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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 ARF-p53 circuit in tumour development and therapy. Activation of Myc and Ras can force proliferation or trigger apoptosis. These oncogenic signals engage the tumor-suppressor network at many points, including through the ARF-p53 circuit shown here. Which components contribute most to tumor suppression depends on context. For example, Myc activates p53 to promote apoptosis while interfering with its ability to induce growth arrest by p21. Conversely, Ras activates p53 to promote growth arrest while suppressing apoptosis. This simplified view helps explain why, despite the potential of p53 to control several processes; apoptosis is primarily responsible for p53-mediated tumor suppression. DNA damage and oncogene signaling engage the tumor-suppressor network at different points and, as such, DNA-damage signaling relies more on p53 than on ARF to elicit an anti-proliferative response. Such a model explains why loss of ARF or p53 confers similar advantages during Myc-induced tumorigenesis but not following treatment with DNA-damaging drugs such as curcumin. Here, drug resistance is an unselected trait conferred by p53 mutations that provides a unique advantage as the tumor encounters a new environment (e.g., chemotherapy).
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Figure 2: The ARF-p53 circuit in tumour development and therapy. Activation of Myc and Ras can force proliferation or trigger apoptosis. These oncogenic signals engage the tumor-suppressor network at many points, including through the ARF-p53 circuit shown here. Which components contribute most to tumor suppression depends on context. For example, Myc activates p53 to promote apoptosis while interfering with its ability to induce growth arrest by p21. Conversely, Ras activates p53 to promote growth arrest while suppressing apoptosis. This simplified view helps explain why, despite the potential of p53 to control several processes; apoptosis is primarily responsible for p53-mediated tumor suppression. DNA damage and oncogene signaling engage the tumor-suppressor network at different points and, as such, DNA-damage signaling relies more on p53 than on ARF to elicit an anti-proliferative response. Such a model explains why loss of ARF or p53 confers similar advantages during Myc-induced tumorigenesis but not following treatment with DNA-damaging drugs such as curcumin. Here, drug resistance is an unselected trait conferred by p53 mutations that provides a unique advantage as the tumor encounters a new environment (e.g., chemotherapy).

Mentions: At least two types of cell cycle control mechanisms are recognized: a cascade of protein phosphorylations that relay a cell from one stage to the next and a set of checkpoints that monitor completion of critical events and delay progression to the next stage if necessary. The first type of control involves a highly regulated kinase family [13-15]. Kinase activation generally requires association with a second subunit that is transiently expressed at the appropriate period of the cell cycle; the periodic "cyclin" subunit associates with its partner "cyclin-dependent kinase" (CDK) to create an active complex with unique substrate specificity. Regulatory phosphorylation and dephosphorylation fine-tune the activity of CDK-cyclin complexes, ensuring well-delineated transitions between cell cycle stages. The orderly progression through G1 phase of the cell cycle is regulated by the sequential assembly and activation of three sets of cyclin-CDK complexes (Figure 2), the D cyclins (D1, D2 and D3) and CDK4 or CDK6, cyclin E and CDK2, cyclin A and CDK2 [14,15]. Genetic aberrations in the regulatory circuits that govern transit through the G1 phase of the cell cycle occur frequently in human cancer, and deregulated over-expression of cyclin D1 is one of the most commonly observed alterations that may serve as a drive oncogene through its cell-cycle regulating function [16]. In normal cells cyclin D1 expression is tightly regulated by mitogenic signals involving Ras pathway [17]. Increased cyclin D1 abundance occurs relatively early during tumorigenesis [18]. In most cancer types cyclin D1 over-expression results from induction by oncogenic signals, rather than a clonal somatic mutation or rearrangement in the cyclin D1 gene [19]. Tissue culture-based experiments evidenced cyclin D1 functions as a collaborative oncogene that enhances oncogenic transformation of other oncogenes (i.e., Ras, Src, E1A) [20,21]. Targeted expression of cyclin D1 or cyclin E induce mammary tumors [22,23]. The cyclin D- and E-dependent kinases contribute sequentially to the phosphorylation of the retinoblastoma gene susceptibility product (pRB), canceling its ability to repress E2F transcription factors and activating genes required for S phase entry [13,14].


