Anti cancer effects of curcumin: cycle of life and death

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.

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.

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).

Figure 3

Curcuma longa Plant and chemical structure of curcumin, the active ingradient of rhizome termeric. The tautomerism of curcumin is demonstrated under different physiological conditions. Under acidic and neutral conditions, the bis-keto form (bottom) is more predominant than the enolate form.

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.

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.