Skip to main content
SpringerLink
Log in

Establishment of doxorubicin-resistant subline derived from HCT15 human colorectal cancer cells

  • Research Articles
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Doxorubicin, one of the clinically most useful anticancer agents, is used alone or in combination with other drugs against a wide variety of tumors, recently. But cancer cells developed resistance to this agent in many ways. This resistance is an important limiting factor of doxorubicin for anticancer drug. We newly established doxorubicin-resistant HCT15/CL02 subline from parental HCT15 human adenocarcinoma colon cancer cells. HCT15/CL02 revealed resistance to doxorubicin about 85-fold of its parental cells, and it also revealed cross-vealed to actinomycin D, etoposide and vinblastine but not to cisplatin and tamoxifen. And verapamil, a reversal agent of multidrug-resistance (MDR) by P-glycoprotein, elevated the cytotoxicity of doxorubicin against both HCT15 and HCT15/CL02 cells. But the relative resistant rate was not reduced. Verapamil had no effects on the toxicity of cisplatin to the both cell lines. These results indicate that HCT15/CL02 cells have some functionally complex mechanisms for MDR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References Cited

  • Abe, T., Hasegawa, S., Taniguchi, K., Yokomizo, A., Kuwano, T., Ono, M., Mori, T., Hori, S., Kohno, K. and Kuwano, M., Possible involvement of multidrug-resistance-associated protein (MRP) gene expression in spontaneous drug resistance to vincristine, etoposide and adriamycin in human glioma cells.Int. J. Cancer, 58, 860–864, (1994).

    Article  PubMed  CAS  Google Scholar 

  • Awashi, S., Singhai, S. S., Srivastava, S. K., Zimniak, P., Bajpai, K. K., Saxena, M., Sharma, R., Ziller III, S. A., Frenkel, E. P., Singh, S. V., He, N. G. and Awashi, Y. C., Adenosin triphosphate-dependent transport of doxorubicin, daunomycin and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein.J. Clin. Invest., 93, 958–965 (1994).

    Article  Google Scholar 

  • Bradley, G., Juranka, P. F. and Ling, V., Mechanism of multidrug resistance.Biochim. Biophys. Acta, 948, 87–128 (1988).

    PubMed  CAS  Google Scholar 

  • Callaghan, R., Zakher, G. and Epand, R., Increased accumulation of drugs in a multidrug resistant cell line by alteration of membrane biophysical properties.Biochim. Biophys. Acta, 1175, 277–282 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Chen, G., Jaffrzou, J. P., Fleming, W. H., Durn, G. E. and Sikic, B. I., Prevalence of multidrug resistance related to activation of themdr gene in human sarcoma mutants derived by single-step doxorubicin selection.Cancer Res., 54, 4980–4987 (1994).

    PubMed  CAS  Google Scholar 

  • Chen, G. L. and Liu, L. F., DNA topoisomerases: essential enzymes and lethal targets.Annu. Rev. Pharmacol. Toxicol., 34, 191–218 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Cole, S. P. C., Pinkoski, M. J., Bhardwaj, G. and Deeley, R. G., Elevated expression of Annexin II (Lipocortin II, p36) in a multidrug resistant small cell lung cancer cell line.Br. J. Cancer, 65, 498–502 (1992).

    PubMed  CAS  Google Scholar 

  • Cornwell, M. M., Gottesman, M. M. and Pastan, I. H., Increased vinblastine binding to membrane vesicles from multidrug-resistant KB cells.J. Biol. Chem., 261, 7921–7928 (1986).

    PubMed  CAS  Google Scholar 

  • Critchfield, J. W., Welsh, C. J., Phang, J. M. and Yeh, G. C., Modulation of adriamycin and efflux by flavonoids in HCT15 colon cells.Biochem. Pharmacol., 48, 1437–1445 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Damle, B. and Desai, P., Dipyridamole reverses the resistance to topoisomerase II inhibitors but not to antimicrotubule agents in multidrug-resistant melanoma cells.Oncol. Res., 6, 49–57 (1994).

    PubMed  CAS  Google Scholar 

  • Dimanche-Boitrel, M. T., Pelletier, H., Genne, P., Petit, J. M., Le Grimellec, C., Canal P., Ardiet, C., Bastian, G. and Chauffert, B., Confluence-dependent resistance in human colon cancer cells; role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells.Int. J. Cancer, 50, 667–682 (1992).

