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Acetylamine derivative of diospyrin, a plant-derived binaphthylquinonoid, inhibits human colon cancer growth in Nod-Scid mice

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Summary

Anticancer activity of diospyrin and its derivatives (1–5) was evaluated against thirteen human cell lines. Compared to diospyrin (1), the acetylamine derivative (4) exhibited increase in cytotoxicity, particularly in HT-29 colon cancer cells, showing GI50 values of 33.90 and 1.96 μM, respectively. Also, enhanced toxicity was observed when cells, pre-treated with compound 4, were exposed to radiation. In vivo assessment of 4 was undertaken on tumour-bearing Nod-Scid mice treated at 4 mg/kg/day. Significant reduction in relative tumour volume (~86–91 %) was observed during the 12th–37th days after drug treatment. Increased caspase-3 activity and DNA ladder formation was observed in HT-29 cells after treatment with 4, suggesting induction of apoptotic death after drug treatment. Moreover, flow cytometric determination of Annexin V- FITC positive and PI negative cells demonstrated 17.4, 26.4, and 27.9 % of early apoptosis, respectively, upon treatment with 5, 10 and 25 μM of 4. HT-29 cells after treatment with 4 (1–25 μM) revealed ~2.5- 3- folds generation of ROS. Furthermore, concentration dependent decrease of mitochondrial trans-membrane potential (∆ψm), and expression of Bcl-2/Bax and other marker proteins suggested involvement of mitochondrial pathway of cell death. Overall, our results demonstrated the underlying cell-death mechanism of the plant-derived naphthoquinonoid (4), and established it as a prospective chemotherapeutic ‘lead’ molecule against colon cancer.

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References

  1. Haggar FA, Boushey RP (2009) Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 22:191–197

    Article  PubMed Central  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  3. Figarola JL, Weng Y, Lincoln C, Horne D, Rahbar S (2012) Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis. Invest New Drugs 30:1413–1425

  4. Senderowicz AM (2004) Targeting cell cycle and apoptosis for the treatment of human malignancies. Curr Opin Cell Biol 16:670–678

    Article  CAS  PubMed  Google Scholar 

  5. Kingston DGI (2011) Modern natural products drug discovery and its relevance to biodiversity conservation. J Nat Prod 74:496–511

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Lown JW (1993) Anthracycline and anthraquinone anticancer agents: current status and recent developments. Pharmacol Ther 60:185–214

    Article  CAS  PubMed  Google Scholar 

  7. Gewirtz DA (1999) A critical evaluation of the mchanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741

    Article  CAS  PubMed  Google Scholar 

  8. Hazra B, Das Sarma M, Sanyal U (2004) Separation methods of quinonoid constituents of plants used in Oriental traditional medicines. J Chromatogr B 812:259–275

    Article  CAS  Google Scholar 

  9. Powolny AA, Singh SV (2008) Plumbagin-induced apoptosis in human prostate cancer cells is associated with modulation of cellular redox status and generation of reactive oxygen species. Pharm Res 25:2171–2180

    Article  CAS  PubMed  Google Scholar 

  10. Jang SY, Jang EH, Jeong SY, Kim JH (2014) Shikonin inhibits the growth of human prostate cancer cells via modulation of the androgen receptor. Int J Oncol 44:1455–1460

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Pardee AB, Li YZ, Li CJ (2002) Cancer therapy with beta-lapachone. Curr Cancer Drug Targets 2:227–242

    Article  CAS  PubMed  Google Scholar 

  12. Kogan NM, Rabinowitz R, Levi P, Gibson D, Sandor P, Schlesinger M, Mechoulam R (2004) Synthesis and antitumor activity of quinonoid derivatives of cannabinoids. J Med Chem 47:3800–3806

    Article  CAS  PubMed  Google Scholar 

  13. da Silva EN, Jr CBC, Guimarães TT, Pinto Mdo C, Cabral IO, Pessoa C, Costa-Lotufo LV, de Moraes MO, de Andrade CK, Dos Santos MR, de Simone CA, Goulart MO, Pinto AV (2011) Synthesis and evaluation of quinonoid compounds against tumor cell lines. Eur J Med Chem 46:399–410

    Article  PubMed  Google Scholar 

  14. de Castro SL, Emery FS, da Silva Júnior EN (2013) Synthesis of quinoidal molecules: strategies towards bioactive compounds with an emphasis on lapachones. Eur J Med Chem 69:678–700

    Article  PubMed  Google Scholar 

  15. Kawamura M, Kuriyama I, Maruo S, Kuramochi K, Tsubaki K, Yoshida H, Mizushina Y (2014) Anti-tumor effects of novel 5-O-acyl plumbagins based on the inhibition of mammalian DNA replicative polymerase activity. PLoS One 9:e88736

    Article  PubMed Central  PubMed  Google Scholar 

  16. Chakrabarty S, Roy M, Hazra B, Bhattacharya RK (2002) Induction of apoptosis in human cancer cell lines by diospyrin, a plant-derived bisnaphthoquinonoid, and its synthetic derivatives. Cancer Lett 188:85–93

    Article  CAS  PubMed  Google Scholar 

  17. Das Sarma M, Ghosh R, Patra A, Hazra B (2007) Synthesis and antiproliferative activity of some novel derivatives of diospyrin, a plant-derived naphthoquinonoid. Bioorg Med Chem 15:3672–3677

