Skin cancer prevention

Posted on July 26, 2011 by Dr. Jonathan

More can be done to prevent skin cancer than shield against excessive exposure to ultraviolet radiation. There is a growing body of evidence supporting the effectiveness of substances taken internally for skin protection and health. Consider a paper published in the journal Photochemical & Photobiological Sciences in which the authors observe:

“Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation as a tumor initiator, tumor promoter and complete carcinogen, and their excessive exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. Sunscreens are useful, but their protection is not adequate to prevent the risk of UV-induced skin cancer…Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of skin carcinogenesis…A wide variety of botanicals, mostly dietary flavonoids or phenolic substances, have been reported to possess substantial anticarcinogenic and antimutagenic activities because of their antioxidant and antiinflammatory properties.”

They examined selected chemopreventive including apigenin, curcumin, grape seed proanthocyanidins, resveratrol, silymarin, and green tea polyphenols, against cancer causing UV radiatoin in laboratory and living systems. Having attended to the mechanism of chemopreventive action of these dietary botanicals they concluded:

“We suggest that in addition to the use of these botanicals as dietary supplements for the protection of photocarcinogenesis, these botanicals may favorably supplement sunscreens protection and may provide additional antiphotocarcinogenic protection including the protection against other skin disorders caused by solar UV radiation.”

A paper published last year in Archives of Dermatological Research updated the data on polyphenols and other phytochemicals as skin cancer chemopreventive agents with special reference to the effect of suboptimal immunefunction on vulnerability to skin cancer . The authors state:

“Chronic UV radiation exposure-induced skin diseases or skin disorders are caused by the excessive induction of inflammation, oxidative stress and DNA damage, etc.. The use of chemopreventive agents, such as plant polyphenols, to inhibit these events in UV-exposed skin is gaining attention. Chemoprevention refers to the use of agents that can inhibit, reverse, or retard the process of these harmful events in the UV-exposed skin.”

They examined data from a number of studies on the photoprotective effects of green tea polyphenols, grape seed proanthocyanidins, resveratrol, silymarin and genistein, particularly in reference to UV-induced skin inflammation, oxidative stress, and DNA damage. The authors conclude:

“The laboratory studies conducted in animal models, suggest that these polyphenols have the ability to protect the skin from the adverse effects of UV radiation, including the risk of skin cancers. It is suggested that polyphenols may favorably supplement sunscreens protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and DNA damage.”

Of great interest is a paper published in the journal Cancer Letters that specifically considers the role of UV radiation-induced immune suppression. The authors note:

“Studies of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that ultraviolet (UV) radiation-induced immune suppression is a risk factor for the development of skin cancer in humans. UV radiation suppresses the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage that is a molecular trigger of UV-mediated immunosuppression…Dietary botanicals are of particular interest as they have been shown to inhibit UV-induced immune suppression and photocarcinogenesis.”

Their summary of studies investigating the photoprotective efficacy of dietary agents included green tea polyphenols, grape seed proanthocyanidins and silymarin. Based on this body of data they…

“…present evidence that these chemopreventive agents prevent UVB-induced immunosuppression and photocarcinogenesis through: (i) The induction of immunoregulatory cytokine interleukin (IL)-12; (ii) IL-12-dependent DNA repair; and (iii) Stimulation of cytotoxic T cells in the tumor microenvironment. The new information regarding the mechanisms of action of these agents supports their potential use as adjuncts in the prevention of photocarcinogenesis….The supplementation of the use of sunscreens with these dietary agents may provide an effective strategy for the prevention of melanoma and nonmelanoma skin cancers in humans. The dietary botanical agents discussed are considered to be non-toxic and pharmacologically safe for human consumption.”

More recently there have been investigations of the chemopreventive properties of specific agents, such as a paper published in Experimental Dermatology on an extract of Curcuma longa (turmeric).

“…[partial purification from C. longa (PPC)] was used to investigate the alpha-melanocyte-stimulating hormone (α-MSH)-stimulated melanogenesis signal pathway…In cells stimulated α-MSH, PPC inhibited cellular melanin contents, tyrosinase activity and expression of melanogenesis-related proteins including microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related protein (TRP)…was activated by PPC in α-MSH-stimulated B16F10 cells…MEK/ERK or Akt activation by PPC may contribute to reduced melanin synthesis via MITF and its downstream signal pathway including tyrosinase and TRPs in α-MSH-induced melanogenesis.”

