Skip to main content
SpringerLink
Log in

Curcumin confers protection to irradiated THP-1 cells while its nanoformulation sensitizes these cells via apoptosis induction

  • Original Article
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Abstract

Protection against ionizing radiation (IR) and sensitization of cancer cells to IR are apparently contrasting phenomena. However, curcumin takes on these contrasting roles leading to either protection or enhanced apoptosis in different irradiated cells. Here we studied whether pretreatment with free curcumin or a novel dendrosomal nanoformulation of curcumin (DNC) could exert protective/sensitizing effects on irradiated THP-1 leukemia cells. We employed assays including MTT viability, clonogenic survival, DNA fragmentation, PI/Annexin V flow cytometry, antioxidant system (ROS, TBARS for lipid peroxidation, 8-OHdG and γH2AX for DNA damage, glutathione, CAT and GPx activity, enzymes gene expression), ELISA (NF-κB and Nrf2 binding, TNF-α release), caspase assay, siRNA silencing of caspase-3, and western blotting to illustrate the observed protective role of curcumin in comparison with the opposite sensitizing role of its nanoformulation at a similar 10 μM concentration. The in vivo relevance of this concentration was determined via intraperitoneal administration in mice. Curcumin significantly enhanced the antioxidant defense, while DNC induced apoptosis and reduced viability as well as survival of irradiated THP-1 cells. Nrf2 binding showed an early rise and fall in DNC-treated cells, despite a gradual increase in curcumin-treated cells. We also demonstrated that DNC induced apoptosis in THP-1 cells via caspase-3 activation; whereas in combination with radiation, DNC alternatively employed a caspase-independent apoptosis pathway involving cytochrome c release from mitochondria.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

8-OHdG:

8-Hydroxydeoxyguanosine

ARE:

Antioxidant response element

CAT:

Catalase

Cur:

Curcumin

DCFH-DA:

2′,7′-Dichlorodihydrofluorescein diacetate

DNC:

Dendrosomal nanoformulation of curcumin

ERK:

Extracellular signal-regulated kinase

GCLM:

Glutamate cysteine ligase modulatory

GPx:

Glutathione peroxidase

GSH:

Glutathione

IR:

Ionizing radiation

HAT:

Histone acetylases

HDAC:

Histone deacetylases

HO-1 and HMOX-1:

Heme oxygenase-1

NF-κB:

Nuclear factor-κB

NQO-1:

NAD(P)H:quinone oxidoreductase

Nrf2:

NF-E2-related factor 2

MAPK:

Mitogen-activated protein kinases

PI:

Propidium iodide

PKC:

Protein kinase C

ROS:

Reactive oxygen species

TNF-α:

Tumor necrosis factor alpha

References

  • Aebi H. [13] Catalase in vitro. Methods Enzymol. 1984;105:121–6.

    Article  CAS  PubMed  Google Scholar 

  • Anto RJ, Mukhopadhyay A, Denning K, Aggarwal BB. Curcumin (diferuloylmethane ) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release : its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis. 2002;23:143–50.

    Article  CAS  PubMed  Google Scholar 

  • Anuranjani, Bala M. Concerted action of Nrf2-ARE pathway, MRN complex, HMGB1 and inflammatory cytokines–implication in modification of radiation damage. Redox Biol. 2014;2:832–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aravindan N, Madhusoodhanan R, Ahmad S, Johnson D, Herman TS. Curcumin inhibits NFkappaB mediated radioprotection and modulate apoptosis related genes in human neuroblastoma cells. Cancer Biol Ther. 2008;7:569–76.

    Article  CAS  PubMed  Google Scholar 

  • 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;12:226–34.

    Article  CAS  PubMed  Google Scholar 

  • Banerjee A, Kunwar A, Mishra B, Priyadarsini KI. Concentration dependent antioxidant/pro-oxidant activity of curcumin. Studies from AAPH induced hemolysis of RBCs. Chem Biol Interact. 2008;174:134–9.

    Article  CAS  PubMed  Google Scholar 

  • Bonay M, Roux AL, Floquet J, Retory Y, Herrmann JL, Lofaso F, et al. Caspase-independent apoptosis in infected macrophages triggered by sulforaphane via Nrf2/p38 signaling pathways. Cell Death Discov. 2015;1:15022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buege JA, Aust SD. [30] Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302–10.

