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Anticancer activities of vitamin K3 analogues

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Summary

In a previous study we reported on the synthesis of 1,4-naphthoquinone-sulfides by thiolation of 1,4-naphthohydroquinones with primary aryl and alkyl thiols using laccase as catalyst. These compounds were synthesized as Vitamin K3 analogues. Vitamin K3 (VK3; 2-methyl-1,4-naphthoquinone; menadione) is known to have potent anticancer activity. This investigation reports on the anticancer activity of these VK3 analogues against TK10 renal, UACC62 melanoma, MCF7 breast, HeLa cervical, PC3 prostate and HepG2 liver cancer cell lines to evaluate their cytostatic effects. A 1,4-naphthohydroquinone derivative exhibited potent cytostatic effects (GI50 = 1.66–6.75 μM) which were better than that of etoposide and parthenolide against several of the cancer cell lines. This compound produces reactive oxygen species and disrupts the mitochondrial membrane potential in the MCF7 breast cancer cell line which is an indication that the cells undergo apoptosis. The 1,4-naphthoquinone sulfides also had potent cytostatic effects (GI50 = 2.82–9.79 μM) which were also better than that of etoposide, parthenolide and VK3 against several of the cancer cell lines. These compounds are generally more selective for cancer cells than for normal human lung fetal fibroblasts (WI-38). They also have moderate to weak cytostatic effects compared to etoposide, parthenolide and VK3 which have potent cytostatic effects against WI-38. One analogue induces apoptosis by activating caspases without arresting the cell cycle in the MCF7 breast cancer cell line. These results inspire further research for possible application in cancer chemotherapy.

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References

  1. World Health organization (WHO) https://www.who.int/cancer/en/. Accessed 20 March 2019

  2. WHO http://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/ Accessed 20 March 2019

  3. WHO http://www.who.int/cancer/prevention/diagnosis-screening/cervical-cancer/en/. Accessed 20 March 2019

  4. World Cancer Research Fund (WCRF) https://www.wcrf.org/dietandcancer/cancer-trends/prostate-cancer-statistics. Accessed 20 March 2019

  5. WCRF https://www.wcrf.org/dietandcancer/cancer-trends/liver-cancer-statistics. Accessed 20 March 2019

  6. WCRF https://www.wcrf.org/dietandcancer/cancer-trends/kidney-cancer-statistics. Accessed 20 March 2019

  7. WHO http://www.who.int/uv/faq/skincancer/en/index1.html. Accessed 20 March 2019

  8. Cranenburg EC, Schurgers LJ, Vermeer C (2007) Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost 98:120–125

    Article  CAS  Google Scholar 

  9. Lamson DW, Plaza SM (2003) The anticancer effects of vitamin K. Altern Med Rev 8:303–318

    PubMed  Google Scholar 

  10. Parcell S (2002) Sulfur in human nutrition and applications in medicine. Altern MedRev 7:22–44

    Google Scholar 

  11. Wu X, Kassie F, Mersch-Sundermann V (2005) Induction of apoptosis in tumour cells by naturally occurring sulfur containing compounds. Mutat Res 589:81–102

    Article  CAS  Google Scholar 

  12. Ariga T, Seki T (2006) Antithrombotic and anticancer effects of garlic-derived sulfur compounds: a review. Biofactors 26:93–103

    Article  CAS  Google Scholar 

  13. Herman-Antosiewicz A, Powolny AA, Singh SV (2007) Molecular targets of cancer chemoprevention by garlic-derived organosulfides. Acta Pharmacol Sin 8:1355–1364

    Article  Google Scholar 

  14. Shukla Y, Kalra N (2007) Cancer chemoprevention with garlic and its constituents. Cancer Lett 47:167–181

    Article  Google Scholar 

  15. Tandon VK, Maurya HK, Mishra NN, Shukla PK (2009) Design, synthesis and biological evaluation of novel nitrogen and sulfur containing hetero-1,4-naphthoquinones as potent antifungal and antibacterial agents. Eur J Med Chem 44:3130–3137

    Article  CAS  Google Scholar 

  16. Tandon VK, Maurya HK, Verma MK, Kumar R, Shukla PK (2010) 'On water' assisted synthesis and biological evaluation of nitrogen and sulfur containing hetero-1,4-naphthoquinones as potent antifungal and antibacterial agents. Eur J Med Chem 45:2418–2426

    Article  CAS  Google Scholar 

  17. Huang G, Zhao HR, Meng QQ, Zhang QJ, Dong JY, Zhu BQ, Li SS (2018) Synthesis and biological evaluation of sulfur-containing shikonin oxime derivatives as potential antineoplastic agents. Eur J Med Chem 143:166–181

    Article  CAS  Google Scholar 

  18. Kaufmann H, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256:42–49

    Article  CAS  Google Scholar 

  19. Wellington KW, Kolesnikova NI (2012) A Laccase-catalysed one-pot synthesis of aminonaphthoquinones and their anticancer activity. Bioorg Med Chem 220:4472–4481

    Article  Google Scholar 

  20. Wellington KW, Kolesnikova NI, Nyoka NBP, McGaw LJ (2018) Investigation of the antimicrobial and anticancer activity of aminonaphthoquinones. Drug Dev Res 80(1):138–146

    Article  Google Scholar 

  21. Qwebani-Ogunleye T, Kolesnikova NI, Steenkamp P, De Koning CB, Brady D, Wellington KW (2017) A one-pot laccase-catalysed synthesis of coumestan derivatives and their anticancer activity. Bioorg Med Chem 25(3):1172–1182

