Clinical Application of “Curcumin”, a Multi-Functional Substance

II) New molecular-targeted therapeutic agent for heart failure: curcumin (Fig. 3)

To evaluate the effect of curcumin on the development of cardiac hypertrophy, econd group of Dahl rats which were on a high- salt diet were orally administered curcumin for 5 weeks, starting at age 6 weeks. Curcumin significantly inhibited the increase in left ventricular posterior wall thickness associated with high-salt-diet-induced hypertension. In addition, inhibition of cardiomyocyte hypertrophy was histologically confirmed. Taken together, these findings demonstrated that curcumin inhibits not only the development and aggravation of hypertensive heart failure (systolic dysfunction) but also the formation of hypertensive cardiac hypertrophy (diastolic dysfunction). In the hypertension model, curcumin directly acted on cardiomyocytes to inhibit hypertrophy without lowering blood pressure, indicating that its mechanism of action importantly differs from that of antihypertensive agents (β-blockers, ARBs, ACE inhibitors). As such, curcumin may be more useful in treating cardiac hypertrophy and heart failure when combined with such antihypertensives.

Clinical application of curcumin will require comparison of its efficacy with that of existing therapeutic agents, as well as extensive evaluation of its additive effects. To this end, the efficacies of curcumin and enalapril, an ACE inhibitor and standard therapeutic agent for heart failure, were compared in a rat model of myocardial infarction ¹⁸⁾. Curcumin was able to match the therapeutic effects of enalapril on heart failure, while heart function was additively improved on combination of the two. These findings indicate that curcumin has an additive effect with ACE inhibitors, indicating that its mechanism of action does indeed differ from those compounds and providing further support to the notion that optimum efficacy against cardiac hypertrophy and heart failure may be achieved via combination treatment with antihypertensives.

Fig. 3. Curcumin inhibits p300 HAT activity and thereby the progression of cardiomyocyte hypertrophy and heart failure.

III) Improvement in heart failure on THERACURMIN ^® administration

Given that curcumin showed poor oral absorption in rats even at 50 mg/kg/day, we used THERACURMIN^® as an alternative in our studies, as orally administrated THERACURMIN^® improved post-MI LV systolic dysfunction in rats at much lower doses (0.5 mg/kg) than curcumin ¹⁹⁾.

IV) Future heart failure therapy

To establish a fundamental pharmacological therapy for heart failure, we examined the common nuclear signaling pathway within cardiomyocytes, ultimately identifying the p300 HAT activity as a molecular target. In addition, we confirmed that curcumin, a p300-specific HAT inhibitor, inhibited hypertrophy in cultured cardiomyocytes and improved heart failure in animal models, with clinical trials in humans currently ongoing. These above-described findings suggest that a new therapy aimed controlling gene expression in the nuclei of cardiomyocytes as well as cardiomyocyte function may be within reach. Developing such a therapeutic regimen will in turn improve the quality of life and prognosis of patients with heart failure.

4. Development of new cancer therapy using THERACURMIN ®

Another potential health benefit of curcumin is its antitumor effects. A Pubmed search using the keywords “curcumin” and “cancer” returned over 1500 articles published since 1983, with more than half published in the past 5 years. Curcumin’s antitumor effects have been shown in a number of preclinical cancer models, including breast cancer, colorectal cancer, head and neck cancer, leukemia, stomach cancer, liver cancer, ovary cancer, pancreatic cancer, prostate cancer, and multiple myeloma ^20-22). Curcumin has been reported to affect the expression and activity of various proteins involved in cancer progression, particularly nuclear transcription factor-ĸB (NF-ĸB). In cancer tissues, upstream signals (growth factors, cytokines, and hypoxemia) can activate NF-ĸB, which in turn upregulates the expression of downstream proteins involved in anti-apoptosis (Bcl-2 and Bcl-xL), cell proliferation (cyclin D1 and c-myc), angiogenesis (vascular endothelial growth factor [VEGF] and interleukin-6), and metastasis (matrix metalloproteinases [MMP]), all of which can induce cancer progression ²³⁾. Curcumin’s NF-ĸB-inhibiting activity, together with its safety profile supported by its widespread use as a spice and traditional medicine for many years, therefore presents this compound as a promising new anticancer agent (Fig. 4).