    Article  CAS  PubMed  Google Scholar 

  18. Das Sarma M, Ghosh R, Patra A, Hazra B (2008) Synthesis of novel aminoquinonoid analogues of diospyrin and evaluation of their inhibitory activity against murine and human cancer cells. Eur J Med Chem 43:1878–1888

    Article  CAS  PubMed  Google Scholar 

  19. Kumar B, Kumar A, Pandey BN, Mishra KP, Hazra B (2009) Role of mitochondrial oxidative stress in the apoptosis induced by diospyrin diethylether in human breast carcinoma (MCF-7) cells. Mol Cell Biochem 320:185–195

    Article  CAS  PubMed  Google Scholar 

  20. Skehan P, Storeng R, Scudiero D, Monks A, McMohan J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112

    Article  CAS  PubMed  Google Scholar 

  21. Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1:1112–1116

    Article  CAS  PubMed  Google Scholar 

  22. Sandhya T, Mishra KP (2006) Cytotoxic response of breast cancer cell lines, MCF 7 and T 47 D to Triphala and its modification by antioxidants. Cancer Lett 238:304–313

    Article  CAS  PubMed  Google Scholar 

  23. Kumar B, Kumar A, Pandey BN, Hazra B, Mishra KP (2008) Increased cytotoxicity by the combination of radiation and diospyrin diethylether in fibrosarcoma in culture and in tumor. Int J Radiat Biol 84:429–440

    Article  CAS  PubMed  Google Scholar 

  24. Kumar B, Kumar A, Ghosh S, Pandey BN, Mishra KP, Hazra B (2012) Diospyrin derivative, an anticancer quinonoid, regulates apoptosis at endoplasmic reticulum as well as mitochondria by modulating cytosolic calcium in human breast carcinoma cells. Biochem Biophys Res Commun 417:903–909

    Article  CAS  PubMed  Google Scholar 

  25. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  26. Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, Van Buren G 2nd, Samuel S, Kim MP, Lim SJ, Ellis LM (2009) Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res 69:1951–1957

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Schwarz SB, Schaffer PM, Kulka U, Ertl-Wagner B, Hell R, Schaffer M (2008) The effect of radio-adaptive doses on HT29 and GM637 cells. Radiat Oncol 3:12

    Article  PubMed Central  PubMed  Google Scholar 

  28. Subramaniya BR, Srinivasan G, Sadullah SS, Davis N, Subhadara LB, Halagowder D, Sivasitambaram ND (2011) Apoptosis inducing effect of plumbagin on colonic cancer cells depends on expression of COX-2. PLoS One 6:e18695

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Kamal A, Reddy KS, Khan MN, Shetti RV, Ramaiah MJ, Pushpavalli SN, Srinivas C, Pal-Bhadra M, Chourasia M, Sastry GN, Juvekar A, Zingde S, Barkume M (2010) Synthesis, DNA-binding ability and anticancer activity of benzothiazole/benzoxazole-pyrrolo[2,1-c][1,4]benzodiazepine conjugates. Bioorg Med Chem 18:4747–4761

    Article  CAS  PubMed  Google Scholar 

  30. Kayashima T, Mori M, Yoshida H, Mizushina Y, Matsubara K (2009) 1, 4-Naphthoquinone is a potent inhibitor of human cancer cell growth and angiogenesis. Cancer Lett 278:34–40

    Article  CAS  PubMed  Google Scholar 

  31. Lee JH, Yeon JH, Kim H, Roh W, Chae J, Park HO, Kim DM (2012) The natural anticancer agent plumbagin induces potent cytotoxicity in MCF-7 human breast cancer cells by inhibiting a PI-5 kinase for ROS generation. PLoS One 7:e45023

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Suzanne M, Steller H (2013) Shaping organism with apoptosis. Cell Death Differ 20:669–675

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The study was funded by the Department of Atomic Energy, Mumbai (Grant No. 2008/37/30/BRNS). SH is funded by a fellowship from the Department of Biotechnology, New Delhi. SG is a recipient of Young Scientist Award, Department of Science and Technology, New Delhi (SERB Grant No. SB/ FT/ LS- 116/ 2012). The authors acknowledge Dr. A.S. Juvekar for organising anticancer drug screening at ACTREC, Mumbai, and Shri Sanjay Shinde for technical assistance in irradiation of samples at BARC, Mumbai.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

    Sudipta Hazra, Subhalakshmi Ghosh & Banasri Hazra

  2. Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India

    Amit Kumar & B. N. Pandey

Authors
  1. Sudipta Hazra
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  2. Subhalakshmi Ghosh
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  3. Amit Kumar
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  4. B. N. Pandey
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  5. Banasri Hazra
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Correspondence to B. N. Pandey or Banasri Hazra.

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Sudipta Hazra and Subhalakshmi Ghosh equal contribution

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Hazra, S., Ghosh, S., Kumar, A. et al. Acetylamine derivative of diospyrin, a plant-derived binaphthylquinonoid, inhibits human colon cancer growth in Nod-Scid mice. Invest New Drugs 33, 22–31 (2015). https://doi.org/10.1007/s10637-014-0165-7

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  • DOI: https://doi.org/10.1007/s10637-014-0165-7

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