Potential applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy

Abstract

Curcumin has attracted great attention in the therapeutic arsenal in clinical oncology due to its chemopreventive, antitumoral, radiosensibilizing and chemosensibilizing activities against various types of aggressive and recurrent cancers. These malignancies include leukemias, lymphomas, multiple myeloma, brain cancer, melanoma and skin, lung, prostate, breast, ovarian, liver, gastrointestinal, pancreatic and colorectal epithelial cancers. Curcumin mediates its anti-proliferative, anti-invasive and apoptotic effects on cancer cells, including cancer stem/progenitor cells and their progenies, through multiple molecular mechanisms. The oncogenic pathways inhibited by curcumin encompass the members of epidermal growth factor receptors (EGFR and erbB2), sonic hedgehog (SHH)/GLIs and Wnt/β-catenin and downstream signaling elements such as Akt, nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription (STATs). In counterbalance, the high metabolic instability and poor systemic bioavailability of curcumin limit its therapeutic efficacy in human. Of great therapeutic interest, the selective delivery of synthetic analogs or nanotechnology-based formulations of curcumin to tumors, alone or in combination with other anticancer drugs, may improve their chemopreventive and chemotherapeutic efficacies against cancer progression and relapse. Novel curcumin formulations may also be used to reverse drug resistance, eradicate the total cancer cell mass and improve the anticarcinogenic efficacy of the current anti-hormonal and chemotherapeutic treatments for patients with various aggressive and lethal cancers.

Figure 1

Tumorigenic cascades initiated by different growth factors in cancer cells and the anticarcinogenic effects induced by dietary curcumin on the transduction signaling elements. The inhibitory effect of curcumin on the expression and/or activity of EGFR, erbB2, IGF-1R, and their downstream signaling elements, sonic hedgehog (SHH/SMO/GLIs), Wnt/β-catenin and ATP-binding cassette multidrug transporters such as ABCG2 in cancer cells are indicated. Moreover, the enhanced expression of p21^WAP1 and p27^KIP1 cyclin-dependent kinase inhibitors and inhibition of mitotic effects induced by curcumin resulting in a cell cycle arrest and reduced expression levels of different gene products involved in the growth, invasion and metastasis of cancer cells as well as the activation by curcumin of mitochondrial factors and caspase pathway-induced apoptosis are also indicated. In addition, the scheme also shows novel nanotechnology-based curcumin delivery systems consisting of using either a poly(β-cyclodextrin)-curcumin complex formulation, or a polymeric micelle-encapsulated curcumin labeled with a ligand or monoclonal antibody (mAb) that specifically interacts with a receptor expressing by cancer cells for the selective targeting of curcumin are also illustrated.

Figure 2

Potential growth factor pathways, intracellular signal components and drug resistance-associated molecules modulated by curcumin involved in its chemopreventive and chemotherapeutic effects on cancer cells. The scheme shows the inhibitory effects induced by curcumin on distinct oncogenic growth factor cascades and their multiple downstream intracellular signaling elements and ABC-multidrug transporters in cancer cells involved in the mediation of its cancer preventive and anticarcinogenic properties.

Figure 3

Chemical structures of naturally occurring curcumin and its novel synthetic analogs. The scheme shows (A) The diketone and keto-enol forms of curcumin. Curcumin exists as an equilibrium mixture of two tautomeric forms in solution. The enol structure of curcumin, which is stabilized by intramolecular H-bonding, is the most energetically stabilized and favored form; (B) chemical structures of novel synthetic analogs of dietary curcumin (dimethoxycurcumin, GO-Y039, EF24, compound 23 and difluorinated-curcumin "CDF") showing improved chemical stability and anticarcinogenic properties on different cancer cell lines.