Curcumin in Advancing Treatment for Gynecological Cancers with Developed Drug- and Radiotherapy-Associated Resistance

  • Amir Abbas Momtazi-BorojeniEmail author
  • Jafar Mosafer
  • Banafsheh NikfarEmail author
  • Mahnaz Ekhlasi-Hundrieser
  • Shahla Chaichian
  • Abolfazl Mehdizadehkashi
  • Atefeh Vaezi
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 176)


The development of resistance toward current cancer therapy modalities is an ongoing challenge in gynecological cancers, especially ovarian and cervical malignancies that require further investigations in the context of drug- and irradiation-induced resistance. In this regard, curcumin has demonstrated beneficial and highly pleiotropic actions and increased the therapeutic efficiency of radiochemotherapy. The antiproliferative, anti-metastatic, anti-angiogenic, and anti-inflammatory effects of curcumin have been extensively reported in the literature, and it could also act as a chemopreventive agent which mitigates the out-of-target harmful impact of chemotherapeutics on surrounding normal tissues. The current review discussed the modulating influences of curcumin on some cell and molecular features, including the cell signaling and molecular pathways altered upon curcumin treatment, the expression of target genes involved in the progression of gynecological cancers, as well as the expression of genes accountable for the development of resistance toward common chemotherapeutics and radiotherapy. The cell molecular targets implicated in curcumin’s resensitizing effect, when used together with cisplatin, paclitaxel, and irradiation in gynecological cancers, are also addressed. Finally, rational approaches for improving the therapeutic benefits of curcumin, including curcumin derivatives with enhanced therapeutic efficacy, using nanoformulations to advance curcumin stability in physiological media and improve bioavailability have been elucidated.


Cervical cancer Cisplatin Curcumin Nanoformulation Ovarian cancer Paclitaxel 



Cyclin-dependent kinase






DNA methyltransferases


Glutathione S-transferases


Histone deacetylases


Inhibitor of apoptosis family of proteins


Intercellular adhesion molecule 1


IκB kinase


Inducible nitric oxide synthase






Phosphatidylinositide 3-kinase


Vascular endothelial growth factor



The authors would like to say special thanks to Dr. Amir Saberi-Demneh and Dr. Leila Ghalichi for their guidance and kindness.

Conflict of Interest

The authors declare that they have no conflicts of interest about this report.


