Curcumin as a cancer chemotherapy sensitizing agent

  • Youngjoo Kwon


The development of cancer chemotherapy made a significant progress in cancer treatment. However, most chemotherapeutic drugs are challenged by drug resistance and druginduced toxicity. Combination therapy has been suggested as an effective strategy to avoid drug resistance and reduce toxicity derived from drug, thereby enhancing clinical treatment of cancer. Many food-derived bioactive compounds have exhibited anticancer activity and can be good candidates for combination therapy with existing chemotherapeutic drugs. Curcumin is one of compounds that present anticancer activity in many types of cancer and has been extensively studied for its anticancer mechanisms including inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Combinational treatment of curcumin enhanced therapeutic efficacy of traditional chemotherapeutic drugs, cisplatin, doxorubicin, 5-fluorouracil, and gemcitabine. NF-κB is a major downstream effector that leads to chemoresistance of many therapeutic drugs. Down-regulation of NF-κB by curcumin is an effective mechanism to sensitize chemotherapeutic drugs and increase therapeutic efficacy. Therefore, combination use of curcumin and available anticancer drugs has great potential to enhance chemotherapy efficacy and improve clinical treatment of cancer. More studies will be required to elucidate cause effect relationship of curcumin-induced suppression of cell survival pathways and enhancement of drug efficacy by curcumin.