Fig. 4. Curcumin inhibits the activity of NF-κB, a factor involved in cancer progression.

I) Clinical trials using curcumin

On searching ClinicalTrials (http://clinicaltrials.gov/), a registry of clinical trials, using the keywords “curcumin” and “cancer,” we found that the number of clinical trials registered increased from 27 in October 2010 to 34 in May 2011.

In our Phase I/II clinical trial using curcumin in patients with pancreatic cancer who were resistant to gemcitabine, a standard therapeutic agent for pancreatic cancer ²⁵⁾, we evaluated the safety and tolerability of curcumin at 8 g/day in combination with gemcitabine-based chemotherapy. The daily dose of 8 g was selected because although no dose- limiting toxicity had been observed up to a daily dose of 12 g in an overseas Phase I clinical trial of curcumin, no additional increase in the blood concentration was achieved at doses exceeding 8 g, and continuing treatment at doses over 8 g is difficult due to the excessive bulk to be ingested. Because no predefined dose-limiting toxicity was observed in the first 3 patients, the Phase II clinical trial was continued at a daily dose of 8 g for all 21 patients.  No notable adverse events related to concomitant curcumin were reported, and the median compliance was as high as 100% (range: 79%-100%). In all patients, the median survival and one-year survival rate were 161 days (95% confidence interval: 109-223 days) and 19% (95% confidence interval: 4.4%-41.4%), respectively, promising attention was paid to the potential effects of habitual exercise results considering a dismal prognosis of this disease after  and eating habits on arterial stiffness, because the increase in getting refractory to gemcitabine, despite the relatively small arterial stiffness was traditionally considered an irrevocable sample size.

However, while the above findings are indeed promising, curcumin’s low bioavailability still compromised its clinical application. A number of studies have cited extremely low blood curcumin concentrations (Table 1), indicating that curcumin bioavailability needs to be improved to exert significant therapeutic benefits.

II) New clinical trials using THERACURMIN ®

In Japan and abroad, efforts are now being made to improve the bioavailability of curcumin by developing new formulations using various drug delivery systems (liposomes, nanoparticles, and phospholipids) as well as derivatives with higher activity. In one pharmacokinetic study, maximum blood concentration (Cmax) in 6 healthy volunteers after ingestion of THERACURMIN® at a dose of 150 mg was 189 ± 48 ng/mL (mean ± standard error), which was higher than that observed with conventional curcumin at a daily dose of 8 g. The same 6 subjects also received THERACURMIN® at a dose of 210 mg after a 2-week period, resulting in a Cmax of 275 ± 67 ng/mL. These results further demonstrate the markedly improved bioavailability of THERACURMIN® compared with curcumin and dose-dependently increased blood curcumin concentration up to 210 mg in human 3). In light of these f indings, THERACURMIN® is expected to provide more reliable effects with higher blood curcumin concentrations, and a new clinical trial using THERACURMIN® is now underway to test its efficacy in cancer patients.

5. Efficacy of exercise and potential effects of curcumin on arterial stiffness

William Osler once stated, “a man is as old as his arteries”. Accordingly, stiffness of the central arteries such as the aorta (arterial stiffness) increases with aging and is an independent risk factor for cardiovascular disease. In the past, little attention was paid to the potential effects of habitual exercise and eating habits on arterial stiffness, because the increase in arterial stiffness was traditionally considered an irrevocable phenomenon of aging. However, since the discovery of the link between habitual aerobic exercise and decreased arterial stiffness, increasing focus has been situated on the importance of exercise in decreasing arterial stiffness. A similar relationship has been identified between diet and arterial stiffness. In this section, we review the relationship between exercise and diet with arterial stiffness, as well as touch on the latest findings regarding the relationship between arterial stiffness and curcumin in particular.