  1. Abdollahi E, Momtazi AA, Johnston TP, Sahebkar A (2018) Therapeutic effects of curcumin in inflammatory and immune-mediated diseases: a nature-made jack-of-all-trades? J Cell Physiol 233:830–848CrossRefGoogle Scholar
  2. Abouzeid AH, Patel NR, Sarisozen C, Torchilin VP (2014) Transferrin-targeted polymeric micelles co-loaded with curcumin and paclitaxel: efficient killing of paclitaxel-resistant cancer cells. Pharm Res 31:1938–1945CrossRefGoogle Scholar
  3. Aggarwal BB, Harikumar KB (2009) Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 41:40–59CrossRefGoogle Scholar
  4. Ak T, Gülçin İ (2008) Antioxidant and radical scavenging properties of curcumin. Chem Biol Interact 174:27–37CrossRefGoogle Scholar
  5. Aqil F, Munagala R, Jeyabalan J, Agrawal AK, Gupta R (2017) Exosomes for the enhanced tissue bioavailability and efficacy of curcumin. AAPS J 19:1691–1702CrossRefGoogle Scholar
  6. Bava SV, Puliappadamba VT, Deepti A, Nair A, Karunagaran D, Anto RJ (2005) Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-κB and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem 280:6301–6308CrossRefGoogle Scholar
  7. Chan MM, Fong D, Soprano KJ, Holmes WF, Heverling H (2003) Inhibition of growth and sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents. J Cell Physiol 194:63–70CrossRefGoogle Scholar
  8. Chen P, Li J, Jiang H-G, Lan T, Chen Y-C (2015a) Curcumin reverses cisplatin resistance in cisplatin-resistant lung cancer cells by inhibiting FA/BRCA pathway. Tumor Biol 36:3591–3599CrossRefGoogle Scholar
  9. Chen Q, Gao Q, Chen K, Wang Y, Chen L, Li X (2015b) Curcumin suppresses migration and invasion of human endometrial carcinoma cells. Oncol Lett 10:1297–1302CrossRefGoogle Scholar
  10. Cheng SCS, Luo D, Xie Y (2001) Taxol induced BCL-2 protein phosphorylation in human hepatocellular carcinoma QGY-7703 cell line. Cell Biol Int 25:261–265CrossRefGoogle Scholar
  11. Debata PR, Castellanos MR, Fata JE, Baggett S, Rajupet S, Szerszen A, Begum S, Mata A, Murty VV, Opitz LM (2013) A novel curcumin-based vaginal cream Vacurin selectively eliminates apposed human cervical cancer cells. Gynecol Oncol 129:145–153CrossRefGoogle Scholar
  12. Duvoix A, Blasius R, Delhalle S, Schnekenburger M, Morceau F, Henry E, Dicato M, Diederich M (2005) Chemopreventive and therapeutic effects of curcumin. Cancer Lett 223:181–190CrossRefGoogle Scholar
  13. Ganta S, Amiji M (2009) Coadministration of paclitaxel and curcumin in nanoemulsion formulations to overcome multidrug resistance in tumor cells. Mol Pharm 6:928–939CrossRefGoogle Scholar
  14. Garcea G, Jones D, Singh R, Dennison A, Farmer P, Sharma R, Steward W, Gescher A, Berry D (2004) Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br J Cancer 90:1011–1015CrossRefGoogle Scholar
  15. Giannakakou P, Sackett DL, Kang Y-K, Zhan Z, Buters JT, Fojo T, Poruchynsky MS (1997) Paclitaxel-resistant human ovarian cancer cells have mutant β-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 272:17118–17125CrossRefGoogle Scholar
  16. Hajavi J, Abbas Momtazi A, Johnston TP, Banach M, Majeed M, Sahebkar A (2017) Curcumin: a naturally occurring modulator of adipokines in diabetes. J Cell Biochem 118:4170–4182CrossRefGoogle Scholar
  17. Huq F, Yu JQ, Beale P, Chan C, Arzuman L, Nessa MU, Mazumder ME (2014) Combinations of platinums and selected phytochemicals as a means of overcoming resistance in ovarian cancer. Anticancer Res 34:541–545PubMedGoogle Scholar
  18. Javvadi P, Segan AT, Tuttle SW, Koumenis C (2008) The chemopreventive agent curcumin is a potent radiosensitizer of human cervical tumor cells via increased reactive oxygen species production and overactivation of the mitogen-activated protein kinase pathway. Mol Pharmacol 73:1491–1501CrossRefGoogle Scholar