In other words, the turmeric extract was shown to regulate pathways intrinsic to the production of melanoma in a way that would inhibit its development. More evidence for the inhibitory effect on melanogenesis of curcumin, the principal medicinal extract of turmeric, was recently reported in the journal Phytotherapy Research. The authors observe:

“Plant derived compounds, as potentially safe and effective skin lightening agents (SLAs), have attracted great attention from many researchers. Curcumin is a plant-derived polyphenol, which has been reported to suppress melanogenesis in B16 melanoma cells.”

They specifically investigated whether curcumin affects the development of melanoma in cultured human melanocytes. Additionally, they sought to elucidate the molecular mechanisms by assessing the effects of curcumin on melanin synthesis, cellular tyrosinase activity, the expression of melanogenesis-related proteins, tyrosinase, tyrosinase-related protein 1 and 2, and the activation of a number of melanogenesis-regulating signals in human melanoma cells. The data they obtained is very promising:

“The results showed that the melanin content and tyrosinase activity, as well as the expression of melanogenesis-related proteins in human melanocytes, were significantly inhibited by curcumin in a dose dependent manner. In addition, PI3K/Akt/ GSK 3β, ERK and p38 MAPK were activated by curcumin, while inhibitors of these signals attenuated the inhibitory effects of curcumin on melanogenesis.”

Thus they concluded…

“These results suggest that curcumin inhibits melanogenesis in human melanocytes through activation of Akt/GSK 3β, ERK or p38 MAPK signaling pathways.”

And another study just published in the International Journal of Molecular Medicine demonstrates the same findings.

”The present study was designed to assess the potential inhibitory activity of curcumin on the α-melanocyte stimulating hormone (α-MSH)-stimulated melanogenesis signal pathway in B16F10 melanoma cells. The molecular mechanism of curcumin-induced inhibitory activity on the α-MSH-stimulated melanogenesis signal pathway, including expression of melanogenesis-related proteins and activation of melanogenesis-regulating proteins, was examined in B16F10 cells.”

The authors report essentially the same effects of curcumin as described in the earlier paper, including the influence of tyrosinase activity, the expression of melanogenesis-related proteins, and melanogenesis-regulating signals. They state in conclusion:

“Our results suggest that the suppressive activity of curcumin on α-MSH-stimulated melanogenesis may involve the down-regulation of MITF and its downstream signal pathway through the activation of MEK/ERK or PI3K/Akt.”

Evidence has been accumulating for some time that green tea polyphenols also protect against skin carcinogenesis. A paper published in Photodermatology, Photoimmunology & Photomedicine reported that green tea constituents protect against UV-induced DNA damage. The authors state:

“Antioxidant compounds in green tea may be able to protect against skin carcinogenesis and it is of interest to investigate the mechanisms involved. A study was therefore conducted to determine whether the isolated green tea polyphenol (−)-epigallocatechin gallate (EGCG) could prevent ultraviolet radiation (UVR)-induced DNA damage in cultured human cells.”

Of special interest is that…

“This work was then extended to investigate whether drinking green tea could afford any UVR protection to human peripheral blood cells collected after tea ingestion.”

They compared DNA damage induced by UVR in cultured human cells with and without EGCG, and then conducted the same assay on peripheral white blood cells isolated from 10 adult human volunteers before and after drinking 540 ml of green tea. What did the data show?

“The in vivo trials of green tea also demonstrated a photoprotective effect, with samples of peripheral blood cells taken after green tea consumption showing lower levels of DNA damage than those taken prior to ingestion when exposed to 12 min ultraviolet A (UVA) radiation.”

Thus they conclude:

“The studies showed that green tea and/or some constituents can offer some protection against UV-induced DNA damage in human cell cultures and also in human peripheral blood samples taken post-tea ingestion.”

A paper more recently published in the Journal of Photochemistry and Photobiology adds further evidence that green tea can protect against DNA damage from ultraviolet radiation. The authors state:

“Oral ingestion of green tea is a potent dietary source of antioxidant polyphenols. These compounds are of interest as they may be able to provide additional protection to the body to help prevent the deleterious effects of ultraviolet A and visible radiation (UVA/VIS) produced indirectly via reactive oxygen species (ROS) in sunlight exposed skin.”