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

Sa G, Das T - Cell Div (2008)

The ARF-p53 circuit in tumour development and therapy. Activation of Myc and Ras can force proliferation or trigger apoptosis. These oncogenic signals engage the tumor-suppressor network at many points, including through the ARF-p53 circuit shown here. Which components contribute most to tumor suppression depends on context. For example, Myc activates p53 to promote apoptosis while interfering with its ability to induce growth arrest by p21. Conversely, Ras activates p53 to promote growth arrest while suppressing apoptosis. This simplified view helps explain why, despite the potential of p53 to control several processes; apoptosis is primarily responsible for p53-mediated tumor suppression. DNA damage and oncogene signaling engage the tumor-suppressor network at different points and, as such, DNA-damage signaling relies more on p53 than on ARF to elicit an anti-proliferative response. Such a model explains why loss of ARF or p53 confers similar advantages during Myc-induced tumorigenesis but not following treatment with DNA-damaging drugs such as curcumin. Here, drug resistance is an unselected trait conferred by p53 mutations that provides a unique advantage as the tumor encounters a new environment (e.g., chemotherapy).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: The ARF-p53 circuit in tumour development and therapy. Activation of Myc and Ras can force proliferation or trigger apoptosis. These oncogenic signals engage the tumor-suppressor network at many points, including through the ARF-p53 circuit shown here. Which components contribute most to tumor suppression depends on context. For example, Myc activates p53 to promote apoptosis while interfering with its ability to induce growth arrest by p21. Conversely, Ras activates p53 to promote growth arrest while suppressing apoptosis. This simplified view helps explain why, despite the potential of p53 to control several processes; apoptosis is primarily responsible for p53-mediated tumor suppression. DNA damage and oncogene signaling engage the tumor-suppressor network at different points and, as such, DNA-damage signaling relies more on p53 than on ARF to elicit an anti-proliferative response. Such a model explains why loss of ARF or p53 confers similar advantages during Myc-induced tumorigenesis but not following treatment with DNA-damaging drugs such as curcumin. Here, drug resistance is an unselected trait conferred by p53 mutations that provides a unique advantage as the tumor encounters a new environment (e.g., chemotherapy).
Mentions: At least two types of cell cycle control mechanisms are recognized: a cascade of protein phosphorylations that relay a cell from one stage to the next and a set of checkpoints that monitor completion of critical events and delay progression to the next stage if necessary. The first type of control involves a highly regulated kinase family [13-15]. Kinase activation generally requires association with a second subunit that is transiently expressed at the appropriate period of the cell cycle; the periodic "cyclin" subunit associates with its partner "cyclin-dependent kinase" (CDK) to create an active complex with unique substrate specificity. Regulatory phosphorylation and dephosphorylation fine-tune the activity of CDK-cyclin complexes, ensuring well-delineated transitions between cell cycle stages. The orderly progression through G1 phase of the cell cycle is regulated by the sequential assembly and activation of three sets of cyclin-CDK complexes (Figure 2), the D cyclins (D1, D2 and D3) and CDK4 or CDK6, cyclin E and CDK2, cyclin A and CDK2 [14,15]. Genetic aberrations in the regulatory circuits that govern transit through the G1 phase of the cell cycle occur frequently in human cancer, and deregulated over-expression of cyclin D1 is one of the most commonly observed alterations that may serve as a drive oncogene through its cell-cycle regulating function [16]. In normal cells cyclin D1 expression is tightly regulated by mitogenic signals involving Ras pathway [17]. Increased cyclin D1 abundance occurs relatively early during tumorigenesis [18]. In most cancer types cyclin D1 over-expression results from induction by oncogenic signals, rather than a clonal somatic mutation or rearrangement in the cyclin D1 gene [19]. Tissue culture-based experiments evidenced cyclin D1 functions as a collaborative oncogene that enhances oncogenic transformation of other oncogenes (i.e., Ras, Src, E1A) [20,21]. Targeted expression of cyclin D1 or cyclin E induce mammary tumors [22,23]. The cyclin D- and E-dependent kinases contribute sequentially to the phosphorylation of the retinoblastoma gene susceptibility product (pRB), canceling its ability to repress E2F transcription factors and activating genes required for S phase entry [13,14].

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