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The short-time treatment with curcumin sufficiently decreases cell viability, induces apoptosis and copper enhances these effects in multidrug-resistant K562/A02 cells

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Abstract

The anti-cancer activities of curcumin (CUR), a polyphenol derived from the plant Curcuma longa, has been extensively studied. In the present study, we found that CUR displayed anti-multidrug-resistant (MDR) activity in K562/A02 cells. A short-time treatment with CUR sufficiently and equally induced DNA damage, decreased cell viability, and triggered apoptosis in parent K562 and MDR K562/A02 cells. The short-time treatment with CUR also caused decrease of pro-caspase 3 in both cell lines and decrease of pro-caspase 9, increase of PARP cleavage and the ratio of Bax/Bcl-xL in MDR K562/A02 cells. Further experiment revealed that CUR was capable of down-regulating P-glycoprotein in MDR K562/A02 cells. Moreover, we observed that Cu2+ enhanced CUR-mediated apoptosis which was blocked by antioxidants N-acetyl-cysteine and catalase. In summary, the short-time treatment with CUR sufficiently induced DNA damage, decreased cell viability and triggered apoptosis in MDR K562/A02 cells and Cu2+ enhanced CUR-mediated apoptosis which due to reactive oxygen species generation.

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Abbreviations

CAT:

Catalase

CUR:

Curcumin

DOX:

Doxorubicin

MDR:

Multidrug-resistant

MTT:

Tetrazolium bromide

NAC:

N-acetyl-cysteine

RF:

Resistance factor

ROS:

Reactive oxygen species

VP16:

Etoposide

References

  1. Perez-Tomas R (2006) Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr Med Chem 13:1859–1876

    Article  PubMed  CAS  Google Scholar 

  2. Gottesman MM, Ling V (2006) The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett 580:998–1009

    Article  PubMed  CAS  Google Scholar 

  3. Hennessy M, Spiers JP (2007) A primer on the mechanics of P-glycoprotein the multidrug transporter. Pharmacol Res 55:1–15

    Article  PubMed  CAS  Google Scholar 

  4. Zhou SF (2008) Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 38:802–832

    Article  PubMed  CAS  Google Scholar 

  5. Joe B, Vijaykumar M, Lokesh BR (2004) Biological properties of curcumin-cellular and molecular mechanisms of action. Crit Rev Food Sci Nutr 44:97–111

    Article  PubMed  CAS  Google Scholar 

  6. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC (2006) Multiple biological activities of curcumin: a short review. Life Sci 78:2081–2087

    Article  PubMed  CAS  Google Scholar 

  7. Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398

    PubMed  CAS  Google Scholar 

  8. Kunnumakkara AB, Anand P, Aggarwal BB (2008) Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett 269:199–225

    Article  PubMed  CAS  Google Scholar 

  9. Das T, Sa G, Saha B, Das K (2010) Multifocal signal modulation therapy of cancer: ancient weapon, modern targets. Mol Cell Biochem 336:85–95

    Article  PubMed  CAS  Google Scholar 

  10. Basile V, Ferrari E, Lazzari S, Belluti S, Pignedoli F, Imbriano C (2009) Curcumin derivatives: molecular basis of their anti-cancer activity. Biochem Pharmacol 78:1305–1315

    Article  PubMed  CAS  Google Scholar 

  11. Hussain AR, Al-Rasheed M, Manogaran PS, Al-Hussein KA, Platanias LC, Al Kuraya K, Uddin S (2006) Curcumin induces apoptosis via inhibition of PI3′-kinase/AKT pathway in acute T cell leukemias. Apoptosis 11:245–254

    Article  PubMed  CAS  Google Scholar 

  12. Zheng S, Chen A (2004) Activation of PPAR gamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro. Biochem J 384:149–157

    Article  PubMed  CAS  Google Scholar 

  13. Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, Price JE (2005) Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res 11:7490–7498

    Article  PubMed  CAS  Google Scholar 

  14. Shishodia S, Amin HM, Lai R, Aggarwal BB (2005) Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. Biochem Pharmacol 70:700–713

    Article  PubMed  CAS  Google Scholar 

  15. Luan FJ (1993) Establishment of the multidrug-resistant cell line K562/A02 and its drug-resistant properties. Zhonghua Zhong Liu Za Zhi 15:101–103

    PubMed  CAS  Google Scholar 

  16. Yang CZ, Luan FJ, Xiong DS, Liu BR, Xu YF, Gu KS (1995) Multidrug resistance in leukemic cell line K562/A02 induced by doxorubicin. Zhongguo Yao Li Xue Bao 16:333–337

    PubMed  Google Scholar 

  17. Cai YJ, Lu JJ, Zhu H, Xie H, Huang M, Lin LP, Zhang XW, Ding J (2008) Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition. Free Radic Biol Med 45:627–635

    Article  PubMed  CAS  Google Scholar 

  18. Cao J, Jia L, Zhou HM, Liu Y, Zhong LF (2006) Mitochondrial and nuclear DNA damage induced by curcumin in human hepatoma G2 cells. Toxicol Sci 91:476–483