They too exposed white blood cells drawn from healthy human volunteers to UV irradiation after ingestion of green tea and measured the levels of DNA damage. They conclude:

“The findings…indicate that drinking green tea did significantly reduce the genotoxic effects observed in peripheral blood cells 60 min following ingestion when artificially exposed to 12 min of UVA/VIS irradiation in the laboratory. It is postulated that this protection is afforded by the polyphenol compounds (known to be contained within green tea) via scavenging or quenching of the damaging ROS induced by this form of light exposure.”

Ellagic acid, another polyphenol found in pomegranate and berries, has also been studied for its ability to reduce skin damage due to UV-B irradiation. The authors of a paper published in Experimental Dermatology state:

“This study examined photoprotective effects of ellagic acid on collagen breakdown and inflammatory responses in UV (ultraviolet)-B irradiated human skin cells and hairless mice. Ellagic acid attenuated the UV-B-induced toxicity of HaCaT keratinocytes and human dermal fibroblasts. Non-toxic ellagic acid markedly prevented collagen degradation by blocking matrix metalloproteinase production in UV-B-exposed fibroblasts.”

Interestingly, in regard to wrinkle production ellagic acid…

“…attenuated UV-B-triggered skin wrinkle formation and epidermal thickening…In addition, this compound mitigated inflammatory intracellular cell adhesion molecule-1 expression in UV-B-irradiated keratinocytes and photoaged mouse epidermis.”

The skin inflammation due to UV exposure noted in the authors’ conclusion is a contributing cause for skin cancer:

“These results demonstrate that ellagic acid prevented collagen destruction and inflammatory responses caused by UV-B. Therefore, dietary and pharmacological interventions with berries [and pomegranate] rich in ellagic acid may be promising treatment strategies interrupting skin wrinkle and inflammation associated with chronic UV exposure leading to photoageing.”

Sulforaphane, a compound found in cruciferous vegetables, has also been shown to reduce carcinogenic inflammation as documented in a paper just published in Molecular Carcinogenesis. The authors state:

“Ultraviolet (UV) of sunlight is a complete carcinogen that can burn skin, enhance inflammation, and drive skin carcinogenesis. Previously, we have shown that sulforaphane (SFN) inhibited chemically induced skin carcinogenesis via nuclear factor (erythroid-derived 2)-like 2 (Nrf2)…Since Nrf2 plays critical roles in the anti-oxidative stress/anti-inflammatory responses, it is relevant to assess the role of Nrf2 for photoprotection against…UVB-induced skin inflammation.”

To do this they induced skin inflammation by UVB irradiation in two groups of mice, with and without the Nrf2 genes that respond to sulforaphane. What did they find?

“SFN treatment of Nrf2 WT ['wild type', with Nrf2 genes] but not Nrf2 KO ['knockout', without Nrf2 genes] mice restored the number of sunburn cells back to their basal level by 8 d after UVB irradiation. Additionally, UVB-induced short-term inflammatory biomarkers (interleukin-1β and interleukin-6) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT. Taken together, our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation, sunburn reaction, and SFN-mediated photoprotective effects in the skin.”

In other words, sulforaphane (SFN) from cruciferous vegetables like broccoli, Brussels sprouts and cabbages activated the Nrf2 genes that conferred protection against UVB-induced inflammation.

While there is evidence that polyphenols, green tea EGCG, curcumin, sulforaphane and other single agents protect against skin cancer, a combination of multiple agents may work best. The authors of a paper published in the journal Dermatologic Surgery note:

“The endogenous antioxidant system of the skin scavenges reactive oxygen species and combats ultraviolet induced oxidative skin damage. Supporting this cutaneous defense system with topical or oral antioxidants may provide a successful strategy for the treatment and prevention of skin cancer.”

They undertook a review of the evidence available in 2002 for treatment and prevention of melanoma and nonmelanoma skin cancers using antioxidants and vitamins. Their findings were mixed:

“Review of the literature demonstrates that the administration of synthetic retinoids has not proved beneficial for otherwise healthy patients with nonmelanoma skin cancer. Selenium supplementation has reduced the incidence of several internal malignancies but not of nonmelanoma skin cancer. Synergistic use of β-carotene with vitamins C and E has demonstrated prophylaxis against reactive oxygen radicals involved in nonmelanoma skin cancer and reduced sunburn reactions significantly. 1,25-dihydroxyvitamin D3 analog CB1093 has demonstrated promise as a therapeutic agent in the regression of the early stages of melanoma in specific cell lines.”