I) Exercise and arterial stiffness

Arterial stiffness is a risk factor for cardiovascular and cerebrovascular diseases that increases with age. To counter these risks, increased physical activity and habitual exercise in daily life may help prevent or inhibit this stiffness, thereby slowing the development of cardiovascular and cerebrovascular diseases in middle-aged and older people. Indeed, arterial stiffness has been shown to be lower in middle-aged and older people who exercised regularly such as by jogging, walking, or cycling than in those who did not ³²⁾. Similar findings were found in those with high levels of physical activity in their daily lives ³³⁾ or in those who took up relatively short-term aerobic exercise regimens (over 2 to 3 months) ^32,34,35), all findings which support the notion that habitual aerobic exercise decreases arterial stiffness. Further, these findings are not limited to merely fit, middle-aged individuals, as habitual aerobic exercise-induced decreases in arterial stiffness have also been noted in both the young and elderly as well as in the obese ^32,34-37).

Regarding the mechanism for these effects, we previously reported the involvement of endothelin-1, which is produced by vascular endothelial cells and has a vasoconstrictive effect and a stimulatory effect on vascular smooth muscle proliferation ³⁸⁾. In middle-aged and older people who received exercise therapy for 3 months, acute administration of an endothelin receptor antagonist decreased arterial stiffness before exercise therapy but had no effect on stiffness after exercise therapy, when both the plasma endothelin-1 concentration and arterial stiffness had already decreased ³⁸⁾. These findings strongly suggest that habitual aerobic exercise may decrease arterial stiffness by decreasing the production of or sensitivity to endothelin-1.

II) Diet and arterial stiffness

Various studies have shown that not only habitual exercise, but also eating habits can decrease arterial stiffness. In one study in obese individuals, diet improvement with calorie restriction over 3 months resulted in a mean weight decrease of approximately 8 kg as well as a decrease in arterial stiffness 39)_. In addition, many studies have reported how certain diets may affect arterial stiffness ⁴⁰⁾. For example, one demonstrated that salt intake substantially affects arterial stiffness as well as blood pressure ^41,42). A cross-sectional study showed that a decrease in salt intake results in not only a decrease in blood pressure but also in arterial stiffness, independent of blood pressure ⁴¹⁾. In a longitudinal study in postmenopausal women with hypertension, arterial stiffness was decreased after 3 months on a low-salt diet ⁴²⁾. Interestingly, the decrease in stiffness was more pronounced following a change in diet than that achieved with habitual exercise ⁴²⁾. Besides salt reduction, fish consumption has also been reported to help reduce arterial stiffness, as increased consumption has been associated with decreased arterial stiffness ⁴³⁾, suggesting that the polyunsaturated fatty acids in fish oil, abundant in blue-skin fish such as mackerel, saury, and sardine, may be involved in decreasing arterial stiffness. In addition, a number of studies have shown a decrease in arterial stiffness due to the isoflavones in soybeans, pungent chili powder, antioxidant vitamins (vitamin C and vitamin E), garlic powder, and milk- derived lactotripeptides.

III) Curcumin and arterial stiffness

We recently evaluated the effects of continuous use of curcumin on arterial stiffness. In postmenopausal middle- aged and older women, arterial stiffness decreased after use of THERACURMIN^® over a period of two months (unpublished data), with efficacy almost equal to that achieved with aerobic exercise over the same period. These findings suggest that curcumin may be an alternative therapy to decrease arterial stiffness in patients who cannot or will not continue exercise. We also evaluated the effects of combining habitual aerobic exercise and THERACURMIN^® on arterial stiffness, finding that arterial stiffness decreased more markedly with combination therapy than with either alone (unpublished data).

IV) To improve arterial stiffness

We demonstrated that the arterial stiffness is decreased by curcumin (Fig. 5). Furthermore, we suggest that maximizing the effects of curcumin against arterial stiffness can best be achieved by combining habitual exercise and eating habits. Such a combination of exercise and diet with curcumin may represent a remarkably effective non-pharmacological therapy.

Fig. 5. Curcumin improves artificial stiffness.

6. Conclusion

Japan’s rapidly aging society is experiencing increased social demand for healthy longevity. Meeting this demand via development of new highly functional food-derived substances and medicinal seeds from foods will require organically combining nutritional, pharmaceutical, and medical sciences using new methodologies and technologies. Studies to date have evaluated the interactions between pharmaceutical products and foods or their safety on an individual rather than comprehensive basis. As reviewed in this article, many studies ranging from basic studies to clinical studies have been conducted on curcumin and its clinical applications in treating various diseases. Given its range of effects, curcumin alone may be useful in treating and preventing a number of diseases, but fully establishing its potential will require further studies and clinical application.