cisplatin combination therapy curcumin doxorubicin gemcitabine 5-fluorouracil 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. AbuHammad S and Zihlif M (2013) Gene expression alterations in doxorubicin resistant MCF7 breast cancer cell line. Genomics 101, 213–220.CrossRefGoogle Scholar
  2. Abuzeid WM, Davis S, Tang AL, Saunders L, Brenner JC, Lin J et al. (2011) Sensitization of head and neck cancer to cisplatin through the use of a novel curcumin analog. Arch Otolaryngol Head Neck Surg 137, 499–507.CrossRefGoogle Scholar
  3. Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM et al. (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.CrossRefGoogle Scholar
  4. Ammon HP and Wahl MA (1991) Pharmacology of Curcuma longa. Planta Med 57, 1–7.CrossRefGoogle Scholar
  5. Arora A and Scholar EM (2005) Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 315, 971–979.CrossRefGoogle Scholar
  6. Artin E, Wang J, Lohman GJ, Yokoyama K, Yu G, Griffin RG et al. (2009) Insight into the mechanism of inactivation of ribonucleotide reductase by gemcitabine 5′-diphosphate in the presence or absence of reductant. Biochemistry 48, 11622–11629.CrossRefGoogle Scholar
  7. Bauer W, Gonias SL, Kam SK, Wu KC, and Lippard SJ (1978) Binding of the antitumor drug platinum uracil blue to closed and nicked circular duplex DNAs. Biochemistry 17, 1060–1068.CrossRefGoogle Scholar
  8. Burgess DJ, Doles J, Zender L, Xue W, Ma B, McCombie WR et al. (2008) Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc Natl Acad Sci USA 105, 9053–9058.CrossRefGoogle Scholar
  9. Calcagno AM, Fostel JM, To KK, Salcido CD, Martin SE, Chewning KJ et al. (2008) Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes. Br J Cancer 98, 1515–1524.CrossRefGoogle Scholar
  10. Chabner BA and Roberts TG Jr (2005) Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer 5, 65–72.CrossRefGoogle Scholar
  11. Chanvorachote P, Pongrakhananon V, Wannachaiyasit S, Luanpitpong S, Rojanasakul Y, and Nimmannit U (2009) Curcumin sensitizes lung cancer cells to cisplatin-induced apoptosis through superoxide anionmediated Bcl-2 degradation. Cancer Invest 27, 624–635.CrossRefGoogle Scholar
  12. Chu E, Koeller DM, Johnston PG, Zinn S, and Allegra CJ (1993) Regulation of thymidylate synthase in human colon cancer cells treated with 5- fluorouracil and interferon-gamma. Mol Pharmacol 43, 527–533.Google Scholar
  13. DeVita VT, Jr. and Chu E (2008) A history of cancer chemotherapy. Cancer Res 68, 8643–8653.CrossRefGoogle Scholar
  14. Dolcet X, Llobet D, Pallares J, and Matias-Guiu X (2005) NF-κB in development and progression of human cancer. Virchows Arch 446, 475–482.CrossRefGoogle Scholar
  15. Duarte VM, Han E, Veena MS, Salvado A, Suh JD, Liang LJ et al. (2010) Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKbeta protein of the NFkappaB pathway. Mol Cancer Ther 9, 2665–2675.CrossRefGoogle Scholar
  16. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C et al. (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer. France.Google Scholar
  17. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, and Gewirtz DA (1994) Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol 45, 649–656.Google Scholar
  18. Forrest RA, Swift LP, Rephaeli A, Nudelman A, Kimura K, Phillips DR et al. (2012) Activation of DNA damage response pathways as a consequence of anthracycline-DNA adduct formation. Biochem Pharmacol 83, 1602–1612.CrossRefGoogle Scholar
  19. Fryer RA, Barlett B, Galustian C, and Dalgleish AG (2011) Mechanisms underlying gemcitabine resistance in pancreatic cancer and sensitisation by the iMiD lenalidomide. Anticancer Res 31, 3747–3756.Google Scholar
  20. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O et al. (2012) Molecular mechanisms of cisplatin resistance. Oncogene 31, 1869–1883.CrossRefGoogle Scholar
  21. Ghoshal K and Jacob ST (1997) An alternative molecular mechanism of action of 5-fluorouracil, a potent anticancer drug. Biochem Pharmacol 53, 1569–1575.CrossRefGoogle Scholar
  22. Hartojo W, Silvers AL, Thomas DG, Seder CW, Lin L, Rao H et al. (2010) Curcumin promotes apoptosis, increases chemosensitivity, and inhibits nuclear factor kappaB in esophageal adenocarcinoma. Transl Oncol 3, 99–108.CrossRefGoogle Scholar
  23. Hatcher H, Planalp R, Cho J, Torti FM, and Torti SV (2008) Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 65, 1631–1652.CrossRefGoogle Scholar
  24. Heiger-Bernays WJ, Essigmann JM, and Lippard SJ (1990) Effect of the antitumor drug cis-diamminedichloroplatinum (II) and related platinum complexes on eukaryotic DNA replication. Biochemistry 29, 8461–8466.CrossRefGoogle Scholar
  25. Howells LM, Sale S, Sriramareddy SN, Irving GR, Jones DJ, Ottley CJ et al. (2011) Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. Int J Cancer 129, 476–486.CrossRefGoogle Scholar
  26. Hu YC, Komorowski RA, Graewin S, Hostetter G, Kallioniemi OP, Pitt HA et al. (2003) Thymidylate synthase expression predicts the response to 5-fluorouracil-based adjuvant therapy in pancreatic cancer. Clin Cancer Res 9, 4165–4171.Google Scholar
  27. Jing N and Tweardy DJ (2005) Targeting Stat3 in cancer therapy. Anticancer Drugs 16, 601–607.CrossRefGoogle Scholar
  28. Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, and 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.CrossRefGoogle Scholar
  29. Kwon Y, Malik M, and Magnuson BA (2004) Inhibition of colonic aberrant crypt foci by curcumin in rats is affected by age. Nutr Cancer 48, 37–43.CrossRefGoogle Scholar
  30. Latorre E, Tebaldi T, Viero G, Sparta AM, Quattrone A, and Provenzani A (2012) Downregulation of HuR as a new mechanism of doxorubicin resistance in breast cancer cells. Mol Cancer 11, 13.CrossRefGoogle Scholar
  31. Longley DB, Harkin DP, and Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3, 330–338.CrossRefGoogle Scholar
  32. Luqmani YA (2005) Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract 14Suppl 1, 35–48.CrossRefGoogle Scholar
  33. Major PP, Egan E, Herrick D, and Kufe DW (1982) 5-Fluorouracil incorporation in DNA of human breast carcinoma cells. Cancer Res 42, 3005–3009.Google Scholar
  34. Martin LP, Hamilton TC, and Schilder RJ (2008) Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 14, 1291–1295.CrossRefGoogle Scholar
  35. Murakami Y, Kazuno H, Emura T, Tsujimoto H, Suzuki N, and Fukushima M (2000) Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells. Int J Oncol 17, 277–283.Google Scholar
  36. Noble S and Goa KL (1997) Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs 54, 447–472.Google Scholar
  37. Notarbartolo M, Poma P, Perri D, Dusonchet L, Cervello M, and D’Alessandro N (2005) Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-κB activation levels and in IAP gene expression. Cancer Lett 224, 53–65.CrossRefGoogle Scholar
  38. Ogiwara H, Ui A, Shiotani B, Zou L, Yasui A, and Kohno T (2013) Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor. Carcinogenesis 34, 2486–2497.CrossRefGoogle Scholar
  39. Orhan B (1999) Doxorubicin cardiotoxicity: growing importance. J Clin Oncol 17, 2294–2296.Google Scholar
  40. Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R et al. (2013) Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat Commun 4, 1908.CrossRefGoogle Scholar
  41. Park GY, Wilson JJ, Song Y, and Lippard SJ (2012) Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile. Proc Natl Acad Sci USA 109, 11987–11992.CrossRefGoogle Scholar
  42. Park S, Cho DH, Andera L, Suh N, and Kim I (2013) Curcumin enhances TRAIL-induced apoptosis of breast cancer cells by regulating apoptosisrelated proteins. Mol Cell Biochem 383, 39–48.CrossRefGoogle Scholar
  43. Parker WB and Cheng YC (1990) Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther 48, 381–395.CrossRefGoogle Scholar
  44. Qiao Q, Jiang Y, and Li G (2013) Curcumin enhances the response of non-Hodgkin’s lymphoma cells to ionizing radiation through further induction of cell cycle arrest at the G2/M phase and inhibition of mTOR phosphorylation. Oncol Rep 29, 380–386.Google Scholar
  45. Reuss DE, Mucha J, Hagenlocher C, Ehemann V, Kluwe L, Mautner V et al. (2013) Sensitivity of malignant peripheral nerve sheath tumor cells to TRAIL is augmented by loss of NF1 through modulation of MYC/MAD and is potentiated by curcumin through induction of ROS. PLoS One 8, e57152.CrossRefGoogle Scholar
  46. Richards AD and Rodger A (2007) Synthetic metallomolecules as agents for the control of DNA structure. Chem Soc Rev 36, 471–483.CrossRefGoogle Scholar
  47. Sadzuka Y, Nagamine M, Toyooka T, Ibuki Y, and Sonobe T (2012) Beneficial effects of curcumin on antitumor activity and adverse reactions of doxorubicin. Int J Pharm 432, 42–49.CrossRefGoogle Scholar
  48. Santi DV, McHenry CS, and Sommer H (1974) Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13, 471–481.CrossRefGoogle Scholar
  49. Selvendiran K, Ahmed S, Dayton A, Kuppusamy ML, Rivera BK, Kalai T et al. (2011) HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition. Cancer Biol Ther 12, 837–845.CrossRefGoogle Scholar