    Article  Google Scholar 

  • Doyle, L. A., Ross, D. D., Sridhara, R., Fojo, A. T., Kaufmann, S. H., Lee, E. J. and Schiffer, C. A., Expression of a 95 kDa membrane protein is associated with low daunorubicin accumulation in leukaemic blast cells.Br. J. Cancer, 71, 52–58 (1995).

    PubMed  CAS  Google Scholar 

  • Eijdems, E. W. H. M., de Haas, M., Timmerman, A. J., Van der Sohans, G. P., Kamst, E., de Nooij, J., Astaldi Ricotti, G. C. B., Borst, P. and Baas, F., Reduced topoisomerase II activity in multidrug-resistant human non-small cell lung cancer cell lines.Br. J. Cancer, 71, 40–47 (1995).

    PubMed  CAS  Google Scholar 

  • Fojo, A. T., Ueda, K., Slaman, D. J., Poplack, D. G., Gottesman, M. M. and Pastan, I., Expression of a multidrug-resistance gene in human tumors and tissues.Proc. Natl. Acad. Sci. USA, 84, 265–269 (1987).

    Article  PubMed  CAS  Google Scholar 

  • Fry, A., Chrest, C., Davies, S., Walker, C., Harris, A., Hartley, J., Masters, J. and Hickson, I., Relationship between topoisomerase II level and chemosensitivity in human tumor cell lines.Cancer Res., 51, 6592–6595 (1991).

    PubMed  CAS  Google Scholar 

  • Gheuens, E., van der Heyden, S., Elst, H., Eggermont, A., Oosterom, A. V. and De Bruijn E., Multidrug resistance in rat colon carcinoma cell lines CC531, CC531mdr+ and CC531rev.Jpn. J. Cancer Res., 84, 1201–1208 (1993).

    PubMed  CAS  Google Scholar 

  • Iwahashi, T., Okochi, E., Ono, K., Sugawara, I., Tsuruo, T. and Mori, S., Establishment of multidrug resistant human colorectal carcinoma HCT15 cell lines and their properties.Anticancer Res., 11, 1309–1312 (1991).

    PubMed  CAS  Google Scholar 

  • Juranka, P. F., Zastawny, R. L. and Ling, V., P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins.FASEB J., 3, 2583–2592 (1989).

    PubMed  CAS  Google Scholar 

  • Kartner, N., Riordan, J. R. and Ling, V., Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines.Science, 221, 1285–1288 (1983).

    Article  PubMed  CAS  Google Scholar 

  • Klohs, W.D. and Steinkampf, R. W., Possible link between the intrinsic drug resistance of colon tumors and a detoxification mechanism of interstinal cells.Cancer Res., 48, 3025–3030 (1988).

    PubMed  CAS  Google Scholar 

  • Kramer, R., Zakher, G. and Kim, J., Role of the glutathione redox cycle in acquired andde novo multidrug resistance.Science, 241, 694–697 (1988).

    Article  PubMed  CAS  Google Scholar 

  • Lai, G. M., Chen, Y. N., Mickley, L. A., Fojo, A. T. and Bates, S. E., P-glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma.Int. J. Cancer, 49, 696–703 (1991a).

    Article  PubMed  CAS  Google Scholar 

  • Lai, G. M., Moscow, J. A., Alvarez, M. G., Fojo, A. T. and Bates, S. E., Contribution of glutathione and glutathione-dependent enzymes in the reversal of adriamycin resistance in colon carcinoma cell lines.Int. J. Cancer., 49, 688–695 (1991b).

    Article  PubMed  CAS  Google Scholar 

  • Lee, S. A., Karaszkiewicz, J. W. and Anderson, W. B., Elevated level of nuclear protein kinase C in multidrug-resistant MCF-7 human breast carcinoma cells.Cancer Res., 52, 3750–3759 (1992).

    PubMed  CAS  Google Scholar 

  • Lock, R. and Ross, W., DNA topoisomerases in cancer therapy. AnticancerDrug Des., 2, 151–164 (1987).

    PubMed  CAS  Google Scholar 

  • Mickley, L. A., Bates, S. E., Richert, N. D., Currier, S., Tanaka, S., Foss, F., Rosen, N. and Fojo, A. T., Modulation of the expression of a multidrug resistance gene (mdr-1/Pglycoprotein) by differentiating agents.J. Biol. Chem., 264, 18031–18040 (1989).

