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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1991 Feb;82(2):184–191. doi: 10.1111/j.1349-7006.1991.tb01827.x

Topoisomerase Inhibitors Have Potent Differentiation‐inducing Activity for Human and Mouse Myeloid Leukemia Cells

Kazuyasu Nakaya 1, Sawako Chou 1, Motohisa Kaneko 2, Yasuharu Nakamura 1
PMCID: PMC5918380  PMID: 1848545

Abstract

DNA topoisomerase inhibitors, camptothecin and 4′‐demethylepipodophyllotoxin ethylidene‐jS‐D‐glucoside (VP16) had strong differentiation‐inducing activity for all five kinds of leukemia cells examined (human HL60, U937, ML1, and K562 cells and mouse Ml cells) as judged from measurements of various differentiation markers. The characteristics that appeared as a result of differentiation induced by these inhibitors were essentially similar in every cell line. Exposure to VP16 for 2 h induced both differentiation and DNA‐strand breaks in K562 cells, whereas podophyl‐lotoxin, which lacks topoisomerase II inhibitory activity, induced neither differentiation nor DNA‐strand breaks in these cells. These results suggest a parallelism between the induction of differentiation and that of DNA‐strand breaks. The combination of VP16 and recomhinant tumor necrosis factor α (rTNFα) synergistically induced differentiation of human U937, ML1, and M1 cells and had an additive effect on HL60 cells. Simultaneous treatment with rTNFa plus camptothecin or VP16, or pretreatment with camptothecin or VP16, followed by rTNFα induced marked differentiation of Ml cells. These results indicate that inhibition of topoisomerase (either topoisomerase I or II) followed by the action of rTNFα was effective in inducing differentiation of leukemia cells.

