The Holy Grail of Curcumin and its Efficacy in Various Diseases
Shusuke Toden, PhD
Ajay Goel, PhD
PDF
HTML

Keywords

Bioactivity
Bioavailability
Curcumin
PDF
HTML

Abstract

The powdered rhizome of turmeric has been extensively used in India and other South Asian cuisines, and is an integral part of Ayurvedic medicine for a broad range of conditions. In particular, curcumin, a major active component of turmeric, is one of the most studied botanicals for its anti-inflammatory, anti-oxidant and anti-cancer properties. Despite its well-documented therapeutic efficacy, for years the limited systemic bioavailability of curcumin has hindered its development as a potential therapeutic agent. However, recent introduction of unique extraction processes and various delivery methods has resulted in the development of new curcumin formulations and significantly improved its bioavailability. While these new formulations will no doubt expand curcumin’s therapeutic potential, there are notable inconsistencies surrounding curcumin’s bioavailability and corresponding bioactivity, raising some important questions. This article dissects various contributing factors of curcumin bioavailability to identify possible causes for the discrepancies associated with its bioactivity and discuss how these new curcumin formulations could further improve its clinical usefulness.

PDF
HTML

References

Sharma RA, McLelland HR, Hill KA, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res. 2001; 7(7):1894–900.
Garcea G, Jones DJ, Singh R, et al. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br J Cancer. 2004; 90(5):1011–5.
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007; 4(6):807–18.
Douglass BJ, Clouatre DL. Beyond yellow curry: assessing commercial curcumin absorption technologies. J Am Coll Nutr. 2015; 34(4):347–58.
Patil K, Guledgud MV, Kulkarni PK, et al. Use of curcumin mouthrinse in radio-chemotherapy induced oral mucositis patients: a pilot study. J Clin Diagn Res. 2015; 9(8):ZC59–62.
Parsons HA, Baracos VE, Hong DS, et al. The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer. Oncotarget. 2016; 7(15):20293–304.
Kuriakose MA, Ramdas K, Dey B, et al. A randomized double-blind placebo-controlled phase IIB trial of curcumin in oral leukoplakia. Cancer Prevent Res. 2016; 9(8):683–91.
Irving GR, Iwuji CO, Morgan B, et al. Combining curcumin (C3-complex, Sabinsa) with standard care FOLFOX chemotherapy in patients with inoperable colorectal cancer (CUFOX): study protocol for a randomised control trial. Trials. 2015; 16:110.
Mahammedi H, Planchat E, Pouget M, et al. The new combination docetaxel, prednisone and curcumin in patients with castration-resistant prostate cancer: a pilot phase II study. Oncology. 2016; 90(2):69–78.
Garcea G, Berry DP, Jones DJ, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prevent. 2005; 14(1):120–5.
Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol. 1978; 43(2):86–92.
Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology. 1980; 16(3):259–65.
Pan MH, Huang TM, Lin JK. Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metab Dispos. 1999; 27(4):486–94.
Shoba G, Joy D, Joseph T, et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998; 64(4):353–6.
Ryu EK, Choe YS, Lee KH, et al. Curcumin and dehydrozingerone derivatives: synthesis, radiolabeling, and evaluation for beta-amyloid plaque imaging. J Med Chem. 2006; 49(20):6111–9.
Wang Y, Yin H, Li J, et al. Amelioration of beta-amyloid-induced cognitive dysfunction and hippocampal axon degeneration by curcumin is associated with suppression of CRMP-2 hyperphosphorylation. Neurosci Lett. 2013; 557 Pt B:112–7.
