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Anti cancer effects of curcumin: cycle of life and death.

Sa G, Das T - Cell Div (2008)

Bottom Line: Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively non-toxic plant derived polyphenol.The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels.The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata, 700054, India. gauri@bic.boseinst.ernet.in.

ABSTRACT
Increasing knowledge on the cell cycle deregulations in cancers has promoted the introduction of phytochemicals, which can either modulate signaling pathways leading to cell cycle regulation or directly alter cell cycle regulatory molecules, in cancer therapy. Most human malignancies are driven by chromosomal translocations or other genetic alterations that directly affect the function of critical cell cycle proteins such as cyclins as well as tumor suppressors, e.g., p53. In this respect, cell cycle regulation and its modulation by curcumin are gaining widespread attention in recent years. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively non-toxic plant derived polyphenol. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. In the present review we discuss how alterations in the cell cycle control contribute to the malignant transformation and provide an overview of how curcumin targets cell cycle regulatory molecules to assert anti-proliferative and/or apoptotic effects in cancer cells. The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation. Taken together, this review seeks to summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention.

No MeSH data available.


Related in: MedlinePlus

Time-lapse determination of approximate cell cycle position of curcumin-induced apoptosis. Time-lapse video-micrography was employed to monitor curcumin-induced apoptosis of breast cancer cells. Age of each cell was analyzed from a time-lapse analysis before curcumin addition. The occurrence and the time of apoptosis after curcumin addition were determined from a time-lapse analysis after addition.
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Figure 4: Time-lapse determination of approximate cell cycle position of curcumin-induced apoptosis. Time-lapse video-micrography was employed to monitor curcumin-induced apoptosis of breast cancer cells. Age of each cell was analyzed from a time-lapse analysis before curcumin addition. The occurrence and the time of apoptosis after curcumin addition were determined from a time-lapse analysis after addition.

Mentions: With elegant time-lapse video-micrography and quantitative imaging approach our works with breast malignant cells and adjacent non-malignant cells indicate that curcumin did not alter the cell cycle progression of carcinoma cells, although it induced apoptosis in the same at G2 phase of cell cycle (Figure 4) while reversibly blocking non-malignant cell cycle progression without apoptosis [6]. An interesting finding in this study was that curcumin appeared to be sparing the normal epithelial cells by arresting them at the G0 phase of the cell cycle via down-regulation of cyclin D1 and its related protein kinases or up-regulation of the inhibitory protein. The experiments with cyclin D1-deregulated cells showed that curcumin did not alter cyclin D1 expression level in cancer cells, but in normal cells, where cyclin D1 expression is tightly regulated by mitogenic signaling, its expression is inhibited by curcumin. This inability of curcumin to inhibit cyclin D1 expression in cyclin D1-deregulated cells may serve as the basis for differential regulation of cancerous and normal cells. In addition, curcumin was found to inhibit the association of cyclin D1 with CDK4/CDK6 or phosphorylation of pRb in some cancer cells where the expression of cyclin D1 is not deregulated and thus arrest them at G0/G1 phase (Figure 1) [82,83]. This yellow pigment has been shown to inhibit neoplastic cell proliferation by decreasing Cdk1 kinase activity and arresting cells at G2/M check point [81]. Ectopically over-expression of cyclin D1 renders susceptibility of these cells towards curcumin toxicity [6]. These results may well explain why in cancer cells, despite up-regulation of p53 and increase in Cip1 level, there was no cell cycle arrest. In fact, the level of cyclin D1 is very high in these cells and remained unchanged upon curcumin treatment. Thus, the amount of Cip1, as up regulated by curcumin, was still not sufficient to overpower cyclin D1 and to stop cell cycle progression. On the other hand, in non-malignant cells, the level of Cip1 increased dramatically with parallel down-regulation of cyclin D1, thereby making the ratio of Cip1 to cyclin D1 > 1 and this might be one of the causes of cell cycle arrest without apoptosis [6]. The above discussion not only relates curcumin activity with cell cycle regulation but also explains the mechanism underlying the differential effect of this phytochemical in normal and malignant cells.