  50. Sen GS, Mohanty S, Hossain DM, Bhattacharyya S, Banerjee S, Chakraborty J et al. (2011) Curcumin enhances the efficacy of chemotherapy by tailoring p65NFkappaB-p300 cross-talk in favor of p53-p300 in breast cancer. J Biol Chem 286, 42232–42247.CrossRefGoogle Scholar
  51. Shakibaei M, Mobasheri A, Lueders C, Busch F, Shayan P, and Goel A (2013) Curcumin enhances the effect of chemotherapy against colorectal cancer cells by inhibition of NF-kappaB and Src protein kinase signaling pathways. PLoS One 8, e57218.CrossRefGoogle Scholar
  52. Shankar S, Chen Q, Sarva K, Siddiqui I, and Srivastava RK (2007) Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: molecular mechanisms of apoptosis, migration and angiogenesis. J Mol Signal 2, 10.CrossRefGoogle Scholar
  53. Sikic BI (1999) New approaches in cancer treatment. Ann Oncol 10 Suppl 6, 149–153.CrossRefGoogle Scholar
  54. Skrypek N, Duchene B, Hebbar M, Leteurtre E, van Seuningen I, and Jonckheere N (2013) The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene 32, 1714–1723.CrossRefGoogle Scholar
  55. Slovak ML, Hoeltge GA, Dalton WS, and Trent JM (1988) Pharmacological and biological evidence for differing mechanisms of doxorubicin resistance in two human tumor cell lines. Cancer Res 48, 2793–2797.Google Scholar
  56. Sreekanth CN, Bava SV, Sreekumar E, and Anto RJ (2011) Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer. Oncogene 30, 3139–3152.CrossRefGoogle Scholar
  57. Stordal B, Pavlakis N, and Davey R (2007) A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship. Cancer Treat Rev 33, 688–703.CrossRefGoogle Scholar
  58. Tian F, Fan T, Zhang Y, Jiang Y, and Zhang X (2012a) Curcumin potentiates the antitumor effects of 5-FU in treatment of esophageal squamous carcinoma cells through downregulating the activation of NF-kappaB signaling pathway in vitro and in vivo. Acta Biochim Biophys Sin (Shanghai) 44, 847–855.CrossRefGoogle Scholar
  59. Tian F, Zhang C, Tian W, Jiang Y, and Zhang X (2012b) Comparison of the effect of p65 siRNA and curcumin in promoting apoptosis in esophageal squamous cell carcinoma cells and in nude mice. Oncol Rep 28, 232–240.Google Scholar
  60. Tsai MS, Weng SH, Kuo YH, Chiu YF, and Lin YW (2011) Synergistic effect of curcumin and cisplatin via down-regulation of thymidine phosphorylase and excision repair cross-complementary 1 (ERCC1). Mol Pharmacol 80, 136–146.CrossRefGoogle Scholar
  61. Vinod BS, Antony J, Nair HH, Puliyappadamba VT, Saikia M, Narayanan SS et al. (2013) Mechanistic evaluation of the signaling events regulating curcumin-mediated chemosensitization of breast cancer cells to 5- fluorouracil. Cell Death Dis 4, e505.CrossRefGoogle Scholar
  62. Wahl H, Tan L, Griffith K, Choi M, and Liu JR (2007) Curcumin enhances Apo2L/TRAIL-induced apoptosis in chemoresistant ovarian cancer cells. Gynecol Oncol 105, 104–112.CrossRefGoogle Scholar
  63. Wang W, Cassidy J, O’Brien V, Ryan KM, and Collie-Duguid E (2004) Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res 64, 8167–8176.CrossRefGoogle Scholar
  64. Wang Z, Li Y, Banerjee S, and Sarkar FH (2008) Exploitation of the Notch signaling pathway as a novel target for cancer therapy. Anticancer Res 28, 3621–3630.Google Scholar
  65. Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M et al. (2007) Curcumin induces G2/M arrest and apoptosis in cisplatinresistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther 6, 178–184.CrossRefGoogle Scholar
  66. Widakowich C, de Castro G, Jr., de Azambuja E, Dinh P, and Awada A (2007) Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist 12, 1443–1455.CrossRefGoogle Scholar
  67. Yardley DA (2013) Drug resistance and the role of combination chemotherapy in improving patient outcomes. Int J Breast Cancer 2013, 137414.CrossRefGoogle Scholar
  68. Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T et al. (2009) Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci USA 106, 12938–12943.CrossRefGoogle Scholar
  69. Yu H, Pardoll D, and Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9, 798–809.CrossRefGoogle Scholar
  70. Zheng C, Jiao X, Jiang Y, and Sun S (2013) ERK1/2 activity contributes to gemcitabine resistance in pancreatic cancer cells. J Int Med Res 41, 300–306.CrossRefGoogle Scholar

Copyright information

© The Korean Society for Applied Biological Chemistry 2014

Authors and Affiliations

  1. 1.Department of Food Science and EngineeringEwha Womans UniversitySeoulRepublic of Korea

Personalised recommendations