Curcumin And Cancer: An Update

James Meschino DC, MS, ROHP
Several lipoxygenase inhibitors are known, including plant and mammalian lipoxygenases, but only a few of them are known inhibitors of P-12-LOX. Curcumin is one of these lipoxygenase inhibitors. (1)

Breast Cancer – Curcumin has also been shown to inhibit the tyrosine kinase activity of ErbB-2 and induces apoptosis in mammary carcinoma cells. Curcumin is also reported to dissociate heat shock GRP94 from ERbB-2, another mechanism through which it may reduce breast cancer in cells prone to malignant activity. (2)

Colon Cancer – It has been established that over-expression of Epidermal Growth Factor Receptors (EGFR) and other members of the tyrosine kinase family are frequently indicated in epithelial cancers, including colon cancer.

The epidermal growth factor (EGF) family of receptor tyrosine kinases consists of four receptors, EGF-R (ErbB1), ErbB2 (Neu), ErbB3, and ErbB4.

In response to these discoveries pharmaceutical companies have produced a number of drugs that inhibit the activation of specific receptors of the EGFR series (EGFR inhibitor drugs). However, in general these drugs have had limited success because cancer cells usually possess more than one type of EGFR receptor. As such, researchers conclude that what is needed to help prevent colon cancer, as well to help treat colon cancer, is a broad-spectrum EGFR receptor inhibitor that inhibits signal transduction for all EGFR cell membrane receptors. (pan-erb signal transduction inhibitors). To this end there is a naturally-occurring pan-erb signal transduction inhibitor that is showing promise in experimental and animal studies, known as EGFR Related Protein. This protein occurs naturally and thus, its use as targeted therapeutic agent is unlikely to produce toxic side effects. Curcumin, the active ingredient in the spice turmeric, also acts as a powerful inhibitor of EGFR receptors. Experimental studies, animal studies and a recent Phase I clinical trial, have shown that curcumin inhibits the growth of colon cancer cells and reduces tumor incidence in high risk human subjects. Curcumin inhibits the EGFR receptor, which in turn inhibits the propagation of metabolic reactions (e.g. decreased synthesis of the tumor promoting messenger NF-kB) leading to inhibition of cell replication of cancer cells and preneoplastic cells.

Curcumin also exerts anti-inflammatory effects on cells by inhibiting synthesis of pro-inflammatory eicosanoids as noted previously.

Researchers examined whether curcumin together with ERRP  will cause a greater inhibition of growth of colon cancer cells than either agent alone and the mechanisms of this inhibition. Results showned that the cell growth inhibition, and stimulation of apoptosis, in response to the combinatorial treatment was significantly greater than that caused by either agent alone.

These changes were associated with decreased activation (tyrosine phosphorylation) of EGFR, ErbB-2, ErbB-3, and/or IGF-1R. Whereas curcumin inhibited constitutive activation of both EGFR and IGF-1R, ERRP decreased activation of EGFR, ErbB-2, and ErbB-3 but had no effect on IGF-1R. Further, the combination therapy caused a greater attenuation of downstream effectors such as NF-κB, Akt and BAD activation, and down-regulation of procaspase-3 than that noted with either agent alone. The superior effects of the combinatorial treatment could partly be attributed to inhibition of constitutive activation of EGFRs and IGF-1R signaling pathways (3)

Familial adenomatous polyposis (FAP) – FAP is an autosomal-dominant disorder characterized by the development of hundreds of colorectal adenomas and eventual colorectal cancer. Regression of adenomas in this syndrome occurs with treatment of anti-inflammatory drugs and cyclo-oxygenase inhibitors. However, these compounds can have considerable side effects. In a 2006 study researchers alternatively used 480 mg of curcumin and 20 mg of quercetin, three times per day in five patients with FAP, who had undergone previous colectomy (4 with retained rectum and 1 an anal pouch). After 6 months all five patients had decreased polyp number and size from baseline assessment, with the mean percentage decrease in number and size from baseline measurements of 60.4% and 50.9%, respectively. No serious or significant side effects were reported. As the dosage of quercetin was not much higher than that which is attainable from daily food sources, researchers suggest that growth retardation effects shown in this study were primarily due to curcumin supplementation (4)

