Curcumin Downregulates NF-kB and Related Genes in Patients with Multiple Myeloma: Results of a Phase I/II Study.

Abstract

Although the role of NF-kB and STAT3 pathways in proliferation/metastasis of various tumor cells is well established, no agent has been described which could downregulate the activation of these transcription factors in cancer patients (pts). Curcumin has been shown to potently suppress the activation of these transcription factors in cultured cells. Based on these observations, we initiated a clinical trial of curcumin alone (administered orally at 2, 4, 6, 8, or 12 grams/day in 2 divided doses) or in combination with Bioperine (10 mg in 2 divided doses) for 12 weeks in multiple myeloma (MM) pts. The objectives of this study were to evaluate the clinical safety and biologic effects in MM pts who had asymptomatic, relapsed/refractory, or plateau phase disease. Blood was collected for PK/PD and PBMCs were examined (baseline and during treatment) for evaluating the effect of treatment on expression of NF-kB (p65), COX-2 and phospho-STAT3 as surrogate biomarkers. NF-kB activation status was also measured by electrophoretic mobility shift assay. At least 6 pts are enrolled at each dose level; 3 on the curcumin arm and 3 on the curcumin + bioperine arm. Pts with at least stable disease were allowed to continue treatment up to one year. Treatment with curcumin and bioperine has been well tolerated, with no significant adverse events. At the 12 grams dose level, 2 of the 5 pts had difficulty swallowing the large number of capsules. Of the 29 evaluable pts treated so far, no objective responses have been seen. Twelve pts continued treatment for more than 12 weeks and 5 (1 patient at 4 grams, 2 pts at 6 grams, and 2 pts at 8 grams dose levels) completed one year of treatment with stable disease. With few exceptions, little if any free drug was found in the plasma. Total curcumin levels (mostly conjugated drug) were dependent on both dose and the duration of administration. PBMCs from 28 MM pts examined showed constitutively active NF-kB (mean ± STD, 74.2% ± 14.0 positive cells), COX2 (66% ± 15.4), and STAT3 (52.8% ± 19.2). Oral administration of curcumin significantly downregulated the constitutive activation of NF-kB (at 3 months a median reduction of 77%, p<0.0001) and STAT3 (69%, p<0.001), and suppressed COX2 (66%, p<0.0001) expression in most of the pts at each of the monthly time points.Conclusions: This is the first report to indicate that curcumin, a highly safe agent, is bioavailable and can downregulate NF-kB, STAT3 and COX2 in MM pts. These findings suggest a potential therapeutic role for curcumin that can be further investigated either alone or as a modulator of chemo-resistance in combination with other active agents.