Phase IIa Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia

Abstract

Curcumin is derived from the spice tumeric and has anti-inflammatory and antineoplastic effects in vitro and in animal models, including preventing aberrant crypt foci (ACF) and adenomas in murine models of colorectal carcinogenesis. Inhibiting the production of the procarcinogenic eicosanoids prostaglandin E2 (PGE2) and 5-hydroxyeicosatetraenoic acid (5-HETE) can suppress carcinogenesis in rodents. Curcumin reduces mucosal concentrations of PGE2 (via inhibition of cyclooxygenases 1 and 2) and 5-HETE (via inhibition of 5-lipoxygenase) in rats. Although preclinical data support curcumin acitivity in many sites, the reported poor bioavailability of this agent supports its use in the colorectum We assessed the effects of oral curcumin (2 g or 4 g per day for 30 days) on PGE2 within ACF (primary endpoint), 5-HETE, ACF number, and proliferation in a non-randomized, open-label clinical trial in 44 eligible smokers with 8 or more ACF on screening colonoscopy. We assessed pre- and post-treatment concentrations of PGE2 and 5-HETE by liquid chromatography tandem mass spectroscopy in ACF and normal-tissue biopsies, ACF number via rectal endoscopy, proliferation by Ki-67 immunohistochemistry; and curcumin concentrations by high-performance liquid chromatography in serum and rectal mucosal samples. 41 Subjects completed the study. Neither dose of curcumin reduced PGE2 or 5-HETE within ACF or normal mucosa or Ki-67 in normal mucosa. A significant 40% reduction in ACF number occurred with the 4 g dose (P < 0.005); while ACF were not reduced in the 2 g group. This reduction was associated with a significant change in plasma curcumin/conjugate levels pre- and post-treatmeeng (5-fold increase; P = 0.009) in the 4 g group. Curcumin was well tolerated at both 2 g and 4g. Our data suggest that curcumin can decrease ACF number, and this is potentially mediated by curcumin conjugates delivered systemically.

Epigenetic changes induced by curcumin and other natural compounds

“…The continuously growing list of natural compounds ( Table 1) that modulate epigenetic mechanisms shows the great interest in this exciting field and clinical trials performed with several of these compounds (Table 2) confirm their efficiency. Quercetin, fisetin, myricetin Lee et al (2005) Caffeic acid Lee and Zhu (2006) Chlorogenic acid Cadaveric renal transplantation 480 mg; 1-2/day 9 30 days 43 Improved renal function, reduced neurotoxicity Shoskes et al (2005) Cardiovascular disease 500 mg/day 9 7 days 10 Decreased serum lipid peroxidase (33%), increased HDL cholesterol (29%), decreased total serum cholesterol (12%) Soni and Kuttan (1992) Chronic anterior uveitis 375 mg; 39/day 9 84 days 32 86% decrease in chronic anterior uveitis Lal et al (1999) Crohn's disease 360 mg; 3/day 9 30 days; 4 for 60 days 5 Improved symptoms Holt et al (2005) CRC 36-180 mg/day 9 120 days 15 Lowered GST Sharma et al (2001) CRC 450-3,600 mg/day 9 120 days 15 Lowered inducible serum PGE2 levels Sharma et al (2004) CRC 450-3,600 mg/day 9 7 days 12 Decreased M1G DNA adducts Garcea et al (2005) Colon cancer 10 g (n = 6) and 12 g (n = 6) 12 Pharmacokinetics Vareed et al (2008) CRC, ACF 2 g or 4 g/day for 30 days 44 A significant 40% reduction in ACF number occurred with the 4 g dose (P \ 0.005), whereas ACF were not reduced in the 2 g group Carroll et al (2011) External cancerous 1% ointment for several months 62 Reduction in smell in 90% patients, reduction of itching in all cases, dry lesions in 70% patients, reduction in lesion size and pain in 10% patients Kuttan et al (1987) Bundy et al (2004) Liver metastasis 450-3,600 mg/day 9 7 day 12 Low bioavailability Garcea et al (2004) (Fig. 2).…”

Codelivery of SH-aspirin and curcumin by mPEG-PLGA nanoparticles enhanced antitumor activity by inducing mitochondrial apoptosis

“…27 Although the therapeutic activities of Cur demonstrate its potential in cancer therapy, the issue of water insolubility greatly limits its further application, such as in drug formulation.…”

Plant-derived anticancer agents: a promising treatment for bone metastasis

“…Curcumin was well tolerated at both doses. 44 In advanced pancreatic cancer, curcumin was found to be safe and well tolerated in a phase II clinical trial in which 25 patients were given 8 g of curcumin per day orally until disease progression. No toxicities associated with curcumin administration were reported in the patients.…”