    Article  PubMed  CAS  Google Scholar 

  19. Lu JJ, Cai YJ, Ding J (2011) Curcumin induces DNA damage and caffeine-insensitive cell cycle arrest in colorectal carcinoma HCT116 cells. Mol Cell Biochem 354:247–252

    Article  PubMed  CAS  Google Scholar 

  20. Cai Y, Lu J, Miao Z, Lin L, Ding J (2007) Reactive oxygen species contribute to cell killing and P-glycoprotein downregulation by salvicine in multidrug resistant K562/A02 cells. Cancer Biol Ther 6:1794–1799

    Article  PubMed  CAS  Google Scholar 

  21. Smyth MJ, Krasovskis E, Sutton VR, Johnstone RW (1998) The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis. Proc Natl Acad Sci USA 95:7024–7029

    Article  PubMed  CAS  Google Scholar 

  22. Yoshino M, Haneda M, Naruse M, Htay HH, Tsubouchi R, Qiao SL, Li WH, Murakami K, Yokochi T (2004) Prooxidant activity of curcumin: copper-dependent formation of 8-hydroxy-2′-deoxyguanosine in DNA and induction of apoptotic cell death. Toxicol In Vitro 18:783–789

    Article  PubMed  CAS  Google Scholar 

  23. Verma SP, Goldin BR (2003) Copper modulates activities of genistein, nitric oxide, and curcumin in breast tumor cells. Biochem Biophys Res Commun 310:104–108

    Article  PubMed  CAS  Google Scholar 

  24. Tang XQ, Bi H, Feng JQ, Cao JG (2005) Effect of curcumin on multidrug resistance in resistant human gastric carcinoma cell line SGC7901/VCR. Acta Pharmacol Sin 26:1009–1016

    Article  PubMed  CAS  Google Scholar 

  25. Zhang J, Zhang T, Ti X, Shi J, Wu C, Ren X, Yin H (2010) Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway. Biochem Biophys Res Commun 399:1–6

    Article  PubMed  CAS  Google Scholar 

  26. Efferth T, Davey M, Olbrich A, Rucker G, Gebhart E, Davey R (2002) Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells. Blood Cells Mol Dis 28:160–168

    Article  PubMed  Google Scholar 

  27. Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58

    Article  PubMed  CAS  Google Scholar 

  28. Avendano C, Menendez JC (2002) Inhibitors of multidrug resistance to antitumor agents (MDR). Curr Med Chem 9:159–193

    PubMed  CAS  Google Scholar 

  29. Ahsan H, Hadi SM (1998) Strand scission in DNA induced by curcumin in the presence of Cu(II). Cancer Lett 124:23–30

    Article  PubMed  CAS  Google Scholar 

  30. Ahsan H, Parveen N, Khan NU, Hadi SM (1999) Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem Biol Interact 121:161–175

    Article  PubMed  CAS  Google Scholar 

  31. Nair J, Strand S, Frank N, Knauft J, Wesch H, Galle PR, Bartsch H (2005) Apoptosis and age-dependant induction of nuclear and mitochondrial etheno-DNA adducts in Long-Evans Cinnamon (LEC) rats: enhanced DNA damage by dietary curcumin upon copper accumulation. Carcinogenesis 26:1307–1315

    Article  PubMed  CAS  Google Scholar 

  32. Yoon MJ, Kim EH, Lim JH, Kwon TK, Choi KS (2010) Superoxide anion and proteasomal dysfunction contribute to curcumin-induced paraptosis of malignant breast cancer cells. Free Radic Biol Med 48:713–726

    Article  PubMed  CAS  Google Scholar 

  33. Lou JR, Zhang XX, Zheng J, Ding WQ (2010) Transient metals enhance cytotoxicity of curcumin: potential involvement of the NF-kappaB and mTOR signaling pathways. Anticancer Res 30:3249–3255

    PubMed  CAS  Google Scholar 

  34. Ebadi M, Swanson S (1988) The status of zinc, copper, and metallothionein in cancer patients. Prog Clin Biol Res 259:161–175

    PubMed  CAS  Google Scholar 

  35. Yoshida D, Ikeda Y, Nakazawa S (1993) Quantitative analysis of copper, zinc and copper/zinc ratio in selected human brain tumors. J Neurooncol 16:109–115

    Article  PubMed  CAS  Google Scholar 

  36. Chen D, Milacic V, Frezza M, Dou QP (2009) Metal complexes, their cellular targets and potential for cancer therapy. Curr Pharm Des 15:777–791

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We extremely thank Ms. Si-Meng Chen, Mr. Guo-Sheng Wu, and Mr. Lin-Jiang Tong, for their technical help.

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Correspondence to Yu-Jun Cai or Jian Ding.

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Lu, JJ., Cai, YJ. & Ding, J. The short-time treatment with curcumin sufficiently decreases cell viability, induces apoptosis and copper enhances these effects in multidrug-resistant K562/A02 cells. Mol Cell Biochem 360, 253–260 (2012). https://doi.org/10.1007/s11010-011-1064-2

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  • DOI: https://doi.org/10.1007/s11010-011-1064-2

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