A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin®) in cancer patients

Abstract

Background

A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin®) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin® in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin® in cancer patients.

Methods

Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin® containing 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin® was orally administered every day with standard gemcitabine-based chemotherapy. In addition to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated.

Results

Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin® administration were 324 ng/mL (range, 47–1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179–1,380 ng/mL) at Level 2. No unexpected adverse events were observed and 3 patients safely continued Theracurmin® administration for >9 months.

Conclusions

Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin® did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.

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References

  1. 1.

    Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC et al (1993) The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, Wang Z, Philip PA, Sarkar FH (2010) 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 70:3606–3617

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Bansal SS, Goel M, Aqil F, Vadhanam MV, Gupta RC (2011) Advanced drug delivery systems of curcumin for cancer chemoprevention. Cancer Prev Res (Phila) 4:1158–1171

    Article  CAS  Google Scholar 

  4. 4.

    Bisht S, Feldmann G, Soni S, Ravi R, Karikar C, Maitra A (2007) Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. J Nanobiotechnol 5:3

    Article  Google Scholar 

  5. 5.

    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413

    PubMed  CAS  Google Scholar 

  6. 6.

    Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang YJ, Tsai CC, Hsieh CY (2001) Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21:2895–2900

    PubMed  CAS  Google Scholar 

  7. 7.

    Cho JW, Lee KS, Kim CW (2007) Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int J Mol Med 19:469–474

    PubMed  CAS  Google Scholar 

  8. 8.

    Corson TW, Crews CM (2007) Molecular understanding and modern application of traditional medicines: triumphs and trials. Cell 130:769–774

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Das RK, Kasoju N, Bora U (2010) Encapsulation of curcumin in alginate-chitosan-pluronic composite nanoparticles for delivery to cancer cells. Nanomedicine 6:153–160

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V, Kurzrock R (2008) Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14:4491–4499

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Du B, Jiang L, Xia Q, Zhong L (2006) Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29. Chemotherapy 52:23–28

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Epelbaum R, Schaffer M, Vizel B, Badmaev V, Bar-Sela G (2010) Curcumin and gemcitabine in patients with advanced pancreatic cancer. Nutr Cancer 62:1137–1141

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Fabre JM, Burgel JS, Navarro F, Boccarat G, Lemoine C, Domergue J (1999) Delayed gastric emptying after pancreaticoduodenectomy and pancreaticogastrostomy. Eur J Surg 165:560–565

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Fayers P, Aaronson N, Bjordal K, Groenvoold M, Curran D (2001) Bottomley A (2001) EORTC QLQ-C30 Scoring Manual, 3rd edn. European Organisation for Research and Treatment of Cancer, Brussels

    Google Scholar 

  15. 15.

    Fox E, Curt GA, Balis FM (2002) Clinical trial design for target-based therapy. Oncologist 7:401–409

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Gescher AJ (2012) Dose escalation and pharmacokinetic study of nanoparticle curcumin… by Kanai et al., CCP 69:65–70, 2012. Cancer Chemother Pharmacol 70:487

    PubMed  Article  Google Scholar 

  17. 17.

    Gupta A, Vij G, Sharma S, Tirkey N, Rishi P, Chopra K (2009) Curcumin, a polyphenolic antioxidant, attenuates chronic fatigue syndrome in murine water immersion stress model. Immunobiology 214:33–39

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Ireson C, Orr S, Jones DJ, Verschoyle R, Lim CK, Luo JL, Howells L, Plummer S, Jukes R, Williams M, Steward WP, Gescher A (2001) 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 61:1058–1064

    PubMed  CAS  Google Scholar 

  19. 19.

    Kanai M, Imaizumi A, Otsuka Y, Sasaki H, Hashiguchi M, Tsujiko K, Matsumoto S, Ishiguro H, Chiba T (2012) Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol 69:65–70

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Kanai M, Matsumoto S, Otsuka Y, Fukuda M, Imaizumi A (2012) In response. Cancer Chemother Pharmacol 70:489

    Article  Google Scholar 

  21. 21.

    Kanai M, Yoshimura K, Asada M, Imaizumi A, Suzuki C, Matsumoto S, Nishimura T, Mori Y, Masui T, Kawaguchi Y, Yanagihara K, Yazumi S, Chiba T, Guha S, Aggarwal BB (2011) A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol 68:157–164

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Kanai M, Yoshimura K, Tsumura T, Asada M, Suzuki C, Niimi M, Matsumoto S, Nishimura T, Nitta T, Yasuchika K, Taura K, Mori Y, Hamada A, Inoue N, Tada S, Yanagihara K, Yazumi S, Osaki Y, Chiba T, Ikai I, Fukushima M, Uemoto S, Hatano E (2010) A multi-institution phase II study of gemcitabine/S-1 combination chemotherapy for patients with advanced biliary tract cancer. Cancer Chemother Pharmacol 67:1429–1434

    PubMed  Article  Google Scholar 

  23. 23.

    Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB (2007) Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 67:3853–3861

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Li L, Aggarwal BB, Shishodia S, Abbruzzese J, Kurzrock R (2004) Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis. Cancer 101:2351–2362

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Li L, Braiteh FS, Kurzrock R (2005) Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 104:1322–1331

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    LoTempio MM, Veena MS, Steele HL, Ramamurthy B, Ramalingam TS, Cohen AN, Chakrabarti R, Srivatsan ES, Wang MB (2005) Curcumin suppresses growth of head and neck squamous cell carcinoma. Clin Cancer Res 11:6994–7002

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Marczylo TH, Verschoyle RD, Cooke DN, Morazzoni P, Steward WP, Gescher AJ (2007) Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemother Pharmacol 60:171–177

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Meyers CA, Albitar M, Estey E (2005) Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 104:788–793

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Morimoto T, Sunagawa Y, Fujita M, Hasegawa K (2010) Novel heart failure therapy targeting transcriptional pathway in cardiomyocytes by a natural compound, curcumin. Circ J 74:1059–1066

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Osoba D, Rodrigues G, Myles J, Zee B, Pater J (1998) Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 16:139–144

    PubMed  CAS  Google Scholar 

  31. 31.

    Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dorken B, Riess H, Oettle H (2011) Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 47:1676–1681

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Pfeiffer E, Hoehle SI, Walch SG, Riess A, Solyom AM, Metzler M (2007) Curcuminoids form reactive glucuronides in vitro. J Agric Food Chem 55:538–544

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Sasaki H, Sunagawa Y, Takahashi K, Imaizumi A, Fukuda H, Hashimoto T, Wada H, Katanasaka Y, Kakeya H, Fujita M, Hasegawa K, Morimoto T (2011) Innovative preparation of curcumin for improved oral bioavailability. Biol Pharm Bull 34(5):660-665

    Google Scholar 

  34. 34.

    Sato A, Kudo C, Yamakoshi H, Uehara Y, Ohori H, Ishioka C, Iwabuchi Y, Shibata H (2011) Curcumin analog GO-Y030 is a novel inhibitor of IKKbeta that suppresses NF-kappaB signaling and induces apoptosis. Cancer Sci 102:1045–1051

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Seruga B, Zhang H, Bernstein LJ, Tannock IF (2008) Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 8:887–899

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Shaikh J, Ankola DD, Beniwal V, Singh D, Kumar MN (2009) Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer. Eur J Pharm Sci 37:223–230

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, Marczylo TH, Morgan B, Hemingway D, Plummer SM, Pirmohamed M, Gescher AJ, Steward WP (2004) Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 10:6847–6854

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Sharma RA, Gescher AJ, Steward WP (2005) Curcumin: the story so far. Eur J Cancer 41:1955–1968

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Strimpakos AS, Sharma RA (2008) Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal 10:511–545

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ (2010) Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363:733–742

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Uddin S, Hussain AR, Manogaran PS, Al-Hussein K, Platanias LC, Gutierrez MI, Bhatia KG (2005) Curcumin suppresses growth and induces apoptosis in primary effusion lymphoma. Oncogene 24:7022–7030

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Vareed SK, Kakarala M, Ruffin MT, Crowell JA, Normolle DP, Djuric Z, Brenner DE (2008) Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects. Cancer Epidemiol Biomarkers Prev 17:1411–1417

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, Li XJ (2005) The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol 518:40–46

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

We thank Kazuyuki Miura and Megumi Horikawa for their contributions to data management and Yasuko Nakagawa for her contribution to sample collection and preparation. This work was supported by a Grant-in-Aid from the Japan Society for the Promotion of Science (24590655) and the Japanese Research Foundation for Clinical Pharmacology.

Conflicts of interest

A. Imaizumi is a consultant to Theravalues Corporation, and Y. Otsuka is an employee of Theravalues Corporation.

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Correspondence to Masashi Kanai.

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Kanai, M., Otsuka, Y., Otsuka, K. et al. A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin®) in cancer patients. Cancer Chemother Pharmacol 71, 1521–1530 (2013). https://doi.org/10.1007/s00280-013-2151-8

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Keywords

  • Curcumin
  • Bioavailability
  • Theracurmin®
  • Gemcitabine
  • Pancreatic cancer