They support the use of a combination approach:

“Delivery of exogenous antioxidants in combination appears to be a more successful strategy for enhancing the cutaneous antioxidant system than the administration of isolated antioxidants alone. Vitamin D analogs may have a role in the medical therapy of melanoma.”

The authors of a paper published recently in the journal Seminars in Cutaneous Medicine and Surgery also assert that combining multiple agents may be significantly more effective than single agents in prevention of UV-induced skin cancer:

“With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer.”

Along these lines a promising study just published in the journal Nutrition and Cancer offers evidence that the multiherbal formulation Zyflamend inhibits melanoma growth. By way of background…

“Though isolated dietary components such as lycopene, resveratrol, and isothiocyanate compounds have been shown to provide limited protection against cancer development, the use of whole herbs and herbal extracts for the treatment of cancer remains of great interest. As suggested by earlier studies, the antiinflammatory activity of many plants available as intact products or as extracts has long been considered for supplemental therapeutics for cancer.”

They further observe:

“Zyflamend, a unique multiherbal extract preparation, is a promising antiinflammatory agent that has also been suggested to regulate multiple pathways in cancer progression. As Zyflamend contains ingredients that can suppress tumor cell proliferation, invasion, angiogenesis, and metastasis through regulation of inflammatory pathway products, we hypothesized that this preparation might inhibit melanoma proliferation.”

The authors designed their study to test the effect of Zyflamend on melanoma proliferation. They found that…

“Zyflamend inhibits melanoma growth by regulating the autophagy–apoptosis switch. Based on the responsible molecular mechanisms of Zyflamend, our study highlights the importance of the use of herbal preparations for the prevention and treatment of cancer.”

Interestingly, two earlier studies published in the same journal report that Zyflamend induces apoptosis (programmed cell death) of prostate cancer cells and inhibits malignant bone destruction and invasion while potentiating cytotoxicity.

A sound strategy for skin cancer prevention requires a comprehensive examination of the various possible contributing causes that addresses the unique needs of the individual. That being said, there is ample evidence that beneficial agents are available to play a role in protection from UV-induced irradiation that are worthy of consideration.

Curcumin—a better COX-2 inhibitor for colorectal cancer prevention

Posted on March 26, 2011 by Dr. Jonathan

COX-2 inhibitors, a form of non-steroidal antiinflammatory drug (NSAID) that targets the COX-2 enzyme, have been recognized for their ability to prevent the growth of colon tumors. They have, however, also been proven to seriously increase the risk for heart attacks and strokes. The authors of paper published recently in the journal Current Colorectal Cancer Reports despite the early hopes for these medications:

“”Nonsteroidal anti-inflammatory drugs are one of the more studied groups of drugs in colorectal cancer chemoprevention because both epidemiological and experimental studies have shown that these drugs reduce the risk of developing colonic tumors. Cyclooxygenase-2 (COX-2), an isoform of cyclooxygenase, plays an important role in colorectal carcinogenesis…However, recent long-term studies have shown that these agents and probably some NSAIDs have an increased risk of cardiovascular events, which has changed the whole scenario.”

In another paper published in the subsequent issue of the same journal, the authors state:

“Recent studies of coxibs indicate that these agents are effective in reducing sporadic adenoma recurrence, but chronic use can result in serious cardiovascular toxicity. These data underscore the need for chemopreventive agents with acceptable risk-to-benefit ratios.”

Happily, a study published in the Annals of the New York Academy of Sciences offers evidence that curcumin, the benign natural phenol extracted from the spice turmeric, also offers a way to inhibit the COX-2 enzyme for colorectal cancer chemoprevention.

“…the AMPK cascade has emerged as an important pathway implicated in cancer control. In this study we investigated the effects of curcumin on apoptosis and the regulatory effect of the AMPK–cyclooxygenase-2 (COX-2) pathway in curcumin-induced apoptosis. Curcumin has shown promise as a chemopreventive agent because of its in vivo regression of various animal-model colon cancers. This study focused on exploiting curcumin to apply antitumorigenic effects through modulation of the AMPK–COX-2 cascade.”

Did curcumin show enough activity in this regard to be meaningful?