    Article  CAS  Google Scholar 

  22. Wellington KW, Qwebani-Ogunleye T, Kolesnikova NI, Brady D, de Koning CB (2013a) A one-pot laccase-catalysed synthesis of 5,6-dihydroxylated benzo[b]furans and catechol derivatives, and their anticancer activity. Arch Pharm (Weinheim) 346:266–277

    Article  CAS  Google Scholar 

  23. Wellington KW, Gordon GER, Ndlovu LA, Kolesnikova NI, Steenkamp P (2013b) Laccase-catalysed C-S and C-C coupling for a one-pot synthesis of 1,4-Naphthoquinone sulfides and 1,4-Naphthoquinone sulfide dimers. ChemCatChem 5:1570–1577

    Article  CAS  Google Scholar 

  24. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer drug screening. J Natl Cancer Inst 82:1107–1112

    Article  CAS  Google Scholar 

  25. Perry SW, Norman JP, Barbieri J, Brown EB, Gelbard HA (2011) Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. Biotechniques 50(2):98–115

    Article  CAS  Google Scholar 

  26. Kaur M, Esau L (2015) Two step protocol for preparing adherent cells for high-throughput flow cytometry. Biotechniques 59(3):119–126

    Article  CAS  Google Scholar 

  27. Yoon DS, Lee M-H, Cha DS (2018) Measurement of intracellular ROS in Caenorhabditis elegans using 2′, 7′-Dichlorodihydrofluorescein Diacetate. Bio–Protocol 8(6):e2774

    Article  Google Scholar 

  28. Wu C-C, Li T-K, Farh L, Lin L-Y, Lin T-S, Yu Y-J, Yen T-J, Chiang C-W, Chan N-L (2011) Structural basis of type II topoisomerase inhibition by the anticancer drug Etoposide. Science 33:59–462

    CAS  Google Scholar 

  29. Carlisi D, D’anneo A, Angileri L, Lauricella M, Emanuele S, Santulli A, Vento R, Tesoriere G (2010) Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation. J Cell Physiol 226:1632–1641

    Article  Google Scholar 

  30. Hayashi S, Koshiba K, Hatashita M, Sato T, Jujo Y, Suzuki R et al (2011) Thermosensitization and induction of apoptosis or cell-cycle arrest via the MAPK cascade by parthenolide, an NF-kB inhibitor, in human prostate cancer androgen-independent cell lines. Int J Mol Med 28:1033–1042

    CAS  PubMed  Google Scholar 

  31. Zhang S, Ong CN, Shen HM (2004) Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett 208:143–153

    Article  CAS  Google Scholar 

  32. Akinboye ES, Bakare O (2011) Biological activities of emetine. Open Nat Product J 4:8–15

    Article  CAS  Google Scholar 

  33. Janicke RU (2008) MCF-7 breast carcinoma cells do not express caspase-3. Breast Cancer Res Treat 117(1):219–221

    Article  Google Scholar 

  34. Silverman RB (1992) The organic chemistry of drug design and drug action. Academic Press, New York

    Google Scholar 

  35. Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1(4):337–341

    Article  CAS  Google Scholar 

  36. Akiyoshi T, Matzno S, Sakai M, Okamura N, Matsuyama K (2009) The potential of vitamin K3 as an anticancer agent against breast cancer that acts via the mitochondria-related apoptotic pathway. Cancer Chemother Pharmacol 65:143–150

    Article  CAS  Google Scholar 

  37. Nutter LM, Ngo EO, Fisher GR, Gutierrez PL (1992) DNA strand scission and free radical production in VK3-treated cells. Correlation with cytotoxicity and role of NADPH quinone acceptor oxidoreductase. J Biol Chem 267:2474–2479

    CAS  PubMed  Google Scholar 

  38. Sakagami H, Satoh K, Hakeda Y, Kumegawa M (2000) Apoptosis-inducing activity of vitamin C and vitamin K. Cell Mol Biol 46(1):129–143

    CAS  PubMed  Google Scholar 

  39. Yip KW, Reed JC (2008) Bcl-2 family proteins and cancer. Oncogene 27:6398–6406

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the CSIR (Thematic A grant) for financial support. The National Research Foundation Incentive Funding (No: 109163) and Claude Leon Foundation Merit Award (2016) to MK is also acknowledged.

Funding

This work was supported by the Biosciences unit, Council for Scientific and Industrial Research, Pretoria, South Africa.

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Authors and Affiliations

  1. CSIR Biosciences, P O Box 395, Pretoria, South Africa

    Kevin W. Wellington & Natasha I. Kolesnikova

  2. Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa

    Vincent Hlatshwayo

  3. Centre for HIV and STI’s, National Institute for Communicable Diseases, Johannesburg, Gauteng, South Africa

    Vincent Hlatshwayo

  4. School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2050, South Africa

    Sourav Taru Saha & Mandeep Kaur

  5. Department of Biochemistry, University of Johannesburg, PO Box 524, Auckland Park, 2006, South Africa

    Lesetja R. Motadi

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  1. Kevin W. Wellington
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  3. Natasha I. Kolesnikova
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  4. Sourav Taru Saha
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Correspondence to Kevin W. Wellington.

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Kevin W. Wellington declares that he has no conflict of interest. Natasha I. Kolesnikova declares that she has no conflict of interest. Vincent Hlatshwayo declares that he has no conflict of interest. Sourav Taru Saha declares that he has no conflict of interest. Mandeep Kaur declares that she has no conflict of interest. Lesetja. R. Motadi declares that he has no conflict of interest.

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Wellington, K.W., Hlatshwayo, V., Kolesnikova, N.I. et al. Anticancer activities of vitamin K3 analogues. Invest New Drugs 38, 378–391 (2020). https://doi.org/10.1007/s10637-019-00855-8

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