Anti cancer effects of curcumin: cycle of life and death.

Sa G, Das T - Cell Div (2008)

Time-lapse determination of approximate cell cycle position of curcumin-induced apoptosis. Time-lapse video-micrography was employed to monitor curcumin-induced apoptosis of breast cancer cells. Age of each cell was analyzed from a time-lapse analysis before curcumin addition. The occurrence and the time of apoptosis after curcumin addition were determined from a time-lapse analysis after addition.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2572158&req=5

Figure 4: Time-lapse determination of approximate cell cycle position of curcumin-induced apoptosis. Time-lapse video-micrography was employed to monitor curcumin-induced apoptosis of breast cancer cells. Age of each cell was analyzed from a time-lapse analysis before curcumin addition. The occurrence and the time of apoptosis after curcumin addition were determined from a time-lapse analysis after addition.
Mentions: With elegant time-lapse video-micrography and quantitative imaging approach our works with breast malignant cells and adjacent non-malignant cells indicate that curcumin did not alter the cell cycle progression of carcinoma cells, although it induced apoptosis in the same at G2 phase of cell cycle (Figure 4) while reversibly blocking non-malignant cell cycle progression without apoptosis [6]. An interesting finding in this study was that curcumin appeared to be sparing the normal epithelial cells by arresting them at the G0 phase of the cell cycle via down-regulation of cyclin D1 and its related protein kinases or up-regulation of the inhibitory protein. The experiments with cyclin D1-deregulated cells showed that curcumin did not alter cyclin D1 expression level in cancer cells, but in normal cells, where cyclin D1 expression is tightly regulated by mitogenic signaling, its expression is inhibited by curcumin. This inability of curcumin to inhibit cyclin D1 expression in cyclin D1-deregulated cells may serve as the basis for differential regulation of cancerous and normal cells. In addition, curcumin was found to inhibit the association of cyclin D1 with CDK4/CDK6 or phosphorylation of pRb in some cancer cells where the expression of cyclin D1 is not deregulated and thus arrest them at G0/G1 phase (Figure 1) [82,83]. This yellow pigment has been shown to inhibit neoplastic cell proliferation by decreasing Cdk1 kinase activity and arresting cells at G2/M check point [81]. Ectopically over-expression of cyclin D1 renders susceptibility of these cells towards curcumin toxicity [6]. These results may well explain why in cancer cells, despite up-regulation of p53 and increase in Cip1 level, there was no cell cycle arrest. In fact, the level of cyclin D1 is very high in these cells and remained unchanged upon curcumin treatment. Thus, the amount of Cip1, as up regulated by curcumin, was still not sufficient to overpower cyclin D1 and to stop cell cycle progression. On the other hand, in non-malignant cells, the level of Cip1 increased dramatically with parallel down-regulation of cyclin D1, thereby making the ratio of Cip1 to cyclin D1 > 1 and this might be one of the causes of cell cycle arrest without apoptosis [6]. The above discussion not only relates curcumin activity with cell cycle regulation but also explains the mechanism underlying the differential effect of this phytochemical in normal and malignant cells.

Bottom Line: Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively non-toxic plant derived polyphenol.The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels.The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata, 700054, India. gauri@bic.boseinst.ernet.in.

ABSTRACT
Increasing knowledge on the cell cycle deregulations in cancers has promoted the introduction of phytochemicals, which can either modulate signaling pathways leading to cell cycle regulation or directly alter cell cycle regulatory molecules, in cancer therapy. Most human malignancies are driven by chromosomal translocations or other genetic alterations that directly affect the function of critical cell cycle proteins such as cyclins as well as tumor suppressors, e.g., p53. In this respect, cell cycle regulation and its modulation by curcumin are gaining widespread attention in recent years. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively non-toxic plant derived polyphenol. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. In the present review we discuss how alterations in the cell cycle control contribute to the malignant transformation and provide an overview of how curcumin targets cell cycle regulatory molecules to assert anti-proliferative and/or apoptotic effects in cancer cells. The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation. Taken together, this review seeks to summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention.

No MeSH data available.


Related in: MedlinePlus