  19. Javvadi P, Hertan L, Kosoff R, Datta T, Kolev J, Mick R, Tuttle SW, Koumenis C (2010) Thioredoxin reductase-1 mediates curcumin-induced radiosensitization of squamous carcinoma cells. Cancer Res 70:1941–1950CrossRefGoogle Scholar
  20. Kasinski AL, Du Y, Thomas SL, Zhao J, Sun S-Y, Khuri FR, Wang C-Y, Shoji M, Sun A, Snyder JP (2008) Inhibition of IκB kinase-nuclear factor-κB signaling pathway by 3, 5-bis (2-flurobenzylidene) piperidin-4-one (EF24), a novel monoketone analog of curcumin. Mol Pharmacol 74:654–661CrossRefGoogle Scholar
  21. Kawamori T, Lubet R, Steele VE, Kelloff GJ, Kaskey RB, Rao CV, Reddy BS (1999) Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 59:597–601PubMedGoogle Scholar
  22. Kumar SSD, Surianarayanan M, Vijayaraghavan R, Mandal AB, Macfarlane D (2014) Curcumin loaded poly (2-hydroxyethyl methacrylate) nanoparticles from gelled ionic liquid–In vitro cytotoxicity and anti-cancer activity in SKOV-3 cells. Eur J Pharm Sci 51:34–44CrossRefGoogle Scholar
  23. Kuttan G, Kumar KBH, Guruvayoorappan C, Kuttan R (2007) Antitumor, anti-invasion, and antimetastatic effects of curcumin. In: The molecular targets and therapeutic uses of curcumin in health and disease. Springer, BostonGoogle Scholar
  24. Lao CD, Ruffin MT, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE (2006) Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 6:10CrossRefGoogle Scholar
  25. Li C, Ge X, Wang L (2017) Construction and comparison of different nanocarriers for co-delivery of cisplatin and curcumin: a synergistic combination nanotherapy for cervical cancer. Biomed Pharmacother 86:628–636CrossRefGoogle Scholar
  26. Liu Z, Zhu Y-Y, Li Z-Y, Ning S-Q (2016) Evaluation of the efficacy of paclitaxel with curcumin combination in ovarian cancer cells. Oncol Lett 12:3944–3948CrossRefGoogle Scholar
  27. Mancarella S, Greco V, Baldassarre F, Vergara D, Maffia M, Leporatti S (2015) Polymer-coated magnetic nanoparticles for curcumin delivery to cancer cells. Macromol Biosci 15:1365–1374CrossRefGoogle Scholar
  28. Maruthur NM, Bolen SD, Brancati FL, Clark JM (2009) The association of obesity and cervical cancer screening: a systematic review and meta-analysis. Obesity 17:375–381CrossRefGoogle Scholar
  29. Mishra S, Kapoor N, Ali AM, Pardhasaradhi B, Kumari AL, Khar A, Misra K (2005a) Differential apoptotic and redox regulatory activities of curcumin and its derivatives. Free Radic Biol Med 38:1353–1360CrossRefGoogle Scholar
  30. Mishra S, Narain U, Mishra R, Misra K (2005b) Design, development and synthesis of mixed bioconjugates of piperic acid–glycine, curcumin–glycine/alanine and curcumin–glycine–piperic acid and their antibacterial and antifungal properties. Bioorg Med Chem 13:1477–1486CrossRefGoogle Scholar
  31. Momtazi AA, Shahabipour F, Khatibi S, Johnston TP, Pirro M, Sahebkar A (2016) Curcumin as a MicroRNA regulator in cancer: a review. Rev Physiol Biochem Pharmacol 171:1–38CrossRefGoogle Scholar
  32. Momtazi-Borojeni AA, Haftcheshmeh SM, Esmaeili S-A, Johnston TP, Abdollahi E, Sahebkar A (2017) Curcumin: a natural modulator of immune cells in systemic lupus erythematosus. Autoimmun Rev 17:125–135CrossRefGoogle Scholar
  33. Montopoli M, Ragazzi E, Froldi G, Caparrotta L (2009) Cell-cycle inhibition and apoptosis induced by curcumin and cisplatin or oxaliplatin in human ovarian carcinoma cells. Cell Prolif 42:195–206CrossRefGoogle Scholar
  34. Nessa MU, Beale P, Chan C, Yu JQ, Huq F (2012) Studies on combination of platinum drugs cisplatin and oxaliplatin with phytochemicals anethole and curcumin in ovarian tumour models. Anticancer Res 32:4843–4850PubMedGoogle Scholar
