of tumor cyclin-dependent kinase inhibitors Cip1/p21 and Kip1/p27 as well as tumor suppressor protein p53 but suppressed the expression of Rb protein. Curcumin also promoted the accumulation of the cells in G1 phase of the cell cycle.

Collectively, it is apparent that dietary agents are important regulators of cellular proliferation and specific modulators of cell cycle-associated proteins. The present studies provide evidence that dietary agents have the ability to control the regulation of cell cycle progression in cancer cells through employing various molecular targets, as summarized in Figure 4; and may have the capability to inhibit the progression of cancers of many organs, if used appropriately and in a systematic manner. These findings reaffirm what Hippocrates said twenty-five centuries ago, “let food be thy medicine and medicine be thy food”.

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