Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer

Abstract

Purpose: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration^approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients.We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-nB (NF-nB) and tumor inhibitory properties, against advanced pancreatic cancer. Experimental Design: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-nB and cyclooxygenase-2 were monitored. Results:Twenty-five patients were enrolled, with 21evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4-to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-nB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41ng/mL and remained relatively constant over the first 4 weeks. Conclusions: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

“…S6). Curcumin, that is found in the diet, has already proven to be useful in chemoprevention for colorectal 45 and pancreatic cancer 46 .…”

Curcumin as “Curecumin”: From kitchen to clinic

“…Curcumin has potential in advanced pancreatic cancer Curcumin has also been examined as a single-agent in patients with advanced pancreatic cancer [196]. A dose of 8 g curcumin per day was administered for 2 months.…”

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.…”