“Curcumin exhibited a potent apoptotic effect on HT-29 colon cancer cells at concentrations of 50 μmol/L and above. These apoptotic effects were correlated with the decrease in pAkt and COX-2, as well as the increase in p-AMPK.”

They further demonstrated that blocking the effect of curcumin resulted in an increase in COX-2 expression resulting in a replacement of apoptosis (cancer cell death)with proliferation. The authors add in conclusion:

“These results indicate that AMPK is crucial in apoptosis induced by curcumin and further that the pAkt–AMPK–COX-2 cascade or AMPK–pAkt–COX-2 pathway is important in cell proliferation and apoptosis in colon cancer cells.”

Therapeutic resources for inflammatory bowel disease

Posted on January 19, 2011 by Dr. Jonathan

Autoimmune disease in general and inflammatory bowel disease in particular arise from a constellation of causes that should be investigated and addressed on an individual basis. Nonetheless, methods that calm the inflammatory cascade (without harmful side-effects) are important practical tools. As forthcoming posts will describe in greater detail, nitric oxide production is a critical step in the production of damaging inflammation. A paper published in the European Journal of Clinical Investigation highlights this fact:

“Nitric oxide (NO) production, as detectable by indirect and direct methods, as well as the expression of inducible nitric oxide synthase (iNOS) in the intestinal mucosa appear to be enhanced in active ulcerative colitis and, when in excess, to play a proinflammatory role in the disease. Despite some conflicting data, there is evidence that NO production is also increased in Crohn’s disease. Many inflammatory features of inflammatory bowel disease are in keeping with the physiological properties of NO…”

And of interest for clinical case managment…

“The drugs currently used in the treatment of inflammatory bowel disease (steroids, salicylates) do not seem to exert substantial effects on intestinal NO synthesis.”

A study published in the British Journal of Pharmacology examines the ability of the natural flavonoid quercitrin (related to quercitin) to inhibit production of iNOS (‘inducible nitric oxide synthase, the ‘bad’ nitric oxide producing enzyme). The authors state:

“Quercitrin, 3-rhamnosylquercetin, is a bioflavonoid with antioxidant properties, which exerts anti-inflammatory activity in experimental colitis. In the present study, different in vivo experiments were performed in order to evaluate the mechanisms of action involved in this effect, with special attention to its effects on proinflammatory mediators, including nitric oxide (NO).”

They examined the effects of quercitrin on inflammation of the intestinal mucosa (‘lining’) induced by DSS (dextran sodium sulfate) both preventatively and, in another cohort, on already established colitis. The results were significant:

“Oral treatment of quercitrin…ameliorated the evolution of the inflammatory process induced when administered in a preventative dosing protocol…on established colitis, it facilitated the recovery of the inflamed mucosa…The beneficial effects exerted by quercitrin were evidenced both histologically and biochemically, and were associated with an improvement in the colonic oxidative status…”

Regarding the role of NO and inflammatory bowel disease…

“…a reduction of colonic NO synthase activity was observed, probably related to a decreased expression in the inducible form of the enzyme [iNOS] via downregulation in the colonic activity of the nuclear factor-κB.”

The authors discuss their findings in summary:

“During the last decade, it has become increasingly clear that NO overproduction by iNOS is deleterious to intestinal function…thus contributing significantly to gastrointestinal immunopathology…the results obtained in the present study reveal that colonic inflammation is associated with a higher colonic NOS activity, mainly attributed to an increase in iNOS expression…the effect showed by quercitrin is most probably related to an inhibition of the expression of this enzyme, which is upregulated as a consequence of the colonic inflammatory process…The antioxidant and/or scavenging properties ascribed to this flavonoid could also contribute to its intestinal anti-inflammatory effect…”

A study published in the European Journal of Immunology sheds more light on the use of quercitin for inflammatory bowel disease. Examining the relationship between quercitrin and quercitin, the authors find…

“…that the in vivo effects of quercitrin…can be mediated by the release of quercetin generated after glycoside’s cleavage by the intestinal microbiota. This is supported by the fact that quercetin, but not quercitrin, is able to down-regulate the inflammatory response of bone marrow-derived macrophages in vitro.”

