The Role of Curcumin in Prevention and Management of Metastatic Disease

Abstract

In the last two decades, targeted therapies have enhanced tumor patient care and treatment success, however, metastatic growth still cannot be stopped efficiently and, therefore, mortality rates remain high. Prevention strategies against formation of metastases are the most promising approach we have, however, due to lack of clinical validation studies, they have not yet entered routine clinical care. In order to smooth the way for efficient prevention, further preclinical and large clinical studies are required. In this context, the underlying molecular mechanisms and factors that lead to metastatic growth have to be explored, and potential preventive agents have to be tested. Thereby, special attention has to be paid to natural bioactive compounds which do not exert major adverse effects, like the plant-derived polyphenol Curcumin, which is known to be a powerful antitumor agent. So far, most of the preclinical studies with Curcumin have focused on its effect on inhibiting tumor cell proliferation and invasion, although, it is known that it also inhibits metastatic spread in vivo. This review discusses the preventive potential of this natural compound not only against tumor onset, but also against formation of metastases.

Keywords: cancer; curcumin; metastases; prevention.

Figure 1

Schematic illustration of nuclear factor-κB (NFκB) signaling in the tumor environment. In resting cells, the NFκB dimer is bound to its inhibitor (IκB) and remains inactive in the cytoplasm. The activation cascade starts through binding of a ligand (TNFα = tumor necrosis factor α, TNFαR = TNFα-receptor, GF/CR = growth-factor/chemokine-receptor) to its receptor. Activation via TNFα occurs mainly through Tak1 (TGFβ-activated kinase 1) and via growth factors and/or cytokines, mainly through Akt (v-akt murine thymoma viral oncogene homolog). This leads to activation of the IKK complex (inhibitor of κB kinases; IKKα, β, γ). By activating the IKK-complex, the inhibitor of κB (IκB) is phosphorylated and the NFκB dimer is released and phosphorylated, which leads to translocation into the nucleus, where NFκB binds to the respective DNA promotor regions, which leads to transcription of genes related to proliferation, immunoregulation, matrix modulation, angiogenesis, and formation of metastasis. Curcumin inhibits the activation of NFκB by blocking the IKK-complex.

Figure 2

Schematic illustration of the effects of curcumin on prostate cancer. Curcumin has various effects on the development and progression of cancer via inhibition of NFκB signaling, followed by a downregulation of its target genes. Curcumin reduces tumor cell proliferation, induces apoptosis (d,e), and inhibits angiogenesis (c). Additionally, Curcumin inhibits gene expression of matrix-degrading proteases (matrix metalloproteases) and thereby invasion of tumor cells (a,b). Furthermore, the expression of metastasis-associated genes is reduced (f). As a summation of the single effects, the inhibition of lung metastasis in an animal model (murine mouse model) can be considered (g).

Figure 3

Feedback loop of CXCL-1 and 2 and NFκB. The proinflammatory chemokines CXCL-1 and -2 activate NFκB (b) by binding to their receptor CXCR-2 (a). In consequence, NFκB translocates into the nucleus and starts transcription of CXCL-1 and 2 (c). The chemokines are secreted and bind again to CXCR-2, activating NFκB (d). Curcumin disrupts this feedback loop by inhibition of NFκB (e).