  35. Pan W, Yang H, Cao C, Song X, Wallin B, Kivlin R, Lu S, Hu G, Di W, Wan Y (2008) AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells. Oncol Rep 20:1553–1559PubMedGoogle Scholar
  36. Panahi Y, Ahmadi Y, Teymouri M, Johnston TP, Sahebkar A (2018) Curcumin as a potential candidate for treating hyperlipidemia: a review of cellular and metabolic mechanisms. J Cell Physiol 233:141–152CrossRefGoogle Scholar
  37. Paulraj F, Abas F, Lajis NH, Othman I, Hassan SS, Naidu R (2015) The curcumin analogue 1, 5-bis (2-hydroxyphenyl)-1, 4-pentadiene-3-one induces apoptosis and downregulates E6 and E7 oncogene expression in HPV16 and HPV18-infected cervical cancer cells. Molecules 20:11830–11860CrossRefGoogle Scholar
  38. Peng S, Xu Q, Ling XB, Peng X, Du W, Chen L (2003) Molecular classification of cancer types from microarray data using the combination of genetic algorithms and support vector machines. FEBS Lett 555:358–362CrossRefGoogle Scholar
  39. Punfa W, Yodkeeree S, Pitchakarn P, Ampasavate C, Limtrakul P (2012) Enhancement of cellular uptake and cytotoxicity of curcumin-loaded PLGA nanoparticles by conjugation with anti-P-glycoprotein in drug resistance cancer cells. Acta Pharmacol Sin 33:823–831CrossRefGoogle Scholar
  40. Rezaee R, Momtazi AA, Monemi A, Sahebkar A (2016) Curcumin: a potentially powerful tool to reverse cisplatin-induced toxicity. Pharmacol Res 117:218–227CrossRefGoogle Scholar
  41. Roy M, Mukherjee S (2014) Reversal of resistance towards cisplatin by curcumin in cervical cancer cells. Asian Pac J Cancer Prev 15:1403–1410CrossRefGoogle Scholar
  42. Saengkrit N, Saesoo S, Srinuanchai W, Phunpee S, Ruktanonchai UR (2014) Influence of curcumin-loaded cationic liposome on anticancer activity for cervical cancer therapy. Colloids Surf B Biointerfaces 114:349–356CrossRefGoogle Scholar
  43. Sarisozen C, Abouzeid AH, Torchilin VP (2014) The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors. Eur J Pharm Biopharm 88:539–550CrossRefGoogle Scholar
  44. Sharma R, Jadav SS, Yasmin S, Bhatia S, Khalilullah H, Ahsan MJ (2015) Simple, efficient, and improved synthesis of Biginelli-type compounds of curcumin as anticancer agents. Med Chem Res 24:636–644CrossRefGoogle Scholar
  45. Singh AK, Misra K (2013) Human papilloma virus 16 E6 protein as a target for curcuminoids, curcumin conjugates and congeners for chemoprevention of oral and cervical cancers. Interdiscip Sci Comput Life Sci 5:112CrossRefGoogle Scholar
  46. Soflaei S, Momtazi A, Majeed M, Derosa G, Maffioli P, Sahebkar A (2017) Curcumin: a natural pan-HDAC inhibitor in cancer. Curr Pharm Des 24:123–129Google Scholar
  47. Song Y-K, Kim C-K (2006) Topical delivery of low-molecular-weight heparin with surface-charged flexible liposomes. Biomaterials 27:271–280CrossRefGoogle Scholar
  48. Sreekanth C, Bava S, Sreekumar E, Anto R (2011) Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer. Oncogene 30:3139–3152CrossRefGoogle Scholar
  49. Tanaka Y, Kobayashi H, Suzuki M, Kanayama N, Terao T (2004) Transforming growth factor-β1-dependent urokinase up-regulation and promotion of invasion are involved in Src-MAPK-dependent signaling in human ovarian cancer cells. J Biol Chem 279:8567–8576CrossRefGoogle Scholar
  50. Teymouri M, Farzaneh H, Badiee A, Golmohammadzadeh S, Sadri K, Jaafari MR (2015) Investigation of Hexadecylphosphocholine (miltefosine) usage in Pegylated liposomal doxorubicin as a synergistic ingredient: in vitro and in vivo evaluation in mice bearing C26 colon carcinoma and B16F0 melanoma. Eur J Pharm Sci 80:66–73CrossRefGoogle Scholar