They also describe evidence for the effect of quercitin on iNOS and the the NF-κB pathway:

“Moreover, we have demonstrated that quercetin inhibits cytokine and inducible nitric oxide synthase expression through inhibition of the NF-κB pathway…(both in vitro and in vivo). As a conclusion, our report suggests that quercitrin releases quercetin in order to perform its anti-inflammatory effect…”

A paper published in the journal Digestive Diseases examines the ability of quercitin to help repair the gut barrier in inflammatory bowel disease. Regarding the intestinal epithelial barrier (‘lining’) the authors state:

“In inflammatory bowel disease (IBD), epithelial barrier function is impaired contributing to diarrhea by a leak flux mechanism and perpetuating inflammation by an increased luminal antigen uptake. This barrier of the intestinal epithelium is composed of the apical enterocyte membrane and the epithelial tight junction (TJ) and can be affected by TJ alterations, induction of epithelial apoptoses and appearance of gross lesions like erosions or ulcers as well as by accelerated transcytotic antigen uptake.”

They note that in addition to therapies that oppose Th1 cytokine activity in Crohn’s disease and Th2 cytokine activity in ulcerative colitis, other agents have been shown to improve barrier function:

“…zinc has been shown to improve barrier function in CD, although the inherent mechanisms are unknown. Finally, food components can strengthen the epithelial barrier as for example the flavonoid quercetin which has been shown to upregulate claudin-4 within the epithelial TJ.”

Curcumin (extracted from the yellow spice turmeric) should also be considered in the functional management of inflammatory bowel disease. The authors of a study published in the journal Inflammatory Bowel Diseases observe:

“Neutrophils (PMN) are the first cells recruited at the site of inflammation. They play a key role in the innate immune response by recognizing, ingesting, and eliminating pathogens and participate in the orientation of the adaptive immune responses. However, in inflammatory bowel disease (IBD) transepithelial neutrophil migration leads to an impaired epithelial barrier function, perpetuation of inflammation, and tissue destruction via oxidative and proteolytic damage. Curcumin (diferulolylmethane) displays a protective role in mouse models of IBD and in human ulcerative colitis, a phenomenon consistently accompanied by a reduced mucosal neutrophil infiltration.”

They investigated the phenomenon of neutrophil modulation by curcumin in vitro and in vivo. Their accumulated data demonstrated that…

“Curcumin attenuated lipopolysaccharide (LPS)-stimulated expression and secretion of macrophage inflammatory protein (MIP)-2, interleukin (IL)-1β, keratinocyte chemoattractant (KC), and MIP-1α in colonic epithelial cells (CECs) and in macrophages. Curcumin significantly inhibited PMN chemotaxis against MIP-2, KC, or against conditioned media from LPS-treated macrophages or CEC, a well as the IL-8-mediated chemotaxis of human neutrophils. At nontoxic concentrations, curcumin inhibited random neutrophil migration, suggesting a direct effect on neutrophil chemokinesis.”

In other words, curcumin was shown to significantly attenuate proinflammatory cytokine expression and white blood cell ‘attack movements’. Thus the authors conclude:

“Our results indicate that curcumin interferes with colonic inflammation partly through inhibition of the chemokine expression and through direct inhibition of neutrophil chemotaxis and chemokinesis.”

A double-blind, placebo-controlled trial of curcumin for the treatment of ulcerative colitis was reported in the journal Clinical Gastroenterology and Hepatology. The authors state:

“Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC).”

They divided a cohort of 89 patients with quiescent UC into a treatment group of 45 who added 1 gram of curcumin taken two times per day to their usual therapy. The other 44 got a placebo. After 6 months the relapse percentages were 4.65% for those who received curcumin and 20.51% for the placebo group.

“Furthermore, curcumin improved both CAI [clinical activity index] and EI [endoscopic index], thus suppressing the morbidity associated with UC.”

The authors conclude:

“Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.”

It’s also worth noting a paper published in the journal Current Pharmaceutical Design examines the multiple anti-inflammatory effects of curcumin. The authors first state:

“Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that afflicts millions of people throughout the world and impairs their daily functions and quality of life… it appears to be driven by inflammatory cytokines such as tumor necrosis factor (TNF)-α. Hence, there is a strong interest in agents that can block the generation or actions of inflammatory cytokines.”

They note that earlier research has demonstrated that curcumin inhibits inflammation through action on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-α, interferon γ (IFN-γ), inducible nitric oxide synthase (iNOS), and the transcriptional nuclear factor kappa B (NF-κB, a key factor in the production of proinflammatory cytokines), and has a strong anti-oxidant effect.

