Tumor Biology

, Volume 36, Issue 5, pp 3591–3599 | Cite as

Curcumin reverses cisplatin resistance in cisplatin-resistant lung caner cells by inhibiting FA/BRCA pathway

  • Ping Chen
  • Jian LiEmail author
  • He-Guo Jiang
  • Ting Lan
  • Yong-Chang Chen
Research Article


Cisplatin (DDP) is the most widely used chemotherapy agent for treatment of malignancies including lung cancer. However, the effectiveness of DDP is often weakened by acquired resistance of tumor cells. DDP kills cancer cells primarily by creating intrastrand and interstrand DNA cross-links, which block DNA replication. The Fanconi anemia (FA)/BRCA pathway is a DNA cross-link damage repair pathway, which regulates cellular resistance to DNA cross-link agents, such as DDP. Some study has shown that natural compound curcumin sensitize human ovarian and breast cancer cells to DDP. However, whether curcumin may reverse resistance to DDP in DDP-resistant lung cancer cells has not been understood. In this study, we showed that curcumin enhanced the proliferation inhibitory effect of DDP and promote DDP-induced apoptosis in A549/DDP cells (DDP-resistant lung adenocarcinoma cells). Moreover, we observed that FA/BRCA pathway DNA damage repair processes, such as DDP-induced FANCD2 monoubiquitination and nuclear foci formation were downregulated in the presence of curcumin, suggesting that curcumin enhanced sensitivity to DDP in A549/DDP cells through the inhibition of FA/BRCA pathway. Furthermore, the calculation of q value and apoptosis analyses revealed that curcumin in combination with DDP could exert a synergistic cytotoxic effect in A549/DDP cells, further demonstrating that curcumin can reverse cisplatin resistance of A549/DDP cells. In conclusion, by suppressing the FA/BRCA pathway DNA repair, curcumin potentiates DDP-induced proliferation inhibitory effect and apoptosis in A549/DDP cell, indicating that curcumin may serve as a chemosensitizer to cross-link-inducing anticancer drugs DDP.


