Phase I Clinical Trial of Oral Curcumin

Abstract

Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E 2 (PGE 2 ) production, or suppression of oxidative DNA adduct (M 1 G) formation. We designed a dose-escalation study to explore the pharmacology of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 months. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by highpressure liquid chromatography and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclinical models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M 1 G, and PGE 2 production induced ex vivo. Dose-limiting toxicity was not observed. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE 2 production in blood samples taken 1 hour after dose on days 1 and 29, respectively, of treatment compared with levels observed immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE 2 production in blood and target tissue may indicate biological activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.

Curcumin as “Curecumin”: From kitchen to clinic

“…In a subsequent dose-escalation study in a similar population, Sharma et al [183] further explored the pharmacology of curcumin administered in capsules at daily doses ranging from 0.45 to 3.6 g daily for up to 4 months. This time, the compound's effects on leukocytes were measured in terms of three potential biomarkers: GST activity, deoxyguanosine adduct M(1)G levels, and PGE 2 production ex vivo.…”

Curcumin derivatives: Molecular basis of their anti-cancer activity

“…Purity of all synthesized compounds was >98%, and it was determined by means of NMR techniques and combustion analysis. 6.82 (dd, J=7.5, 1Hz, 2H; H-9), 7.49 (dd, J=7.5, 2 Hz, 2H; H-10). 13 …”

“…Curcumin exhibits cancer growth inhibition both in vitro and in vivo [5,6]: it suppresses cell proliferation in a variety of cancer cell lines and it inhibits tumorigenesis [7][8][9][10][11][12][13][14][15][16][17]. Multiple mechanisms of action are likely responsible for Curcumin various effects on cancer cells: G1/S arrest and apoptosis induction have been observed other than the mitotic block in different tumor cell lines [18][19][20].…”

Identification of Siah-interacting protein as a potential regulator of apoptosis and curcumin resistance

“…Growing evidences indicate that curcumin is able to induce apoptosis in various cancer cells (Karunagaran et al, 2005) and to suppress tumorigenesis, angiogenesis and metastasis in diverse chemical-induced or xenograft tumor models (Kawamori et al, 1999;Li et al, 2002;Aggarwal et al, 2005;Bhandarkar and Arbiser, 2007). Moreover, both phase I and phase II clinical trials show that curcumin is effective and well tolerated for cancer patients (Sharma et al, 2004;Dhillon et al, 2008). To date, comprehensive studies have been conducted to characterize the anticancer effect of curcumin, but little is known about its resistance.…”