Hoehle SI, Pfeiffer E, Solyom AM, Metzler M. Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver. J Agric Food Chem. 2006; 54(3):756–64.
Wahlang B, Pawar YB, Bansal AK. Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model. Eur J Pharm Biopharm. 2011; 77(2):275–82.
Khopde SM, Priyadarsini KI, Guha SN, et al. Inhibition of radiation-induced lipid peroxidation by tetrahydrocurcumin: possible mechanisms by pulse radiolysis. Biosci Biotechnol Biochem. 2000; 64(3):503–9.
Okada K, Wangpoengtrakul C, Tanaka T, et al. Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. J Nutr. 2001; 131(8):2090–5.
Bansal SS, Goel M, Aqil F, et al. Advanced drug delivery systems of curcumin for cancer chemoprevention. Cancer Prevent Res. 2011; 4(8):1158–71.
Asai A, Miyazawa T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life Sci. 2000; 67(23):2785–93.
Sandur SK, Pandey MK, Sung B, et al. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis. 2007; 28(8):1765–73.
Pfeiffer E, Hoehle SI, Walch SG, et al. Curcuminoids form reactive glucuronides in vitro. J Agric Food Chem. 2007; 55(2):538–44.
Kim JM, Araki S, Kim DJ, et al. Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation. Carcinogenesis. 1998; 19(1):81–5.
Pari L, Murugan P. Tetrahydrocurcumin: effect on chloroquine-mediated oxidative damage in rat kidney. Basic Clin Pharmacol Toxicol. 2006; 99(5):329–34.
Ireson C, Orr S, Jones DJ, et al. Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production. Cancer Res. 2001; 61(3):1058–64.
Suresh D, Srinivasan K. Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats. Indian J Med Res. 2010; 131:682–91.
Piyachaturawat P, Glinsukon T, Toskulkao C. Acute and subacute toxicity of piperine in mice, rats and hamsters. Toxicol Lett. 1983; 16(3–4):351–9.
Ji HF, Shen L. Can improving bioavailability improve the bioactivity of curcumin? Trends Pharmacol Sci. 2014; 35:265–6.
Wang YJ, Pan MH, Cheng AL, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. 1997; 15(12):1867–76.
Sultana R. Ferulic acid ethyl ester as a potential therapy in neurodegenerative disorders. Biochim Biophys Acta. 2012; 1822(5):748–52.
Barone E, Calabrese V, Mancuso C. Ferulic acid and its therapeutic potential as a hormetin for age-related diseases. Biogerontology. 2009; 10(2):97–108.
Kurien BT, Singh A, Matsumoto H, Scofield RH. Improving the solubility and pharmacological efficacy of curcumin by heat treatment. Assay Drug Dev Technol. 2007; 5(4):567–76.
Kurien BT, Scofield RH. Curcumin/turmeric solubilized in sodium hydroxide inhibits HNE protein modification–an in vitro study. J Ethnopharmacol. 2007; 110(2):368–73.
Bisht S, Feldmann G, Soni S, et al. Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. J Nanobiotechnol. 2007; 5:3.
Bawarski WE, Chidlowsky E, Bharali DJ, Mousa SA. Emerging nanopharmaceuticals. Nanomedicine. 2008; 4(4):273–82.
Sou K, Inenaga S, Takeoka S, Tsuchida E. Loading of curcumin into macrophages using lipid-based nanoparticles. Int J Pharm. 2008; 352(1–2):287–93.
Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles in brain targeting. J Control Release. 2008; 127(2):97–109.
Naksuriya O, Okonogi S, Schiffelers RM, Hennink WE. Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment. Biomaterials. 2014; 35(10):3365–83.
Sunagawa Y, Hirano S, Katanasaka Y, et al. Colloidal submicron-particle curcumin exhibits high absorption efficiency–a double-blind, 3-way crossover study. J Nutr Sci Vitaminol (Tokyo). 2015; 61(1):37–44.
Cheng KK, Yeung CF, Ho SW, et al. Highly stabilized curcumin nanoparticles tested in an in vitro blood-brain barrier model and in Alzheimer’s disease Tg2576 mice. AAPS J. 2013; 15(2):324–36.