Curcumin Cisplatin Lung cancer cells FA/BRCA pathway DNA repair Resistance 


Conflicts of interest



  1. 1.
    Spira SG, Silvestri GA. The treatment of advanced non-small cell lung cancer. Curr Opin Pulm Med. 2005;11:287–91.CrossRefGoogle Scholar
  2. 2.
    Massarelli E, Herbst RS. Use of novel second-line target therapies in non-small cell lung cancer. Semin Oncol. 2006;33 suppl 1:s9–16.CrossRefPubMedGoogle Scholar
  3. 3.
    Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med. 2004;350:379–92.CrossRefPubMedGoogle Scholar
  4. 4.
    Resell R, Cecere F, Santarpia M, Noemi R, Miquel T. Predicting the outcome of chemotherapy for lung cancer. Curr Opin Pharmacol. 2006;6:323–31.CrossRefGoogle Scholar
  5. 5.
    Kartalou M, Essigmann JM. Mechanisms of resistance to cisplatin. Mutat Res. 2001;478:23–43.CrossRefPubMedGoogle Scholar
  6. 6.
    Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7:573–84.CrossRefPubMedGoogle Scholar
  7. 7.
    Kennedy RD, D’Andrea AD. DNA repair pathway in clinical practice: lesions from pediatric cancer susceptibility syndromes. J Clin Oncol. 2006;24:3799–808.CrossRefPubMedGoogle Scholar
  8. 8.
    Kim H, D’Andrea AD. Regulation of DNA Cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev. 2012;26:1393–408.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Auerbach AD. Fanconi anemia and its diagnosis. Mutat Res. 2009;668:4–10.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Alan D. The Fanconi anemia and breast susceptibility pathway. N Engl J Med. 2010;362:1909–19.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Kee Y, D’Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes Dev. 2010;24:1680–94.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Su X, Huang J. The Fanconi anemia pathway and DNA interstrand cross-link repair. Protein Cell. 2011;2:704–11.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, et al. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med. 2003;9:568–74.CrossRefPubMedGoogle Scholar
  14. 14.
    Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA-mutated cancers. Nature. 2008;451:1116–20.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jagtap S, Meganathan K, Wagh V, Winkler J, Hescheler J, Sachinidis A. Chemoprotective mechanism of the natural compounds, epigallocatechin-3-O-gallate, quercetin and curcumin against cancer and cardiovascular diseases. Curr Med Chem. 2009;16:1451–62.CrossRefPubMedGoogle Scholar
  16. 16.
    Shishodia S, Chalurvedi MM, Aggarwal BB. Role of curcumin in cancer therapy. Curr Probl Cancer. 2007;31:243–305.CrossRefPubMedGoogle Scholar
  17. 17.
    Ye MX, Li Y, Yin H, Zhang J. Curcumin: updated molecular mechanisms and intervention targets in human lung cancer. Int J Mol Sci. 2012;13:3959–78.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Duarte VM, Han E, Veena MS, Salvado A, Suh JD, Liang LJ, et al. Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKβ protein of the NFκB pathway. Mol Cancer Ther. 2010;9:2665–75.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Xu XB, Chen B, Liu WY. Curcumin inhibits the invasion of thyroid cancer cells via down-regulation of PI3K/kt signaling pathway. Gene. 2014;546:226–32.CrossRefPubMedGoogle Scholar
  20. 20.
    Zang S, Liu T, Shi J, Qiao L. Curcumin: a promising agent targeting cancer stem cells. Anticancer Agents Med Chem. 2014;14:787–92.CrossRefPubMedGoogle Scholar
  21. 21.
    Chirnomas D, Taniguchi T, de la Vaga M, Vaidya AP, Vasserman M, Hartman A-R, et al. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol Cancer Ther. 2006;5:952–61.CrossRefPubMedGoogle Scholar
  22. 22.
    Xiao H, Xiao Q, Zhang K, Zuo X, Shresthan UK. Reversal of multidrug resistance by curcumin through FA/BRCA pathway in multiple myeloma cell line MOLP-2/R. Ann Hematol. 2010;89:399–404.CrossRefPubMedGoogle Scholar
  23. 23.
    Shao Z-M, Shen Z-Z, Liu C-H, Sartippour MR, Heber D, Nguyen M. Curcumin exerts multiples suppressive effects on human breast carcinoma cells. Int J Cancer. 2002;98:234–40.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen Q, Van der Sluis PC, Boulware D, Hazlehurst LA, Dalton WS. The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells. Blood. 2005;106:698–705.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    van der Heijden MS, Brody JR, Gallemier E, Cunningham SC, Dezentje DA, Shen D, et al. Function defects in the Fanconi anemia pathway in pancreatic cancer cells. Am J Pathol. 2004;165:651–7.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Burkitt K, Ljungman M. Compromised Fanconi anemia response due to BRCA1 deficiency in cisplatin-sensitive head and neck cancer cell lines. Cancer Lett. 2007;8:131–7.CrossRefGoogle Scholar
  27. 27.
    Zhang J, Wang X, Lin C-J, Conch FJ, Fei P. Altered expression of FANCL confers mitomycin C sensitivity in calu-6 lung cancer cells. Cancer Biol Ther. 2006;5:1632–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Burkitt K, Ljurgman M. Phenylbutyrate interferes with the Fanconi anemia and BRCA pathway and sensitized head and neck cancer cells to cisplatin. Mol Cancer. 2008;7:24.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yarde DN, Oliveira V, Mathews L, Wang X, Villagra A, Boulware D, et al. Targeting the Fanconi anemial BRCA pathway circumvents drug resistance in multiple myeloma. Cancer Res. 2009;69:9367–75.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Chen J, Dexheimer TS, Ai Y, Liang G, Villamil MA, Inglese J, et al. Selective and cell-active inhibitors of the USP1/UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells. Chem Biol. 2011;18:1390–400.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kee Y, Huang M, Chang S, Moreau LA, Park E, Smith PG, et al. Inhibition of the Nedd8 system sensitive cells to DNA interstrand cross-linking agents. Mol Cancer Res. 2012;10:369–77.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Litan R, Gupta R, Brosh Jr RM, Cantor SB. BRCA-FA pathway as a target for anti-tumor drugs. Anticancer Agents Med Chem. 2008;8:423–30.Google Scholar
  33. 33.
    Hucl T, Gallmeier E. DNA repair: exploiting the Fanconi anemia pathway as a potential therapeutic target. Physiol Res. 2011;60:453–65.PubMedGoogle Scholar
  34. 34.
    Shukl P, Solank A, Ghos K, Vundinit BR. DNA interstrand cross-link repair: understanding role of Fanconi anemia pathway and therapeutic implications. Eur J Haematol. 2013;9:381–93.CrossRefGoogle Scholar
  35. 35.
    Kunnunakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling protein. Cancer Lett. 2008;269:199–255.CrossRefGoogle Scholar
  36. 36.
    Yu LL, Wu JG, Dai HG, Si JM. Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-Kappa B transcritption factor. Oncol Rep. 2011;26:1197–203.PubMedGoogle Scholar
  37. 37.
    Jana NR, Diskshit P, Goswami A, Nukina N. Inhibition of proteasomal function by curcumin induces apoptosis through mitochondrial pathway. J Biol Chem. 2004;219:11680–5.CrossRefGoogle Scholar
  38. 38.
    Jacquemont C, Taniguchi T. Proteasome function is required for DNA damage response and Fanconi anemia pathway activation. Cancer Res. 2007;67:7395–405.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Ping Chen
    • 1
  • Jian Li
    • 1
    Email author
  • He-Guo Jiang
    • 1
  • Ting Lan
    • 2
  • Yong-Chang Chen
    • 2
  1. 1.Department of Pulmonary MedicineAffiliated Hospital of Jiangsu UniversityZhenjiangChina
  2. 2.Institute of Medical ScienceJiangsu UniversityZhenjianChina

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