Keywords: Topoisomerase inhibitor, Leukemia cell, Differentiation

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REFERENCES

  • 1. ) Trinchieri , G. , Kobayashi , M. , Rosen , M. , Loudon , R. , Murphy , M. and Perussia , B.Tumor necrosis factor and lymphotoxin induce differentiation of human myeloid cell lines in synergy with immune interferon . J. Exp. Med. , 164 , 1206 – 1225 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. ) Takeda , K.Iwamoto , S. , Sugimoto , H. , Takuraa , T. , Kawatani , N. , Noda , M. , Masaki , A. , Morise , H. , Ari‐mura , H. and Konno , K.Identity of differentiation inducing factor and tumor necrosis factor . Nature , 323 , 338 – 340 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Nakaya , K. , Nakajo , S. , Shimizu , T. , Hayashi , Y. , and Nakamura , Y.Tumor necrosis factor is partly responsible for the differentiation of mouse myeloid leukemia cells . Biochem. Int. , 15 , 1213 – 1219 ( 1987. ). [PubMed] [Google Scholar]
  • 4. ) Ball , E.D. , Guy re , P.M. , Shen , L. , Glynn , J.M. , Maliszewski , C. R. , Baker , P. E. and Fanger , M. W.Gamma interferon induces monocytoid differentiation in the HL‐60 cell line . J. Clin. Invest. , 73 , 1072 – 1077 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Takei , M. , Takeda , K , and Konno , K.The role of interferon‐γ in inductionof differentiationof human myeloid leuikemia cell lines, ML‐1 and HL‐60 . Biochem. Biophys. Res. Commun. , 124 , 100 – 105 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Tomida , M. , Yamamoto‐Yamaguchi , Y. , Hozumi , M. , Okabe , T. and Takaku , F.Induction by recombinant human granulocyte colony‐stimulating factor of differentiation of mouse myeloid leukemic Ml cells . FEBS Lett. , 207 , 271 – 275 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Nicola , N. A. , Metcalf , D. , Matsumoto , M. and Johndon , G. R.Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. / . Biol Chem. , 258 , 9017 – 9023 ( 1983. ). [PubMed] [Google Scholar]
  • 8. ) Hilton , D. , Nicola , N. A. and Metcalf , D.Purification of a murine inhibitory factor from Krebs ascites cells . Anal. Biochem. , 173 , 359 – 367 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Tomida , M. , Yamaguchi , Y. and Hozumi , M.Purification of a factor inducing differentiation of mouse myeloid leukemic Ml cells from conditioned medium of mouse fibroblast L929 cells . J. Biol Chem. , 259 , 10978 – 10983 ( 1984. ). [PubMed] [Google Scholar]
  • 10. ) Miyaura , C. , Abe , E. , Kuribayashi , T. , Tanaka , H. , Konno , K. , Nishii , Y. and Suda , T.la,25‐Dihydroxy‐vitamin D3 induces differentiation of human myeloid leukemia cells . Biochem. Biophys. Res. Commun. , 102 , 937 – 943 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Breitman , T. R. , Selonick , S. E. and Collins , S. J.Induction of differentiation of the human promyelocytic leukemia cell line (HL‐60) by retinoic acid . Proc. Natl. Acad. Set. USA , 77 , 2936 – 2940 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Honma , Y. , Takenaga , K. , Kasukabe , T. , and Hozumi , M.Induction ofdifferentiation of cultured human pro‐myelotic leukemia cells by retinoids . Biochem. Biophys. Res. Commun. , 95 , 507 – 512 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Fujii , Y. , Yuki , N. , Taakeichi , N. , Kobayashi , H. and Miyazaki , T.Differentiation therapy of a myelomonocytic leukemia (c‐WRT‐7)in rats by injection of lipopoly‐saccharide and daunomycin . Cancer Res. , 47 , 1668 – 1673 ( 1987. ). [PubMed] [Google Scholar]
  • 14. ) Honma , Y. , Kasukabe , T. , Okabe , J. and Hozumi , M.Glucocorticoid‐induced differentiation of cultured mouse myeloid leukemia cells . Gann , 68 , 241 – 246 ( 1977. ). [PubMed] [Google Scholar]
  • 15. ) Lotem , J. and Sachs , L.Regulation of normal differentiationin mouse and human myeloid leukemic cells by phorbol esters and the mechanism of tumor promotion . Proc. Natl. Acad. Sci. USA , 76 , 5058 – 5162 ( 1979. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Rovera , G. , Santoli , D. , and Damsky , C.Human pro‐myelocyticleukemia cells in culture differentiate into macrophage‐like cells when treated with a phorbol diester . Proc. Natl. Acad. Sci. USA , 76 , 2779 – 2783 ( 1979. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Weiss , B. and Sachs , L.Indirect induction of differentiation in myeloid leukemia cells by lipid A . Proc. Natl. Acad. Sci. USA , 75 , 1374 – 1378 ( 1978. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. ) Collins , S. J. , Ruscetti , F. W. , Gallagher , R. E. and Gallo , R. C.Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds . Proc. Natl. Acad. Sci. USA , 75 , 2458 – 2462 ( 1978. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Chou , S. , Kaneko , M. , Nakaya , K. and Nakamura , Y.Induction of differentiation of human and mouse myeloid leukemia cells by camptothecin . Biochem. Biophys. Res. Commun. , 166 , 160 – 167 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Sahyoun , N. , Wolf , M. , Besterman , J. , Hsieh , T. , Sander , M. , LeVine , H. , Chang , K‐J. and Cuatrecasas , P.Protein kinase C phosphorylates topoisomerase II: topoisomerase activation and its possible role in phorbol ester‐induced differentiation of HL‐60 cells . Proc. Natl. Acad. Sci. USA , 83 , 1603 – 1607 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Constantinou , A. , Henning‐Chubb , C. and Huberman , E.Novobiocin‐ and phorbol‐ 12‐myristate‐13‐acetate‐induced differentiation of human leukemia cells associated with a reduction in topoisomerase II activity . Cancer Res. , 49 , 1110 – 1117 ( 1989. ). [PubMed] [Google Scholar]
  • 22. ) Hozumi , M.Fundamentals of chemotherapy of myeloid leukemia by induction of leukemia cell differentiation . Adv. Cancer Res. , 38 , 121 – 169 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Nakaya , K. , Kumakawa , N. , Linuma , H. and Nakamura , Y.Purification of a low molecular weight factor that induces differentiation and inhibits growth in myeloid leukemia cells . Cancer Res. , 48 , 4201 – 4205 ( 1988. ). [PubMed] [Google Scholar]
  • 24. ) Kerbel , R. S. , Pross , H. F. and Elliott , E. V.Origin and partial characterization of Fc receptor‐bearing cells found within experimental carcinomas and sarcomas . Int. J. Cancer , 15 , 918 – 932 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Orkin , S. H. , Harosi , F. I. and Leder , P.Differentiation in erythroleukemic cells and their somatic hybrids . Proc. Natl. Acad. Sci. USA , 72 , 98 – 102 ( 1975. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Kohn , K. W. , Ewig , R. A. G. , Erickson , L. C. and Zwelling , L. A.Measurement of strand breaks and crosslinks by alkaline elution . In “ DNA Repair: A Laboratory Manual of Research Procedures ”, ed. Friedberg R. C. and Hasnawalt P. C. , pp. 379 – 401 ( 1981. ). Marcel Dekker; , New York . [Google Scholar]
  • 27. ) Kaneko , M. , Nakayama , T. , Komada , M. and Nagata , C.Detection of DNA lesions in cultured human fibroblasts induced by activeoxygen species generated from a hydroxylated metabolite of 2‐naphthylamine . Gann , 75 , 349 – 354 ( 1984. ). [PubMed] [Google Scholar]
  • 28. ) Kaneko , M. , Horikoshi , J. and Komada , M.Topoisomerase inhibitors reduced DNA single strand breaks induced by bile acids in cultured human fibroblasts . Cancer J. , 1 , 169 – 174 ( 1986. ). [Google Scholar]
  • 29. ) Chen , G. , Yang , L. , Rowe , T. C. , Halligan , B. D. , Tewey , K. M. and Liu , L. F.Nonintercalative antitumor drugs interfere with the breakage‐reunion reaction of mammalian DNA topoisomerase II . J. Biol. Chem. , 259 , 13560 – 13566 ( 1984. ). [PubMed] [Google Scholar]
  • 30. ) Sugino , A. , Higgins , N. P. , Brown , P. O. , Peebles , C. L. and Cozzarelli , N. R.Energy coupling in DNA gyrase and the mechanism of action of novobiocin . Proc. Natl. Acad. Sci. USA , 75 , 4838 – 4842 ( 1978. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. ) Miller , K. G. , Liu , L. F. and England , P. T.A homogenous type II DNA topoisomerase from HeLa cell nuclei . J. Biol. Chem. , 256 , 9334 – 9339 ( 1981. ). [PubMed] [Google Scholar]
  • 32. ) Wozniak , A. J. and Ross , W. E.DNA damage as a basis for 4′‐demethylepipodophyllotoxin‐9‐(4,6‐O‐ethylidene‐,β‐D‐glucopyranoside) (Etoposide) cytotoxicity . Cancer Res. , 43 , 120 – 124 ( 1983. ). [PubMed] [Google Scholar]
  • 33. ) Kaneko , M. and Horikoshi , J.Nalidixic acid and oxolinic acid reversibly suppress 3‐methylchoIanthrene‐induced cell transformation of Balb/3T3 mouse cells . Int. J. Cancer , 42 , 913 – 916 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Hassan , H. T.Differentiation inducers of human myeloid leukemia cell lines . Folia Haematoi , 6 , 887 – 896 ( 1988. ). [PubMed] [Google Scholar]
  • 35. ) Lee , H. P. , Sander , M. and Hsieh , T. S.Single strand DNA cleavage reaction of duplex DNA by Drosophila topoisomerase II . J. Biol. Chem. , 264 , 13510 – 13518 ( 1989. ). [PubMed] [Google Scholar]
  • 36. ) Takuma , T. , Takeda , K. and Konno , K.Synergism of tumor necrosis factor and interferon‐in induction of differentiation of human myeloblastic leukemic ML‐1 cells . Biochem. Biophys. Res. Commun. , 145 , 514 – 521 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Alexander , R. B. , Nelson , W. G. and Coffey , D. S.Syn‐ergistic enhancement by tumor necrosis factor of in vitro cytotoxicityfrom chemotherapeuticdrugstargetedat DNA topoisomerase II . CancerRes. , 47 , 2403 – 2406 ( 1987. ). [PubMed] [Google Scholar]
  • 38. ) Constantinou , A. , Kiguchi , K. and Huberman , E.Induction of differentiation and DNA strand breakage in human HL‐60 and K‐562 leukemia cells by genistein . Cancer Res. , 50 , 2618 – 2624 ( 1990. ). [PubMed] [Google Scholar]

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