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Luteolin, an Abundant Dietary Component is a Potent Anti-leishmanial Agent that Acts by Inducing Topoisomerase II-mediated Kinetoplast DNA Cleavage Leading to Apoptosis

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Abstract

Background

Plant-derived flavonoids, which occur abundantly in our daily dietary intake, possess antitumor, antibacterial, and free radical scavenging properties. They form active constituents of a number of herbal and traditional medicines. Several flavonoids have been shown to exert their action by interacting with DNA topoisomerases and promoting site-specific DNA cleavage. Therefore, flavonoids are potential candidates in drug design. We report here that, although the flavonoids luteolin and quercetin are potent antileishmanial agents, luteolin has great promise for acting as a lead compound in the chemotherapy of leishmaniasis, a major concern in developing countries.

Materials and Methods

Kinetoplast DNA (kDNA) minicircle cleavage in drug-treated parasites was measured by electrophoresis of the total cellular DNA, followed by Southern hybridization using 32P labeled kDNA as a probe. Cell cycle progression and apoptosis were measured by flow cytometry using propidium iodide and fluorescein isothiocyanate (FITC)-labeled Annexin V.

Results

Luteolin and quercetin inhibited the growth of Leishmania donovani promastigotes and amastigotes in vitro, inhibited DNA synthesis in promastigotes, and promoted topoisomerase-II-mediated linearization of kDNA minicircles. The IC50 values of luteolin and quercetin were 12.5 µM and 45.5 µM, respectively. These compounds arrest cell cycle progression in L. donovani promastigotes, leading to apoptosis. Luteolin has no effect on normal human T-cell blasts. Both luteolin and quercetin reduced splenic parasite burden in animal models.

Conclusion

Luteolin and quercetin are effective antileishmanial agents. Quercetin has nonspecific effects on normal human T cells, but luteolin appears nontoxic. So, luteolin can be a strong candidate for antileishmanial drug design.

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References

  1. Havsteen B. (1983) Flavonoids, a class of natural products of high pharmacological potency. Biochem. Pharmacol. 32: 1141–1148.

    Article  CAS  PubMed  Google Scholar 

  2. Wollenweber E. (1988). Occurrence of flavonoid aglycones in medicinal plants. Prog. Clin. Biol. Res. 280: 44–55.

    Google Scholar 

  3. Herrmann K. (1976) Flavonols and flavonones in food plants. J. Food Technol. 11: 433–448.

    Article  CAS  Google Scholar 

  4. Hertog MGL, Hollman PCH, Katan MB, Krombout D. (1993) Intake of potentially anticarcinogenic flavonoids and their determinants in adults in Netharlands. Nutr. Cancer 20: 21–29.

    Article  CAS  PubMed  Google Scholar 

  5. Suolinna EM, Buchsbaun RN, Racker E. (1975) The effect of flavonoids on aerobic glycolysis and growth of tumor cells. Cancer Res. 35: 1865–1872.

    PubMed  CAS  Google Scholar 

  6. Castillo MH, Perkins E, Campbell JH, et al. (1989) The effects of the bioflavonoid quercetin on squamous cell carcinoma of head and neck origin. American J. Surg. 188: 351–355.

    Article  Google Scholar 

  7. Bibby MC, Double JA. (1993) Flavone acetic acid-from laboratory to clinic and back. Anticancer Drugs 4: 3–17.

    Article  CAS  PubMed  Google Scholar 

  8. Yoshida M, Yamato M, Nakaido T. (1992) Quercetin arrests human leukemic T-cells in late G1 phase of the cell cycle. Cancer Res. 55: 6676–6681.

    Google Scholar 

  9. Scambia G, Ranelletti FO, Benedetti PP, et al. (1990) Synergistic antiproliferative activity of quercetin and cisplatin on ovarian cancer cell growth. Anticancer Drugs 1: 45–48.

    Article  CAS  PubMed  Google Scholar 

  10. Teofili L, Pierelli L, Iovino MS, et al. (1992) The combination of quercetin and cytosine arabinoside synergistically inhibits leukemic cell growth. Leuk. Res. 16: 497–503.

    Article  CAS  PubMed  Google Scholar 

  11. Hofmann J, Fielig HH, Winterhalter BR, Berger DR, Grunicke H. (1990) Enhancement of the antiproliferative activity of cis-diamminedichloroplatinum(II) by quercetin. Int. J. Cancer 45: 536–539.

    Article  CAS  PubMed  Google Scholar 

  12. Wang JC. (1996) DNA topoisomerases. Annu. Rev. Biochem. 65: 635–692.

    Article  CAS  PubMed  Google Scholar 

  13. Yamashita Y, Kowada SZ, Nakano H. (1990) Induction of mammalian topoisomerase II dependent DNA cleavage by non-intercalative flavonoids, genistein and orobol. Biochem. Pharmacol. 39: 737–744.

    Article  CAS  PubMed  Google Scholar 

  14. Austin CA, Patel S, Ono K, Nakane H, Fisher LM. (1992) Site-specific DNA cleavage by mammalian DNA topoisomerase II induced by novel flavone and catechin derivatives. Biochem. J. 282: 883–889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boege F, Straub T, Kehr A, et al. (1996) Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I. J. Biol. Chem. 271: 2262–2270.

    Article  CAS  PubMed  Google Scholar 

  16. Walton BC, Peters W, Killick-Kendrick R. (1987) American cutaneous and mucocutaneous leishmaniasis. In: Peters W, Killick-Kendrick R (eds.) The Leishmaniasis in Biology and Medicine. Academic Press, London, pp. 636–664.