    Article  CAS  PubMed  Google Scholar 

  • Calini V, Urani C, Camatini M. Comet assay evaluation of DNA single- and double-strand breaks induction and repair in C3H10T1/2 cells. Cell Biol Toxicol. 2002;18:369–79.

    Article  CAS  PubMed  Google Scholar 

  • Chendil D, Ranga RS, Meigooni D, Sathishkumar S, Ahmed MM. Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene. 2004;23:1599–607.

    Article  CAS  PubMed  Google Scholar 

  • Dahl TA, Bilski P, Reszka KJ, Chignell CF. Photocytotoxicity of curcumin. Photochem Photobiol. 1994;59:290–4.

    Article  CAS  PubMed  Google Scholar 

  • Darvesh SA, Aggarwal BB, Bishayee A. Curcumin and liver cancer: a review. Curr Pharm Biotechnol. 2012;13:218–28.

    Article  CAS  PubMed  Google Scholar 

  • Davis GDJ, Masilamoni JG, Arul V, Kumar MSM, Baraneedharan U, Paul SFD, et al. Radioprotective effect of DL-alpha-lipoic acid on mice skin fibroblasts. Cell Biol Toxicol. 2009;25:331–40.

    Article  CAS  PubMed  Google Scholar 

  • Deng X, Rui W, Zhang F, Ding W. PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells. Cell Biol Toxicol. 2013;29:143–57.

    Article  CAS  PubMed  Google Scholar 

  • Di Zanni E, Fornasari D, Ravazzolo R, Ceccherini I, Bachetti T. Identification of novel pathways and molecules able to down-regulate PHOX2B gene expression by in vitro drug screening approaches in neuroblastoma cells. Exp Cell Res. 2015;336:43–57.

    Article  CAS  PubMed  Google Scholar 

  • Dudás J, Fullár A, Romani A, Pritz C, Kovalszky I, Hans Schartinger V, et al. Curcumin targets fibroblast–tumor cell interactions in oral squamous cell carcinoma. Exp Cell Res. 2013;319:800–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fürst R, Zündorf I. Plant-derived anti-inflammatory compounds: hopes and disappointments regarding the translation of preclinical knowledge into clinical progress. Mediat Inflamm. 2014;2014:146832.

    Article  CAS  Google Scholar 

  • Goel A, Aggarwal BB. Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr Cancer. 2010;62:919–30.

    Article  CAS  PubMed  Google Scholar 

  • Gogada R, Amadori M, Zhang H, Jones A, Verone A, Pitarresi J, et al. Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis. Cell Cycle. 2011;10:4128–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heath DD, Pruitt MA, Brenner DE, Rock CL. Curcumin in plasma and urine: quantitation by high-performance liquid chromatography. J Chromatogr B Anal Technol Biomed Life Sci. 2003;783:287–95.

    Article  CAS  Google Scholar 

  • Jagetia GC. Radioprotection and radiosensitization by curcumin. Adv Exp Med Biol. 2007;595:301–20.

    Article  PubMed  Google Scholar 

  • Javvadi P, Segan AT, Tuttle SW, Koumenis C. 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. 2008;73:1491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jelveh S, Kaspler P, Bhogal N, Mahmood J, Lindsay PE, Okunieff P, et al. Investigations of antioxidant-mediated protection and mitigation of radiation-induced DNA damage and lipid peroxidation in murine skin. Int J Radiat Biol. 2013;89:618–27.

    Article  CAS  PubMed  Google Scholar 

  • Joiner M, van der Kogel A. Basic clinical radiobiology. 4th ed. London: Hodder Arnold; 2009. p. 11–352.

    Google Scholar 

  • Kang KA, Lee IK, Zhang R, Piao MJ, Kim KC, Kim SY, et al. Radioprotective effect of geraniin via the inhibition of apoptosis triggered by γ-radiation-induced oxidative stress. Cell Biol Toxicol. 2011;27:83–94.

    Article  CAS  PubMed  Google Scholar 

  • Kunnumakkara AB, Diagaradjane P, Guha S, Deorukhkar A, Shentu S, Aggarwal BB, et al. Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products. Clin Cancer Res. 2008;14:2128–36.

    Article  CAS  PubMed  Google Scholar 

  • Kunwar A, Narang H, Priyadarsini KI, Krishna M, Pandey R, Sainis KB. Delayed activation of PKCdelta and NFkappaB and higher radioprotection in splenic lymphocytes by copper (II)-curcumin (1:1) complex as compared to curcumin. J Cell Biochem. 2007;102:1214–24.

    Article  CAS  PubMed  Google Scholar 

  • Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun. 1976;71:952–8.

    Article  CAS  PubMed  Google Scholar 

  • Li M, Zhang Z, Hill DL, Wang H, Zhang R. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res. 2007;67:1988–96.

    Article  CAS  PubMed  Google Scholar 

  • Loft S, Møller P, Cooke MS, Rozalski R, Olinski R. Antioxidant vitamins and cancer risk: is oxidative damage to DNA a relevant biomarker? Eur J Nutr. 2008;47:19–28.

    Article  CAS  PubMed  Google Scholar 

  • Lundvig DMS, Pennings SWC, Brouwer KM, Mtaya-Mlangwa M, Mugonzibwa E, Kuijpers-Jagtman AM, et al. Cytoprotective responses in HaCaT keratinocytes exposed to high doses of curcumin. Exp Cell Res. 2015a;336:298–307.

    Article  CAS  PubMed  Google Scholar 

  • Lundvig DMS, Pennings SWC, Brouwer KM, Mtaya-Mlangwa M, Mugonzibwa EA, Kuijpers-Jagtman AM, et al. Curcumin induces differential expression of cytoprotective enzymes but similar apoptotic responses in fibroblasts and myofibroblasts. Exp Cell Res. 2015b;330:429–41.

    Article  CAS  PubMed  Google Scholar 

  • Mah LJ, El-Osta A, Karagiannis TC. gammaH2AX: a sensitive molecular marker of DNA damage and repair. Leuk. 2010;24:679–86.

    Article  CAS  Google Scholar 

  • Mirgani MT, Isacchi B, Sadeghizadeh M, Marra F, Bilia AR, Mowla SJ, et al. Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells. Int J Nanomedicine. 2014;9:403–17.

    Google Scholar 

  • Nagata S. Apoptotic DNA fragmentation. Exp Cell Res. 2000;256:12–8.

    Article  CAS  PubMed  Google Scholar 

  • Ormsby RJ, Lawrence MD, Blyth BJ, Bexis K, Bezak E, Murley JS, et al. Protection from radiation-induced apoptosis by the radioprotector amifostine (WR-2721) is radiation dose dependent. Cell Biol Toxicol. 2014;30:55–66.

    Article  CAS  PubMed  Google Scholar 

  • Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. Curcumin, a component of golden spice: from bedside to bench and back. Biotechnol Adv. 2014;32:1053–64.

    Article  CAS  PubMed  Google Scholar 

  • Rushworth SA, Ogborne RM, Charalambos CA, O’Connell MA. Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes. Biochem Biophys Res Commun. 2006;341:1007–16.

    Article  CAS  PubMed  Google Scholar 

  • 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;75:919–22.

    Article  CAS  Google Scholar 

  • Sellins KS, Cohen JJ. Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J Immunol. 1987;139:3199–206.

    CAS  PubMed  Google Scholar 

  • Shehzad A, Khan S, Shehzad O, Lee YS. Curcumin therapeutic promises and bioavailability in colorectal cancer. Drugs of Today. 2010;46:523–32.

    Article  CAS  PubMed  Google Scholar 

  • Shi HS, Gao X, Li D, Zhang QW, Wang YS, Zheng Y, et al. A systemic administration of liposomal curcumin inhibits radiation pneumonitis and sensitizes lung carcinoma to radiation. Int J Nanomedicine. 2012;7:2601–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shinojima N, Yokoyama T, Kondo Y, Kondo S. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy. 2007;3:635–7.

    Article  CAS  PubMed  Google Scholar 

  • Srinivasan M, Rajendra Prasad N, Menon VP. Protective effect of curcumin on gamma-radiation induced DNA damage and lipid peroxidation in cultured human lymphocytes. Mutat Res. 2006;611:96–103.

