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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

The cell division cycle and its control. The cell cycle is divided into four distinct phases (G1, S, G2, and M). The progression of a cell through the cell cycle is promoted by CDKs, which are positively and negatively regulated by cyclins and CKis, respectively. As shown, cyclin D isoforms interact with CDK4 and CDK6 to drive the progression of a cell through G1. Cyclin D/CDK4,6 complexes phosphorylate pRb, which releases E2F to transcribe genes necessary for cell cycle progression. The association of cyclin E with CDK2 is active at the G1-S transition and directs entry into S-phase. The INK4s bind and inhibit cyclin D-associated kinases (CDK4 and CDK6). The kinase inhibitor protein group of CKi, p21Cip1/Waf-1, p27Kip1, and p57Kip2, negatively regulate cyclin D/CDK4,6 and cyclin E/CDK2 complexes. S-phase progression is directed by the cyclinA/CDK2 complex, and the complex of cyclin A with Cdk1 is important in G2. CDK1/cyclin B is necessary for the entry into mitosis. Curcumin modulates CKis, CDK-cyclin and Rb-E2F complexes to render G1-arrest and alters CDK/cyclin B complex formation to block G2/M transition.
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Figure 1: The cell division cycle and its control. The cell cycle is divided into four distinct phases (G1, S, G2, and M). The progression of a cell through the cell cycle is promoted by CDKs, which are positively and negatively regulated by cyclins and CKis, respectively. As shown, cyclin D isoforms interact with CDK4 and CDK6 to drive the progression of a cell through G1. Cyclin D/CDK4,6 complexes phosphorylate pRb, which releases E2F to transcribe genes necessary for cell cycle progression. The association of cyclin E with CDK2 is active at the G1-S transition and directs entry into S-phase. The INK4s bind and inhibit cyclin D-associated kinases (CDK4 and CDK6). The kinase inhibitor protein group of CKi, p21Cip1/Waf-1, p27Kip1, and p57Kip2, negatively regulate cyclin D/CDK4,6 and cyclin E/CDK2 complexes. S-phase progression is directed by the cyclinA/CDK2 complex, and the complex of cyclin A with Cdk1 is important in G2. CDK1/cyclin B is necessary for the entry into mitosis. Curcumin modulates CKis, CDK-cyclin and Rb-E2F complexes to render G1-arrest and alters CDK/cyclin B complex formation to block G2/M transition.

Mentions: The process of replicating DNA and dividing a cell can be described as a series of coordinated events that compose a "cell division cycle". The mammalian cell cycle has been divided into a series of sequential phases. The G1, S, G2, and M phases are sequentially transitioned in response to growth factor or mitogenic stimulation (Figure 1). The DNA synthetic (S phase) and mitotic (M phase) phases are preceded by gap phases (G1, G2). Cell proliferation is tightly regulated by multiple interactions between molecules in normal cells. One molecular system senses growth-promoting conditions and sends a signal to a second set of molecules that actually regulates cell division. In addition, cells are equipped with signaling pathway that can sense unfavorable conditions for proliferation. This pathway antagonizes the proliferative signaling pathway and can directly block cell division [13-15]. Loss of integrity of these signaling pathways due to mutations can result in a hyper-proliferative state of cells, manifested as cancer [9,10]. Therefore, cancer is a disease of deregulated cell proliferation. It is becoming clear that many external signals including both those that stimulate growth, such as growth factors, and those that inhibit growth, such as DNA damaging agents, control cell proliferation through regulating the cell cycle. Thus, elucidating the machinery of cell cycle progression and its regulation by these signals is essential for understanding and controlling cell proliferation. Recent advances in our understanding of the cell cycle machinery in the last years have demonstrated that disruption of normal cell cycle control is frequently observed in human cancer [10,15].


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

Sa G, Das T - Cell Div (2008)

The cell division cycle and its control. The cell cycle is divided into four distinct phases (G1, S, G2, and M). The progression of a cell through the cell cycle is promoted by CDKs, which are positively and negatively regulated by cyclins and CKis, respectively. As shown, cyclin D isoforms interact with CDK4 and CDK6 to drive the progression of a cell through G1. Cyclin D/CDK4,6 complexes phosphorylate pRb, which releases E2F to transcribe genes necessary for cell cycle progression. The association of cyclin E with CDK2 is active at the G1-S transition and directs entry into S-phase. The INK4s bind and inhibit cyclin D-associated kinases (CDK4 and CDK6). The kinase inhibitor protein group of CKi, p21Cip1/Waf-1, p27Kip1, and p57Kip2, negatively regulate cyclin D/CDK4,6 and cyclin E/CDK2 complexes. S-phase progression is directed by the cyclinA/CDK2 complex, and the complex of cyclin A with Cdk1 is important in G2. CDK1/cyclin B is necessary for the entry into mitosis. Curcumin modulates CKis, CDK-cyclin and Rb-E2F complexes to render G1-arrest and alters CDK/cyclin B complex formation to block G2/M transition.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The cell division cycle and its control. The cell cycle is divided into four distinct phases (G1, S, G2, and M). The progression of a cell through the cell cycle is promoted by CDKs, which are positively and negatively regulated by cyclins and CKis, respectively. As shown, cyclin D isoforms interact with CDK4 and CDK6 to drive the progression of a cell through G1. Cyclin D/CDK4,6 complexes phosphorylate pRb, which releases E2F to transcribe genes necessary for cell cycle progression. The association of cyclin E with CDK2 is active at the G1-S transition and directs entry into S-phase. The INK4s bind and inhibit cyclin D-associated kinases (CDK4 and CDK6). The kinase inhibitor protein group of CKi, p21Cip1/Waf-1, p27Kip1, and p57Kip2, negatively regulate cyclin D/CDK4,6 and cyclin E/CDK2 complexes. S-phase progression is directed by the cyclinA/CDK2 complex, and the complex of cyclin A with Cdk1 is important in G2. CDK1/cyclin B is necessary for the entry into mitosis. Curcumin modulates CKis, CDK-cyclin and Rb-E2F complexes to render G1-arrest and alters CDK/cyclin B complex formation to block G2/M transition.
Mentions: The process of replicating DNA and dividing a cell can be described as a series of coordinated events that compose a "cell division cycle". The mammalian cell cycle has been divided into a series of sequential phases. The G1, S, G2, and M phases are sequentially transitioned in response to growth factor or mitogenic stimulation (Figure 1). The DNA synthetic (S phase) and mitotic (M phase) phases are preceded by gap phases (G1, G2). Cell proliferation is tightly regulated by multiple interactions between molecules in normal cells. One molecular system senses growth-promoting conditions and sends a signal to a second set of molecules that actually regulates cell division. In addition, cells are equipped with signaling pathway that can sense unfavorable conditions for proliferation. This pathway antagonizes the proliferative signaling pathway and can directly block cell division [13-15]. Loss of integrity of these signaling pathways due to mutations can result in a hyper-proliferative state of cells, manifested as cancer [9,10]. Therefore, cancer is a disease of deregulated cell proliferation. It is becoming clear that many external signals including both those that stimulate growth, such as growth factors, and those that inhibit growth, such as DNA damaging agents, control cell proliferation through regulating the cell cycle. Thus, elucidating the machinery of cell cycle progression and its regulation by these signals is essential for understanding and controlling cell proliferation. Recent advances in our understanding of the cell cycle machinery in the last years have demonstrated that disruption of normal cell cycle control is frequently observed in human cancer [10,15].

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