“Therefore, in recent years, the efficacy of curcumin has been investigated in several experimental models of IBD. The results indicate striking suppression of induced IBD colitis and changes in cytokine profiles…”

And in an early successful human IBD study..

“…patients were given curcumin (360mg/dose) 3 or 4 times/day for three months. Further, curcumin significantly reduced clinical relapse in patients with quiescent IBD.”

While it’s difficult to predict ahead of time which patients will have the best response to agents such as curcumin and quercitin, since they are so safe and wholesome we can welcome the authors’ conclusion:

“The inhibitory effects of curcumin on major inflammatory mechanisms like COX-2, LOX, TNF-α, IFN-γ, NF-κB and its unrivaled safety profile suggest that it has bright prospects in the treatment of IBD.”

Cancer, TGF-β and curcumin

Posted on March 31, 2010 by Dr. Jonathan

Cytokines are signalling molecules that orchestrate immune system activity, among which TGF-β (Transforming Growth Factor-Beta) is being recognized by numerous studies to have an important role in the immune response to cancers.

The authors of a paper just now being published in the European Journal of Cancer note the dual activity of TGF-β, and acknowledge that related treatments are being pursued:

“Transforming growth factor (TGF)-β signalling plays a dichotomous role in tumour progression, acting as a tumour suppressor early and as a pro-metastatic pathway in late-stages. There is accumulating evidence that advanced-stage tumours produce excessive levels of TGF-β, which acts to promote tumour growth… In light of the pro-metastasis function, many strategies are currently being explored to antagonise the TGF-β pathway as a treatment for metastatic cancers.”

A similar paper published in the journal Expert Opinion on Investigational Drugs also states:

“The transforming growth factor-ß (TGF-β) signaling pathway plays a pivotal role in diverse cellular processes. TGF-β switches its role from a tumor suppressor in normal or dysplastic cells to a tumor promoter in advanced cancers.”

They too note the enthusiasm for TGF-β inhibition in developed malignancies:

“TGF-β signaling has been considered a useful therapeutic target. The discovery of oncogenic actions of TGF-β has generated a great deal of enthusiasm for developing TGF-β signaling inhibitors for the treatment of cancer.”

A review published a month later in Expert Opinion on Therapeutic Targets considers inhibition of TGF-β specifically for prostate cancer:

“TGF-β regulates prostate growth by inhibiting epithelial cell proliferation and inducing apoptosis through eliciting a dynamic signaling pathway. In metastatic prostate cancer, however, TGF-β serves as a tumor promoter.”

They define very nicely the need to take a balanced approach in consideration of the dual role of TGF-β:

“”The molecular basis for effective therapeutic targeting of TGF-β must be directed towards the double-edge-sword nature of the cytokine: Inhibiting the TGF-β tumor promoter capabilities in advanced metastatic prostate cancer, although retaining the growth-inhibitory abilities exhibited in early stages of prostate tumorigenesis.”

Cellular & Molecular Biology Now consider this fascinating research just now being published in the journal Cellular & Molecular Immunology on the ability of curcumin (an extract of turmeric) to reduce the undesirable action of TGF-β. The authors begin by observing:

“Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion…Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells.”

Interestingly, not only did curcumin prevent the loss of T cells and reverse the type 2 immune bias…

“Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-β and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-β and IL-10 in these cells…curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.”

You may also wish to read an earlier post on cytokines and prostate cancer. I hope this makes it clear why I consider the measurement of TGF-β an important laboratory test for my patients in these circumstances, and curcumin a potentially valuable therapeutic ally. Be sure to discuss these with your doctor if the need arises.

Curcumin also helps brain trauma

Posted on February 22, 2010 by Dr. Jonathan

When the brain is traumatized there is “an energy crisis that compromises the capacity of the brain to cope with challenges, and often reduces cognitive ability.” This paper recently published in the journal Neuroscience reports that curcumin, extracted from the spice turmeric, has a significant beneficial impact on the ability of brain tissue to cope with “events that regulate energy homeostasis crucially impact synaptic function and this can compromise the capacity of the brain to respond to challenges during the acute and chronic phases of TBI.” The authors conclude that curcumin and similar compounds show value in recovering from brain injury: “Results show the potential of curcumin to regulate molecules involved in energy homeostasis following TBI. These studies may foster a new line of therapeutic treatments for TBI patients by endogenous upregulation of molecules important for functional recovery.”