    Article  CAS  PubMed  Google Scholar 

  • Srinivasan M, Sudheer AR, Rajasekaran KN, Menon VP. Effect of curcumin analog on gamma-radiation-induced cellular changes in primary culture of isolated rat hepatocytes in vitro. Chem Biol Interact. 2008;176:1–8.

    Article  CAS  PubMed  Google Scholar 

  • Stresser DM, Blanchard AP, Turner SD, Erve JCL, Dandeneau AA, Miller VP, et al. Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates. Drug Metab Dispos. 2000;28:1440–8.

    CAS  PubMed  Google Scholar 

  • Thresiamma KC, George J, Kuttan R. Protective effect of curcumin, ellagic acid and bixin on radiation induced toxicity. Indian J Exp Biol. 1996;34:845–7.

    CAS  PubMed  Google Scholar 

  • Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem. 1969;27:502–22.

    Article  CAS  PubMed  Google Scholar 

  • Valavanidis A, Vlachogianni T, Fiotakis C. 8-Hydroxy-2′ -deoxyguanosine (8-OHdG): a critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health Part C. 2009;27:120–39.

    Article  CAS  Google Scholar 

  • Villeneuve NF, Sun Z, Chen W, Zhang DD. Nrf2 and p21 regulate the fine balance between life and death by controlling ROS levels. Cell Cycle. 2009;8:3255–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wieckowski MR, Giorgi C, Lebiedzinska M, Duszynski J, Pinton P. Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat Protoc. 2009;4:1582–90.

    Article  CAS  PubMed  Google Scholar 

  • Wilken R, Veena MS, Wang MB, Srivatsan ES. Curcumin: a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer. 2011;10:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie Y, Zhao QY, Li HY, Zhou X, Liu Y, Zhang H. Curcumin ameliorates cognitive deficits heavy ion irradiation-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways. Pharmacol Biochem Behav. 2014;126:181–6.

    Article  CAS  PubMed  Google Scholar 

  • Yang CW, Chang CL, Lee HC, Chi CW, Pan JP, Yang WC. Curcumin induces the apoptosis of human monocytic leukemia THP-1 cells via the activation of JNK/ERK pathways. BMC Complement Altern Med. 2012;12:22.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yun JM, Jialal I, Devaraj S. Epigenetic regulation of high glucose-induced proinflammatory cytokine production in monocytes by curcumin. J Nutr Biochem. 2011;22:450–8.

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Cheng X, Gao Y, Zhang C, Bao J, Guan H, et al. Curcumin inhibits metastasis in human papillary thyroid carcinoma BCPAP cells via down-regulation of the TGF-β/Smad2/3 signaling pathway. Exp Cell Res. 2016;341:157–65.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by grants from University of Tehran and Tarbiat-Modares University as well as a student’s research grant from Iranian Scholars Association.

Author information

Authors and Affiliations

  1. Department of Biotechnology, College of Science, University of Tehran, Enghelab St., Tehran, 14155-6455, Iran

    Behrooz Soltani & Nasser Ghaemi

  2. School of Chemistry, College of Science, University of Tehran, Tehran, Iran

    Nasser Ghaemi

  3. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

    Majid Sadeghizadeh

  4. Department of Resin and Additives, Institute for Color Science and Technology, Tehran, Iran

    Farhood Najafi

Authors
  1. Behrooz Soltani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nasser Ghaemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Majid Sadeghizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Farhood Najafi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nasser Ghaemi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interests.

Additional information

Nasser Ghaemi and Majid Sadeghizadeh contributed equally to this work

Highlights

• THP-1 cells are radioresistant but γ-ray still induces oxidative stress and damage

• Curcumin protects THP-1 cells against radiation

• DNC sensitizes THP-1 cells to radiation

• Nrf2 pathway is differentially activated by DNC

• Distinct apoptosis pathways are used by DNC and DNC+IR

Electronic supplementary material

ESM 1

(PDF 7 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soltani, B., Ghaemi, N., Sadeghizadeh, M. et al. Curcumin confers protection to irradiated THP-1 cells while its nanoformulation sensitizes these cells via apoptosis induction. Cell Biol Toxicol 32, 543–561 (2016). https://doi.org/10.1007/s10565-016-9354-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-016-9354-9

Keywords

Search

Navigation