Prostate Cancer – Curcumin has been shown to decrease the proliferative potential and induce the apoptosis potential of both androgen-dependent and androgen-independent prostate cancer cells in vitro, largely by modulating the apoptosis suppressor proteins and by interfering with the growth factor receptor signaling pathways as exemplified by the EGF-receptor. Further observations showed that in vitro treatment with curcumin, caused a marked decrease in the extent of cell proliferation the growth of LNCaP cells as implanted tumors in nude mice was followed. (5)

There is also increasing evidence that the selective pressure imposed by androgen ablation therapy (via castration or anti-androgen drugs) on the residual prostate cancer cells may actually accelerate the development of the hormone refractory and bone metastatic phenotype. The propensity of prostate cancer to establish osseous metastases is very likely mediated by the osteomimetic properties of the prostate cancer cells. Prostate cancer cells acquire these “bone-like” properties in order to survive in the bony microenvironment. This process is facilitated by common growth factor trophisms between the bone stromal cells, osteoblasts, and the prostate cancer cells wherein a number of growth factors and their receptors are involved.

As such, a general inhibition of the tyrosine kinase signaling pathways may have a therapeutic advantage in interfering with the metastatic potential of these prostate cancer cells. A study conducted with curcumin on bone like properties of C4-2B, a highly metastatic derivative of LNCaP prostate cancer cell line showed that curcumin inhibited the ligand-stimulated autophosphorylation of EGF-R and CSF1-R that were crucially involved in the development of osteomimetic properties of C4-2B cells. When C4-2B cells were grown under promineralization conditions, curcumin prevented the formation of the mineralized nodules. It also inhibited the expression of the core-binding factor a-1 in C4-2B cells which was responsible for the expression of several bone-specific proteins. The IKK activity was severely impaired, showing marked NF-kappa B inhibition. The experiments indicate that curcumin can also interfere with the development of the osteoblast and the osteoclast-like properties by these prostate cancer cells, thus exhibiting a potential to prevent the establishment of bony metastases. (6)

Curcumin and Angionesis – Curcumin has also beeen shown to inhibit angiogenesis in cancer cells via a number of pathways (see Angiogenesis)

Curcumin Can Aid Chemotherapy and Radiation Treatment – Curcumin also interacts with cancer cells at a number of levels and can enhance the tumoricidal efficacy of cytotoxic chemotherapy and radiotherapy. Its anti-invasive effects are partly mediated by downregulation of matrix metalloproteinase-2 (MMP2) and upregulation of tissue inhibitor of metalloproteinase-1 (TIMP1). These enzymes are involved in the regulation of tumour cell invasion. (7)

References:

1. Jankun J, Ansari M, Aleem AM, Malgorzewicz S, Szkudlarek M et al. Synthetic curcumonoids modulate the arachidonic acid metabolism of human platelet 12-lipoxygenase and reduce sprout formation of human endothelial cells. Mol Cancer. 2005;5:1371-1382
2. Tikhomirov O, Carpenter G. Caspase-dependent cleavage of ErbB-2 by geldanamycin and staurosporin. J Biological Chem. 2001;276 (36):33675-33680
3. Reddy S, Rishi AK, Xu H, Levi E, Sarkar FH, Majamdar APN. Mechanisms of Curcumin and EGF-Receptor Related (ERRP)- dependent growth inhibition of colon cancer cells
4. Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind L. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polys. Clin Gastroenterol and Hepatol. 2006;4:1035-1038.
5. Dorai Y, Cao Y, Dorai B, Buttyan R, Katz A. Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo. The Prostate. 2001;47 (4):293-303
6. Dorai T Dutcher JP, Dempster DW, Wienik PH. Therapeutic potential of curcumin in prostate cancer – IV: Inteference with osteomimetic properties of hormone refractory C4-2B  prostate cells. 2003;60 (1):1-7
7. Sagar SM, Yance D, Wong RK. Natrual health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer – Part 1. Current Oncology. 2006;13 (1):1-13