    Google Scholar 

  17. Iwu MM, Jackson JE, Schuster BG. (1994) Medicinal plants in the fight against leishmaniasis. Parasitol. Today 10: 65–68.

    Article  CAS  PubMed  Google Scholar 

  18. Shapiro TA, Englund PT. (1995) The structure and replication of kinetoplast DNA. Annu. Rev. Microbiol. 49: 117–143.

    Article  CAS  PubMed  Google Scholar 

  19. Shapiro TA, Englund PT. (1990) Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs. Proc. Natl. Acad. Sci. U.S.A. 87: 950–954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shapiro TA, Klein VA, Englund PT. (1989) Drug-promoted cleavage of kinetoplast DNA minicircles, the evidence for type II topoisomerase activity in trypanosome mitochondria. J. Biol. Chem. 264: 4173–4178.

    PubMed  CAS  Google Scholar 

  21. Chakraborty AK, Majumder HK. (1991) An ATP independent catenating enzyme from the kineplast hemoflagellate Leishmania donovani. Biochem. Biophys. Res. Commun. 180: 279–285.

    Article  CAS  PubMed  Google Scholar 

  22. Chakraborty AK, Gupta A, Majumder HK. (1993) A type I DNA topoisomerase from the kinetoplast hemoflagellate Leishmania donovani. Ind. J. Biochem. Biophys. 30: 257–263.

    CAS  Google Scholar 

  23. Ray S, Hazra B, Mittra B, Das A, Majumder HK. (1998) Diospyrin, a bisnaphthoquinone: novel inhibitor of type I DNA topoisomerase of Leishmania donovani. Mol. Pharmacol. 54: 994–999.

    Article  CAS  PubMed  Google Scholar 

  24. Dutta PK, Chaudhury US, Chakravarty AK, Achari B, Pakrashi SC. (1983) Nishindaside, a novel iridoid glycoside from Vitex negundo. Tetrahedron 39: 3067–3072.

    Article  CAS  Google Scholar 

  25. Achari B, Chaudhury US, Dutta PK (1984) Two isomeric flavonones from Vitex negundo. Phytochemistry 23: 703–704.

    Article  CAS  Google Scholar 

  26. Dasgupta S, Adhya S, Majumder HK. (1986) A simple procedure for the preparation of pure kinetoplast DNA network free of nuclear DNA from the kinetoplast hemoflagellate Leishmania donovani. Anal. Biochem. 158: 189–194.

    Article  CAS  PubMed  Google Scholar 

  27. Ghosh AK, Bhattacharya FK, Ghosh DK. (1985) Leishmania donovani: Amastigote inhibition and mode of action of berberine. Exp. Parasitol. 60: 404–413.

    Article  CAS  PubMed  Google Scholar 

  28. Sambrook J, Fritsch EF, Maniatis T. (1989) Molecular Cloning. A laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.

    Google Scholar 

  29. Strauber LA, Franchino EM, Grun J. (1989) An eight day method for screening compounds against Leishmania donovani in the golden hamster. J. Protozool. 5: 269–273.

    Article  Google Scholar 

  30. D’Arpa P, Liu LF. (1989) Topoisomerase-targeting antitumor drugs. Biochim. Biophys. Acta 989: 163–177.

    PubMed  Google Scholar 

  31. Moriera MEC, Portillo HAD, Milder RV, Balanco MF, Barcinski J. (1996) Heat shock induction of apoptosis in promastigotes of the unicellular organism Leishmania (Leishmania) amazonensis. J. Cell. Physiol. 167: 305–313.

    Article  Google Scholar 

  32. Martin BS, Reutelingsperger LPM, McGahon AJ, VanSchiee RCAA, La Face DM, Greenn DR. (1995) Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl 2 and Ab 1. J. Exp. Med. 182: 1345–1350.

    Article  Google Scholar 

  33. Chakrabarti G, Basu A, Manna PP, Mahato SB, Mandal NB, Bandyopadhyay S. (1999) Indolylquinoline derivatives are cytotoxic to Leishmania donovani promastigotes in vitro and are effective in treating murine visceral leishmaniasis. J. Antimicrob. Chemother. 43: 359–366.

    Article  CAS  PubMed  Google Scholar 

  34. Del Bino G, Bruno S, Yi PN, Darzynkiewicz Z. (1992) Apoptotic cell death triggered by camptothecin or teniposide. The cell cycle specificity and effects of ionizing radiation. Cell. Prolif. 25: 537–548.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Prof. A. N. Bhaduri, Ex-Director of this Institute for constructive criticism and interest in this work. The work was supported by a grant from Department of Biotechnology, Government of India (BT/PRO493/MED/09/096/96) to HKM.

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Authors and Affiliations

  1. Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Calcutta, 700 032, India

    Bidyottam Mittra, Arnab Roy Chowdhury &  Hemanta K. Majumder

  2. Cellular Immunology Division, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Calcutta, India

    Asim Saha, Chiranjib Pal & Santu Bandyopadhyay

  3. Medicinal Chemistry Division, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Calcutta, India

    Suparna Mandal & Sibabrata Mukhopadhyay

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  1. Bidyottam Mittra
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Correspondence to Hemanta K. Majumder.

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Mittra, B., Saha, A., Roy Chowdhury, A. et al. Luteolin, an Abundant Dietary Component is a Potent Anti-leishmanial Agent that Acts by Inducing Topoisomerase II-mediated Kinetoplast DNA Cleavage Leading to Apoptosis. Mol Med 6, 527–541 (2000). https://doi.org/10.1007/BF03401792

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