Skip to main content
SpringerLink
Log in

Reversal of multidrug resistance by phenothiazines and structurally related compounds

  • Original Articles
  • Multidrug Resistance, Phenothiazenes, Reversal, SAR
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

The multidrug-resistance (MDR)-reversal activity of 232 phenothiazines and structurally related compounds was tested in MDR P388 cells. Such activity was found among compounds exhibiting two ring structures (phenyl, cyclopentyl, cyclohexyl, thienyl or 5-norbornen-2-yl but not pyridinyl) linked by a variety of bridge types and possessing a secondary or tertiary amine group. Among 192 such compounds, 31.8% displayed good activity (MDR-reversal ratio, ≥10) and 8.3%, outstanding activity (MDR-reversal ratio, ≥30). In a subgroup comprising 56 compounds with a carbonyl residue, 4 with sulfuryl residue and 1 with thienyl residue, 42.7% showed good activity and 18%, outstanding activity. The contribution of these residues to the MDR-reversal activity was particularly evident among compounds containing a cyclic tertiary amine. Among 49 such compounds, 51% displayed good activity and 20.4%, outstanding activity, whereas among the 85 compounds lacking such groups, only 31.8% showed good activity and 4.7%, outstanding activity. Enhancement of this activity by the carbonyl group is also obtained when the latter is part of an amide bond of a tertiary amine. As compounds with a carbonyl group located on the rings, on the bridge to the amine group or beyond the amine are efficient MDR reversers, it seems that the cxact molecular location of the carbonyl group is not critical for the elicitation of this activity.

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

Abbreviations

ADR:

Adriamycin

MDR:

multidrug resistance

P388/ADR:

multidrug-resistant P388 cells

References

  1. Cass CE, Janowska-Wieczorek A, Lynch MA, Sheinin H, Hindenburg AA, Beck WT (1989) Effect of duration of exposure to verapamil on vincristine activity against multidrug-resistant human leukemic cell lines. Cancer Res 49:5798–5804

    Google Scholar 

  2. Ford JM, Hait WN (1990) Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 42:155–199

    Google Scholar 

  3. Ford JM, Prozialeck WC, Hait WN (1989) Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug resistance. Mol Pharmacol 35: 105–115

    Google Scholar 

  4. Ford JM, Bruggemann EP, Pastan I, Gottesman MM, