Metastasis reduced by low carb diet plus anti-inflammatory

Metastasis is what makes cancer lethal. Inflammation promotes cancer stem cell proliferation and a metabolic milieu of elevated insulin and glucose also favors malignancy. In keeping with this are two papers just published in the journal Carcinogenesis presenting evidence that a low carbohydrate/high protein diet plus anti-inflammatory agent markedly reduces cancer metastasis.

Low carbohydrate, high protein plus anti-inflammatory

The authors of the first paper earlier demonstrated that human and murine carcinomas grow much slower in mice on a low carb, high protein diet plus an anti-inflammatory agent:

"We recently demonstrated that both murine and human carcinomas grow significantly slower in mice on low carbohydrate (CHO), high protein diets than on isocaloric Western diets and that a further reduction in tumor growth rates occur when the low CHO diets are combined with the cyclooxygenase-2 inhibitor, celecoxib. Following upon these studies, we asked herein what effect low CHO, high protein diets, with or without celecoxib, might have on tumor metastasis."

Metastasis reduced in models of breast, lung and prostate cancer

A diet with between 15% and 25% carbohydrate performed best:

"In the highly metastatic 4T1 mouse mammary tumor model, a 15% CHO, high protein diet supplemented with celecoxib (1 g/kg chow) markedly reduced lung metastases. Moreover, in longer-term studies using male Transgenic Adenocarcinoma of the Mouse Prostate mice, which are predisposed to metastatic prostate cancer, the 15% CHO diet, with and without celecoxib (0.3 g/kg chow), gave the lowest incidence of metastases, but a more moderate 25% CHO diet containing celecoxib led to the best survival. Metabolic studies with 4T1 tumors suggested that the low CHO, high protein diets may be forcing tumors to become dependent on amino acid catabolism for survival/growth."

The authors conclude:

"Taken together, our results suggest that a combination of a low CHO, high protein diet with celecoxib substantially reduces metastasis."

Curcumin inhibits metastasis in prostate cancer

Since COX-2 inhibitors like celecoxib have some drawbacks, the second paper in the latest Carcinogenesis offering evidence that the natural anti-inflammatory agent curcumin (derived from turmeric) also reduces metastasis is very welcome. The authors note:

"In America and Western Europe, prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer. We previously reported that the chemopreventive polyphenol curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. In this study, we analyze the effects of curcumin on prostate carcinoma growth, apoptosis and metastasis."

Curcumin inhibits the key inflammation promoter NFκB

NFκB (nuclear factor kappa beta) is a pivotal pro-inflammatory agent and a key player in autoimmune inflammation.

"Curcumin is a plant-derived compound that is particularly suited for prevention of prostate cancer formation and progression because it is known to act on the central activator of inflammation, NFκB, and prostate hyperplasia and cancer are known to be driven by inflammation...We show that curcumin inhibits translocation of NFκB to the nucleus through the inhibition of the IκB-kinase (IKKβ, leading to stabilization of the inhibitor of NFκB, IκBα, in PC-3 prostate carcinoma cells. Inhibition of NFκB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFκB...Treatment of the cells with curcumin and siRNA-based knockdown of CXCL1 and -2 induce apoptosis, inhibit proliferation and downregulate several important metastasis-promoting factors like COX2, SPARC and EFEMP. In an orthotopic mouse model of hematogenous metastasis, treatment with curcumin inhibits statistically significantly formation of lung metastases."

The authors' conclusion is of great clinical significance for cancer treatment and prevention:

"In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive proinflammatory and prometastatic feedback loop between NFκB and CXCL1/-2. Curcumin disrupts this feedback loop by the inhibition of NFκB signaling leading to reduced metastasis formation in vivo. Taken together, these data delineate the molecular mechanisms by which curcumin reduces survival and growth of prostate cancer cells on the one hand, and the ability of the cells to form metastases on the other hand. Curcumin interrupts an important positive feedback loop between the cytokines and NFκB that is responsible for the activation of several mediators of metastasis. This is particularly important in prostate cancer because inflammation plays a crucial role in its progression toward more aggressive growth and metastasis. "

More than just 'watchful waiting'

Regarding the use of curcumin in clinical practice the authors state:

"Curcumin, therefore, appears particularly suited for prostate cancer prevention in healthy elder men, in patients with benign prostate hyperplasia and eventually low-grade prostate cancers in elder patients where ‘watchful waiting’ might remain an option."

Curcumin inhibits breast cancer metastasis

Mention should also be made of an earlier study published in Cellular Physiology and Biochemistry showing reduction of hematogenous (blood-borne) spread of breast cancer by curcumin by inhibiting NFκB (NFkappa B):

"Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitro and in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA-MB-231 cells in correlation with reduced activation of the survival pathway NFkappaB, as a consequence of diminished IotakappaB and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NFkappa B activity and transcriptional downregulation of AP-1. NFkappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NFkappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NFkappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible."