Studies on combination of oxaliplatin and dendrosomal nanocurcumin on proliferation, apoptosis induction, and long non-coding RNA expression in ovarian cancer cells

  • Elahe Seyed Hosseini
  • Marziyeh Alizadeh Zarei
  • Sadegh Babashah
  • Roohollah Nakhaei Sistani
  • Majid Sadeghizadeh
  • Hamad Haddad Kashani
  • Javad Amini Mahabadi
  • Fatemeh Izadpanah
  • Mohhamad Ali Atlasi
  • Hossein NikzadEmail author


Drug resistance remains a major challenge in the treatment of patients with ovarian cancer. Therefore, the development of new anticancer drugs is a clinical priority to develop more effective therapies. New approaches to improve clinical outcomes and limit the toxicity of anticancer drugs focus on chemoprevention. The aim of this study was to determine the effects of dendrosomal nanocurcumin (DNC) and oxaliplatin (Oxa) and their combination on cell death and apoptosis induction in human ovarian carcinoma cell lines analyzed by MTT assay and flow cytometry, respectively. The synergism effect of Oxa and DNC was analyzed using the equation derived from Chou and Talalay. In addition, real-time PCR was used to measure the effect of this combination on the expression levels of long non-coding RNAs with different expression in ovarian cancer and normal ovaries. Our data showed that the effect of DNC on cell death is more than curcumin alone in the same concentration. The greatest cell death effect was observed in combination of Oxa with DNC, while Oxa was added first, followed by DNC at 4 h interval (0/4 h). The findings indicated that DNC induced apoptosis significantly in both cell lines as compared to control groups; however, combination of both agents had no significant effect in apoptosis induction. In addition, combination of both agents significantly affects the relative expression of long non-coding RNAs investigated in the study as compared with mono therapy.


Ovarian cancer Oxaliplatin Dendrosomal nanocurcumin Long non-coding RNA 



Dendrosomal nanocurcumin






Long non-coding RNA


Dimethyl formamide


Dimethyl sulfoxide


Fourier transform infrared


Nuclear magnetic resonance


High-performance liquid chromatography with a diode-array detector


Dynamic light scattering


Fetal bovine serum




3-(4,5-Dimethylthiazole-yl)-2, 5-diphenyltetrazolium bromide


The half maximal inhibitory concentration of cells



The original research described in this paper is part of the Ph.D. thesis of ESH. The present work was supported financially by grant no. 94123 from Kashan University of Medical Sciences, Kashan, Iran, and grant no. 95819873 from Iran National Science Foundation. We also thank the Deputy of Research and Technology, Ministry of Health and Medical Education of Iran for research grant support.

Availability of data and materials

All the authors confirm the availability of data and materials.

Authors’ contributions

ESH and HN provided direction and guidance throughout the preparation of this manuscript. ESH and HN conducted the literature and drafted the manuscript. Other authors reviewed the manuscript and made significant revisions on the drafts. All authors read and approved the final version.

Compliance with ethical standards

Competing interests

The authors declare that they have no competing interests.

Consent for publication

All the authors confirm that the manuscript represents their honest work and agree to consent to its publication in Cell Biology and Toxicology.

Ethics approval and consent to participate

Not applicable.

Supplementary material

10565_2018_9450_MOESM1_ESM.docx (306 kb)
ESM 1 (DOCX 306 kb)


  1. Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol. 2006;71(10):1397–421.CrossRefPubMedGoogle Scholar
  2. Alizadeh AM, Khaniki M, Azizian S, Mohaghgheghi MA, Sadeghizadeh M, Najafi F. Chemoprevention of azoxymethane-initiated colon cancer in rat by using a novel polymeric nanocarrier–curcumin. Eur J Pharmacol. 2012;689(1–3):226–32.CrossRefPubMedGoogle Scholar
  3. Amin AR, et al. Perspectives for cancer prevention with natural compounds. J Clin Oncol. 2009;27(16):2712–25.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4(6):807–18.CrossRefPubMedGoogle Scholar
  5. Babaei E, Sadeghizadeh M, Hassan ZM, Feizi MAH, Najafi F, Hashemi SM. Dendrosomal curcumin significantly suppresses cancer cell proliferation in vitro and in vivo. Int Immunopharmacol. 2012;12(1):226–34.CrossRefPubMedGoogle Scholar
  6. Bekaii-Saab TS, Liu J, Chan KK, Balcerzak SP, Ivy PS, Grever MR, et al. A phase I and pharmacokinetic study of weekly oxaliplatin followed by paclitaxel in patients with solid tumors. Clin Cancer Res. 2008;14(11):3434–40.CrossRefPubMedGoogle Scholar
  7. Chen Y-R, Tan T-H. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin. Oncogene. 1998;17(2):173–8.CrossRefPubMedGoogle Scholar
  8. Cheng Z, Guo J, Chen L, Luo N, Yang W, Qu X. A long noncoding RNA AB073614 promotes tumorigenesis and predicts poor prognosis in ovarian cancer. Oncotarget. 2015;6(28):25381–9.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chou T-C. Relationships between inhibition constants and fractional inhibition in enzyme-catalyzed reactions with different numbers of reactants, different reaction mechanisms, and different types and mechanisms of inhibition. Mol Pharmacol. 1974;10(2):235–47.PubMedGoogle Scholar
  10. Chou T-C. Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands. J Theor Biol. 1976;59(2):253–76.CrossRefPubMedGoogle Scholar
  11. Chou T-C, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.CrossRefGoogle Scholar
  12. Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFκB transcription factors. J Neurochem. 2007;102(2):522–38.CrossRefPubMedGoogle Scholar
  13. Dong Y, Liang G, Yuan B, Yang C, Gao R, Zhou X. MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumor Biol. 2015;36(3):1477–86.CrossRefGoogle Scholar
  14. Dyer J, et al. Curcumin: a new cell-permeant inhibitor of the inositol 1, 4, 5-trisphosphate receptor. Cell Calcium. 2002;31(1):45–52.CrossRefPubMedGoogle Scholar
  15. Erfani-Moghadam V, et al. A novel diblock of copolymer of (monomethoxy poly [ethylene glycol]-oleate) with a small hydrophobic fraction to make stable micelles/polymersomes for curcumin delivery to cancer cells. Int J Nanomedicine. 2014;9:5541.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.CrossRefPubMedGoogle Scholar
  17. Garcea G, Jones DJL, Singh R, Dennison AR, Farmer PB, Sharma RA, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Garg R, Ingle A, Maru G. Dietary turmeric modulates DMBA-induced p21ras, MAP kinases and AP-1/NF-κB pathway to alter cellular responses during hamster buccal pouch carcinogenesis. Toxicol Appl Pharmacol. 2008;232(3):428–39.CrossRefPubMedGoogle Scholar
  19. Gou M, Men K, Shi HS, Xiang ML, Zhang J, Song J, et al. Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo. Nanoscale. 2011;3(4):1558–67.CrossRefPubMedGoogle Scholar
  20. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15(1):195–218.CrossRefPubMedGoogle Scholar
  21. He B, Wei W, Liu J, Xu Y, Zhao G. Synergistic anticancer effect of curcumin and chemotherapy regimen FP in human gastric cancer MGC-803 cells. Oncol Lett. 2017;14(3):3387–94.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Heger M, van Golen R, Broekgaarden M, Michel MC. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancer. Pharmacol Rev. 2014;66(1):222–307.CrossRefPubMedGoogle Scholar
  23. Howells L, Manson M. Prospects for plant-derived chemopreventive agents exhibiting multiple mechanisms of action. Current Medicinal Chemistry-Anti-Cancer Agents. 2005;5(3):201–13.CrossRefPubMedGoogle Scholar
  24. Howells LM, Sale S, Sriramareddy SN, Irving GRB, Jones DJL, Ottley CJ, et al. Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. Int J Cancer. 2011;129(2):476–86.CrossRefPubMedGoogle Scholar
  25. Huang K-C, Rao PH, Lau CC, Heard E, Ng SK, Brown C, et al. Relationship of XIST expression and responses of ovarian cancer to chemotherapy 1 this work was partly supported by NIH grants CA70216 and GM 59920 (to SW. N.). 1. Mol Cancer Ther. 2002;1(10):769–76.PubMedGoogle Scholar
  26. Huang S, Qing C, Huang Z, Zhu Y. The long non-coding RNA CCAT2 is up-regulated in ovarian cancer and associated with poor prognosis. Diagn Pathol. 2016;11(1):49.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21(11):1253–61.CrossRefPubMedGoogle Scholar
  28. Jaggi, B.K., S.C. Chauhan, and M. Jaggi. Review of curcumin effects on signaling pathways in cancer. in Proceedings of the South Dakota Academy of Science. 2007.Google Scholar
  29. Kanai M, Imaizumi A, Otsuka Y, Sasaki H, Hashiguchi M, Tsujiko K, et al. Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol. 2012;69(1):65–70.CrossRefPubMedGoogle Scholar
  30. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7(8):573–84.CrossRefPubMedGoogle Scholar
  31. Kim M-K, Kim K, Han JY, Lim JM, Song YS. Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer. Genes Nutr. 2011;6(2):109–15.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kuttan R, Sudheeran P, Josph C. Turmeric and curcumin as topical agents in cancer therapy. Tumori Journal. 1987;73(1):29–31.CrossRefPubMedGoogle Scholar
  33. Kwon Y. Curcumin as a cancer chemotherapy sensitizing agent. J Korean Soc Appl Biol Chem. 2014;57(2):273–80.CrossRefGoogle Scholar
  34. Liu S-P, Yang JX, Cao DY, Shen K. Identification of differentially expressed long non-coding RNAs in human ovarian cancer cells with different metastatic potentials. Cancer Biol Med. 2013;10(3):138–41.PubMedPubMedCentralGoogle Scholar
  35. Machover D, Diaz-Rubio E, de Gramont A, Schif A, Gastiaburu JJ, Brienza S, et al. Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol. 1996;7(1):95–8.CrossRefPubMedGoogle Scholar
  36. Martinez-Balibrea E, Martinez-Cardus A, Gines A, Ruiz de Porras V, Moutinho C, Layos L, et al. Tumor-related molecular mechanisms of oxaliplatin resistance. Mol Cancer Ther. 2015;14:1767–76.CrossRefPubMedGoogle Scholar
  37. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.CrossRefPubMedGoogle Scholar
  38. Meryet-Figuière M, Lambert B, Gauduchon P, Vigneron N, Brotin E, Poulain L, et al. An overview of long non-coding RNAs in ovarian cancers. Oncotarget. 2016;7(28):44719–34.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Mirgani MT, et al. Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells. Int J Nanomedicine. 2014a;9(1):403–17.Google Scholar
  40. Mirgani MT, et al. Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells. Int J Nanomedicine. 2014b;9:403.Google Scholar
  41. Montopoli M, Ragazzi E, Froldi G, Caparrotta L. Cell-cycle inhibition and apoptosis induced by curcumin and cisplatin or oxaliplatin in human ovarian carcinoma cells. Cell Prolif. 2009;42(2):195–206.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. Nessa MU, Beale P, Chan C, Yu JQ, Huq F. Studies on combination of platinum drugs cisplatin and oxaliplatin with phytochemicals anethole and curcumin in ovarian tumour models. Anticancer Res. 2012;32(11):4843–50.PubMedGoogle Scholar
  44. Pasmant E, Sabbagh A, Vidaud M, Bièche I. ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J. 2011;25(2):444–8.CrossRefPubMedGoogle Scholar
  45. Polytarchou C, Hatziapostolou M, Papadimitriou E. Hydrogen peroxide stimulates proliferation and migration of human prostate cancer cells through activation of activator protein-1 and up-regulation of the heparin affin regulatory peptide gene. J Biol Chem. 2005;280(49):40428–35.CrossRefPubMedGoogle Scholar
  46. Prusty BK, Das BC. Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin. Int J Cancer. 2005;113(6):951–60.CrossRefPubMedGoogle Scholar
  47. Ren C, Li X, Wang T, Wang G, Zhao C, Liang T, et al. Functions and mechanisms of long noncoding RNAs in ovarian cancer. Int J Gynecol Cancer. 2015;25(4):566–9.CrossRefPubMedGoogle Scholar
  48. Sadeghizadeh M, Ranjbar B, Damaghi M, Khaki L, Sarbolouki MN, Najafi F, et al. Dendrosomes as novel gene porters-III. J Chem Technol Biotechnol. 2008;83(6):912–20.CrossRefGoogle Scholar
  49. Sarbolouki MN, Sadeghizadeh M, Yaghoobi MM, Karami A, Lohrasbi T. Dendrosomes: a novel family of vehicles for transfection and therapy. J Chem Technol Biotechnol. 2000;75(10):919–22.CrossRefGoogle Scholar
  50. Sasaki H, Sunagawa Y, Takahashi K, Imaizumi A, Fukuda H, Hashimoto T, et al. Innovative preparation of curcumin for improved oral bioavailability. Biol Pharm Bull. 2011;34(5):660–5.CrossRefPubMedGoogle Scholar
  51. Seol D-W, Chen Q, Zarnegar R. Transcriptional activation of the hepatocyte growth factor receptor (c-met) gene by its ligand (hepatocyte growth factor) is mediated through AP-1. Oncogene. 2000;19(9):1132–7.CrossRefPubMedGoogle Scholar
  52. Shishodia S, Chaturvedi MM, Aggarwal BB. Role of curcumin in cancer therapy. Curr Probl Cancer. 2007;31(4):243–305.CrossRefPubMedGoogle Scholar
  53. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.CrossRefPubMedGoogle Scholar
  54. Silva JM, Boczek NJ, Berres MW, Ma X, Smith DI. LSINCT5 is over expressed in breast and ovarian cancer and affects cellular proliferation. RNA Biol. 2011;8(3):496–505.CrossRefPubMedGoogle Scholar
  55. Spizzo R, Almeida MI, Colombatti A, Calin GA. Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene. 2012;31(43):4577–87.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Tahmasebi Birgani M, et al. Dendrosomal nano-curcumin; the novel formulation to improve the anticancer properties of curcumin. Proc Biol Sci. 2015;5(2):143–58.Google Scholar
  57. Testa A, Kaijser J, Wynants L, Fischerova D, van Holsbeke C, Franchi D, et al. Strategies to diagnose ovarian cancer: new evidence from phase 3 of the multicentre international IOTA study. Br J Cancer. 2014;111(4):680–8.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tharakan, S.T., et al., RETRACTED: curcumin potentiates the antitumor effects of gemcitabine in an orthotopic model of human bladder cancer through suppression of proliferative and angiogenic biomarkers. 2010, Elsevier.Google Scholar
  59. Wang X, Wang Q, Ives KL, Evers BM. Curcumin inhibits neurotensin-mediated interleukin-8 production and migration of HCT116 human colon cancer cells. Clin Cancer Res. 2006;12(18):5346–55.CrossRefPubMedPubMedCentralGoogle Scholar
  60. Woo M-S, Jung SH, Kim SY, Hyun JW, Ko KH, Kim WK, et al. Curcumin suppresses phorbol ester-induced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells. Biochem Biophys Res Commun. 2005;335(4):1017–25.CrossRefPubMedGoogle Scholar
  61. Wu D, et al. Downregulation of BC200 in ovarian cancer contributes to cancer cell proliferation and chemoresistance to carboplatin. Oncol Lett. 2016;11(2):1189–94.CrossRefPubMedGoogle Scholar
  62. Xie X, Tang B, Xiao YF, Xie R, Li BS, Dong H, et al. Long non-coding RNAs in colorectal cancer. Oncotarget. 2016;7(5):5226–39.CrossRefPubMedGoogle Scholar
  63. Ying L, Chen Q, Wang Y, Zhou Z, Huang Y, Qiu F. Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition. Mol BioSyst. 2012;8(9):2289–94.CrossRefPubMedGoogle Scholar
  64. Yunos NM, Beale P, Yu JQ, Huq F. Synergism from the combination of oxaliplatin with selected phytochemicals in human ovarian cancer cell lines. Anticancer Res. 2011;31(12):4283–9.PubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Elahe Seyed Hosseini
    • 1
  • Marziyeh Alizadeh Zarei
    • 1
  • Sadegh Babashah
    • 2
  • Roohollah Nakhaei Sistani
    • 3
  • Majid Sadeghizadeh
    • 3
  • Hamad Haddad Kashani
    • 4
  • Javad Amini Mahabadi
    • 1
  • Fatemeh Izadpanah
    • 5
  • Mohhamad Ali Atlasi
    • 4
  • Hossein Nikzad
    • 1
    • 4
    Email author
  1. 1.Gametogenesis Research CenterKashan University of Medical ScienceKashanIran
  2. 2.Department of Molecular Genetics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran
  3. 3.Department of Cell Biology Faculty of ChemistryUniversity of KashanKashanIran
  4. 4.Anatomical Sciences Research CenterKashan University of Medical SciencesKashanIran
  5. 5.Food and Drug Laboratory Research Center and Food and Drug Reference Control Laboratories CenterFood & Drug Administration of Iran, MOH & METehranIran

Personalised recommendations