    PubMed  CAS  Google Scholar 

  • Naito, M. and Tsuruo, T., Competitive inhibition by verapamil of ATP-dependent high-affinity vincristine binding to the plasma membrane of multidrug-resistant K562 cells without calcium-ion involvement.Cancer Res., 49, 1452–1455 (1989).

    PubMed  CAS  Google Scholar 

  • Nitiss, J. L., Vilalta, P. M., Wu, H. and McMahon, J., Mutations in the gyrB domain of eukaryotic topoisomerase II can lead to partially dominant resistance to etoposide and amsacrine.Mol. Pharmacol., 46, 773–777 (1994).

    PubMed  CAS  Google Scholar 

  • Park, J. G., Lee, S. K., Hong, I. G., Kim, H. S., Lim, K. H., Choe, K. J., Kim, W. H., Kim, Y. I., Tsuruo, T. and Gottesman, M. M., MDR1 gene expression: its effects on drug resistance to doxorubicin in human hepatocellular carcinoma cell lines.J. Natl. Cancer Inst., 86, 700–705 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Ryu, S. Y., Choi, S. U., Lee, C. O. and Zee, O. P., Anticancer activity ofPsoralea corylifolia.Arch. Pharm. Res., 15, 356–359 (1992).

    Article  CAS  Google Scholar 

  • Skehan, P., Streng, R., SCudiero, D., Monks, A., McMahon, J., Vistica, D., Warren, J. T., Bokesch, H., Kenney, S. and Boyd, M.R., New colorimetric cytotoxicity assay for anticancer-drug screening.J. Natl. Cancer. Inst., 82, 1107–1112 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Tompkins, W. A. F., Watrach, A. M., Schmale, J. D., Schultz, R. M. and Harris, J. A., Cultural and antigenic properties of newly established cell strains derived from adenocarcinomas of the human colon and rectum.J. Natl. Cancer Inst., 52, 1101–1110 (1974).

    PubMed  CAS  Google Scholar 

  • Tsuruo, T., Reversal of acquired resistance to vinca alkaloids and anthracycline antibiotics.Cancer Treat. Rep., 67, 889–894 (1983).

    PubMed  CAS  Google Scholar 

  • Tsuruo, T., Iida, H., Tsukayoshi, S. and Sukarai, Y., Overcoming of vincristine-resistance in P388 leukemiain vivo andin vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil.Cancer Res., 41, 1967–1972 (1981).

    PubMed  CAS  Google Scholar 

  • Turner, M., Everman, D., Ellington, S. and Fields, C., Detection of free radicals during the cellular metabolism of adriamycin.Free Rad. Biol. Med., 9, 415–421 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Ueda, K., Cardarelli, C., Gottesman, M. M. and Pastan, I., Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin and vinblastin.Proc. Natl. Acad. Sci. USA, 84, 3004–3008 (1987).

    Article  PubMed  CAS  Google Scholar 

  • Wang, J. C., DNA topoisomerases.Annu. Rev. Biochem., 54, 665–697 (1985).

    Article  PubMed  CAS  Google Scholar 

  • Weiss, R., Sarory, G., Clagett-Carr, K., Russo, M. and Leyland-Jones, B., Anthracycline analogues: the past, present, and future.Cancer Chemother. Pharmacol., 18, 185–197 (1986).

    Article  PubMed  CAS  Google Scholar 

  • Zunino, F. and Capramco, G., DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Anticancer Drug Des., 5, 30–52 (1990).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmaceutical Screening Team, Korea Research Institute of Chemical Technology, Daedeog-Danji, Yoosung, P.O. Box 107, 305-606, Taejeon, Korea

    Sang Un Choi, Nam Young Kim, Eun Jung Choi, Kwang Hee Kim & Chong Ock Lee

Authors
  1. Sang Un Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nam Young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eun Jung Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kwang Hee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chong Ock Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choi, S.U., Kim, N.Y., Choi, E.J. et al. Establishment of doxorubicin-resistant subline derived from HCT15 human colorectal cancer cells. Arch. Pharm. Res. 19, 342–347 (1996). https://doi.org/10.1007/BF02976376

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02976376

Key words

Search

Navigation