Cutrin JC, Crich SG, Burghelea D, et al. Curcumin/Gd loaded apoferritin: a novel “theranostic” agent to prevent hepatocellular damage in toxic induced acute hepatitis. Mol Pharm. 2013; 10(5):2079–85.
Kakkar V, Muppu SK, Chopra K, Kaur IP. Curcumin loaded solid lipid nanoparticles: an efficient formulation approach for cerebral ischemic reperfusion injury in rats. Eur J Pharm Biophar. 2013; 85(3 Pt A):339–45.
Sunagawa Y, Wada H, Suzuki H, et al. A novel drug delivery system of oral curcumin markedly improves efficacy of treatment for heart failure after myocardial infarction in rats. Biol Pharm Bull. 2012; 35(2):139–44.
Thangapazham RL, Puri A, Tele S, et al. Evaluation of a nanotechnology-based carrier for delivery of curcumin in prostate cancer cells. Int J Oncol. 2008; 32(5):1119–23.
Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer. 2005; 104(6):1322–31.
Karewicz A, Bielska D, Loboda A, et al. Curcumin-containing liposomes stabilized by thin layers of chitosan derivatives. Colloids Surf B Biointerfaces. 2013; 109:307–16.
Shishu, Maheshwari M. Comparative bioavailability of curcumin, tumeric, and BiocurcumaxTM in traditional vehicles using non-everted rat intestinal sac model. J Funct Foods. 2010; 2:60–5.
Antony B, Merina B, Iyer VS, et al. A pilot cross-over study to evaluate human oral bioavailability of BCM-95CG (Biocurcumax), a novel bioenhanced preparation of curcumin. Indian J Pharm Sci. 2008; 70(4):445–9.
Toden S, Theiss AL, Wang X, Goel A. Essential turmeric oils enhance anti-inflammatory efficacy of curcumin in dextran sulfate sodium-induced colitis. Sci Rep. 2017; 7(1):814.
Aggarwal BB, Yuan W, Li S, Gupta SC. Curcumin-free turmeric exhibits anti-inflammatory and anticancer activities: Identification of novel components of turmeric. Mol Nutr Food Res. 2013; 57(9):1529–42.
Liju VB, Jeena K, Kuttan R. An evaluation of antioxidant, anti-inflammatory, and antinociceptive activities of essential oil from Curcuma longa. L. Indian J Pharmacol. 2011; 43(5):526–31.
Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012; 26(11):1719–25.
Sanmukhani J, Satodia V, Trivedi J, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res. 2014; 28:579–85.
Baum L, Lam CW, Cheung SK, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008; 28(1):110–3.
Padhye S, Yang H, Jamadar A, et al. New difluoro Knoevenagel condensates of curcumin, their Schiff bases and copper complexes as proteasome inhibitors and apoptosis inducers in cancer cells. Pharm Res. 2009; 26(8):1874–80.
Qiu X, Du Y, Lou B, et al. Synthesis and identification of new 4-arylidene curcumin analogues as potential anticancer agents targeting nuclear factor-kappaB signaling pathway. J Med Chem. 2010; 53(23):8260–73.
Bao B, Ali S, Banerjee S, et al. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 2012; 72(1):335–45.
Bao B, Ali S, Kong D, et al. Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer. PLoS One. 2011; 6(3):e17850.
Roy S, Yu Y, Padhye SB, et al. Difluorinated-curcumin (CDF) restores PTEN expression in colon cancer cells by down-regulating miR-21. PLoS One. 2013; 8(7):e68543.
Ali S, Ahmad A, Banerjee S, et al. Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res. 2010; 70(9):3606–17.
Ramalingam P, Ko YT. A validated LC-MS/MS method for quantitative analysis of curcumin in mouse plasma and brain tissue and its application in pharmacokinetic and brain distribution studies. J Chromatogr B Analyt Technolog Biomed Life Sci. 2014; 969:101–8.
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.