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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

Oncogenic signaling targets many levels curcumin. Curcumin enhances apoptotic death, inhibits deregulated cellular proliferation, dedifferentiation and progression towards the neoplastic phenotype by altering key signaling molecules required for cell cycle progression. Such a network organization allows the cell to sense many aspects of the intracellular and extra-cellular milieu, yet ensures that cell death proceeds efficiently once activated. Excessive oncogenic signaling is coupled to apoptosis by a complex mechanism that targets key control points in the pathways. Blunt-head lines indicate that these molecules can be down-regulated by curcumin, where as arrow-head lines indicate that these molecules are often up-regulated by curcumin.
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Figure 5: Oncogenic signaling targets many levels curcumin. Curcumin enhances apoptotic death, inhibits deregulated cellular proliferation, dedifferentiation and progression towards the neoplastic phenotype by altering key signaling molecules required for cell cycle progression. Such a network organization allows the cell to sense many aspects of the intracellular and extra-cellular milieu, yet ensures that cell death proceeds efficiently once activated. Excessive oncogenic signaling is coupled to apoptosis by a complex mechanism that targets key control points in the pathways. Blunt-head lines indicate that these molecules can be down-regulated by curcumin, where as arrow-head lines indicate that these molecules are often up-regulated by curcumin.

Mentions: It is evident that curcumin can induce selective cancer cell killing in a p53-dependent manner, but impaired p53 expression or activity is associated with a variety of neoplastic transformations. Increasing reports are indicating that curcumin can block cell cycle progression or even apoptosis in a p53-independent manner as well, especially in the cells that lack functional p53 [83]. Curcumin induces apoptosis in p53- lung cancer cells [61]. It induces melanoma cell apoptosis by activating caspase-8 and caspase-3 via Fas receptor aggregation in a FasL-independent manner, blocks NFκB cell survival pathway and suppresses the apoptotic inhibitor XIAP [87]. Curcumin inhibits cellular isopeptidases, and cause cell death independently of p53 in isogenic pairs of RKO and HCT 116 cells with differential p53 status [88]. It enhances the chemotherapy-induced cytotoxicity in p53- prostate cancer cell line PC-3, via up-regulation of Cip1 and C/EBPβ expressions and suppression of NFκB activation [89]. It also induces apoptosis in multiple myloma cells by inhibiting IKK and NFκB activity [64]. Study indicates that curcumin down regulates NFκB and AP-1 activity in androgen-dependent and -independent prostate cancer cell lines [70]. Curcumin is a potent inhibitor of protein kinase C (PKC), EGF (epidermal growth factor)-receptor tyrosine kinase and IκB kinase. Subsequently, curcumin inhibits the oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ELK, PI3K, Akt, CDKs and iNOS [63,90]. In contrast to the mentioned reports, studies by Collet et al. shows that curcumin induces JNK-dependent apoptosis of colon cancer cells and it can induce JNK-dependent sustained phosphorylation of c-jun and stimulation of AP-1 transcriptional activity [68]. The oxidized form of cancer chemopreventive agent curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain of the enzyme [90]. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has also been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway [90]. All these reports suggests that curcumin can induce apoptosis or block cell cycle progression in a variety of cancer cell lines, predominantly via p53-dependent pathways, but it can also act in a p53-independent manner (Figure 5).


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

Sa G, Das T - Cell Div (2008)

Oncogenic signaling targets many levels curcumin. Curcumin enhances apoptotic death, inhibits deregulated cellular proliferation, dedifferentiation and progression towards the neoplastic phenotype by altering key signaling molecules required for cell cycle progression. Such a network organization allows the cell to sense many aspects of the intracellular and extra-cellular milieu, yet ensures that cell death proceeds efficiently once activated. Excessive oncogenic signaling is coupled to apoptosis by a complex mechanism that targets key control points in the pathways. Blunt-head lines indicate that these molecules can be down-regulated by curcumin, where as arrow-head lines indicate that these molecules are often up-regulated by curcumin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Oncogenic signaling targets many levels curcumin. Curcumin enhances apoptotic death, inhibits deregulated cellular proliferation, dedifferentiation and progression towards the neoplastic phenotype by altering key signaling molecules required for cell cycle progression. Such a network organization allows the cell to sense many aspects of the intracellular and extra-cellular milieu, yet ensures that cell death proceeds efficiently once activated. Excessive oncogenic signaling is coupled to apoptosis by a complex mechanism that targets key control points in the pathways. Blunt-head lines indicate that these molecules can be down-regulated by curcumin, where as arrow-head lines indicate that these molecules are often up-regulated by curcumin.
Mentions: It is evident that curcumin can induce selective cancer cell killing in a p53-dependent manner, but impaired p53 expression or activity is associated with a variety of neoplastic transformations. Increasing reports are indicating that curcumin can block cell cycle progression or even apoptosis in a p53-independent manner as well, especially in the cells that lack functional p53 [83]. Curcumin induces apoptosis in p53- lung cancer cells [61]. It induces melanoma cell apoptosis by activating caspase-8 and caspase-3 via Fas receptor aggregation in a FasL-independent manner, blocks NFκB cell survival pathway and suppresses the apoptotic inhibitor XIAP [87]. Curcumin inhibits cellular isopeptidases, and cause cell death independently of p53 in isogenic pairs of RKO and HCT 116 cells with differential p53 status [88]. It enhances the chemotherapy-induced cytotoxicity in p53- prostate cancer cell line PC-3, via up-regulation of Cip1 and C/EBPβ expressions and suppression of NFκB activation [89]. It also induces apoptosis in multiple myloma cells by inhibiting IKK and NFκB activity [64]. Study indicates that curcumin down regulates NFκB and AP-1 activity in androgen-dependent and -independent prostate cancer cell lines [70]. Curcumin is a potent inhibitor of protein kinase C (PKC), EGF (epidermal growth factor)-receptor tyrosine kinase and IκB kinase. Subsequently, curcumin inhibits the oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ELK, PI3K, Akt, CDKs and iNOS [63,90]. In contrast to the mentioned reports, studies by Collet et al. shows that curcumin induces JNK-dependent apoptosis of colon cancer cells and it can induce JNK-dependent sustained phosphorylation of c-jun and stimulation of AP-1 transcriptional activity [68]. The oxidized form of cancer chemopreventive agent curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain of the enzyme [90]. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has also been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway [90]. All these reports suggests that curcumin can induce apoptosis or block cell cycle progression in a variety of cancer cell lines, predominantly via p53-dependent pathways, but it can also act in a p53-independent manner (Figure 5).

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