  51. Teymouri M, Badiee A, Golmohammadzadeh S, Sadri K, Akhtari J, Mellat M, Nikpoor AR, Jaafari MR (2016) Tat peptide and hexadecylphosphocholine introduction into pegylated liposomal doxorubicin: an in vitro and in vivo study on drug cellular delivery, release, biodistribution and antitumor activity. Int J Pharm 511:236–244CrossRefGoogle Scholar
  52. Teymouri M, Pirro M, Johnston TP, Sahebkar A (2017) Curcumin as a multifaceted compound against human papilloma virus infection and cervical cancers: a review of chemistry, cellular, molecular, and preclinical features. Biofactors 43:331–346CrossRefGoogle Scholar
  53. Teymouri M, Barati N, Pirro M, Sahebkar A (2018) Biological and pharmacological evaluation of dimethoxycurcumin: a metabolically stable curcumin analogue with a promising therapeutic potential. J Cell Physiol 233:124–140CrossRefGoogle Scholar
  54. Wang W-M, Cheng H-C, Liu Y-C, Chang Y-L, Liu S-T (2011) Effect of dimethoxycurcumin beyond degradation of androgen receptor. Dermatol Sin 29:115–120CrossRefGoogle Scholar
  55. Watson JL, Greenshields A, Hill R, Hilchie A, Lee PW, Giacomantonio CA, Hoskin DW (2010) Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling. Mol Carcinog 49:13–24PubMedGoogle Scholar
  56. Xu Y-Q, Chen W-R, Tsosie JK, Xie X, Li P, Wan J-B, He C-W, Chen M-W (2016) Niosome encapsulation of curcumin. J Nanomater 2016:15Google Scholar
  57. Yang YL, Ji C, Cheng L, He L, Lu CC, Wang R, Bi ZG (2012) Sphingosine kinase-1 inhibition sensitizes curcumin-induced growth inhibition and apoptosis in ovarian cancer cells. Cancer Sci 103:1538–1545CrossRefGoogle Scholar
  58. Yunos NM, Beale P, Yu JQ, Huq F (2011) Synergism from sequenced combinations of curcumin and epigallocatechin-3-gallate with cisplatin in the killing of human ovarian cancer cells. Anticancer Res 31:1131–1140PubMedGoogle Scholar
  59. Yusuf R, Duan Z, Lamendola D, Penson R, Seiden M (2003) Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets 3:1–19CrossRefGoogle Scholar
  60. Zaman MS, Chauhan N, Yallapu MM, Gara RK, Maher DM, Kumari S, Sikander M, Khan S, Zafar N, Jaggi M (2016) Curcumin nanoformulation for cervical cancer treatment. Sci Rep 6:20051CrossRefGoogle Scholar
  61. Zhang J, Liu J, Xu X, Li L (2017) Curcumin suppresses cisplatin resistance development partly via modulating extracellular vesicle-mediated transfer of MEG3 and miR-214 in ovarian cancer. Cancer Chemother Pharmacol 79:479–487CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Amir Abbas Momtazi-Borojeni
    • 1
    • 2
    Email author
  • Jafar Mosafer
    • 3
  • Banafsheh Nikfar
    • 4
    Email author
  • Mahnaz Ekhlasi-Hundrieser
    • 5
  • Shahla Chaichian
    • 6
  • Abolfazl Mehdizadehkashi
    • 7
  • Atefeh Vaezi
    • 8
  1. 1.Nanotechnology Research Center, Bu-Ali Research InstituteMashhad University of Medical SciencesMashhadIran
  2. 2.Department of Medical Biotechnology, Student Research Committee, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  3. 3.Research Center of Advanced Technologies in MedicineTorbat Heydarieh University of Medical SciencesTorbat HeydariehIran
  4. 4.Pars Advanced and Minimally Invasive Medical Manners Research CenterPars Hospital, Iran University of Medical SciencesTehranIran
  5. 5.Werlhof-InstitutHannoverGermany
  6. 6.Minimally Invasive Techniques Research Center in Women, Tehran Medical Sciences BranchIslamic Azad UniversityTehranIran
  7. 7.Endometriosis Research CenterIran University of Medical SciencesTehranIran
  8. 8.Department of Community Medicine, School of MedicineIsfahan University of Medical SciencesIsfahanIran

Personalised recommendations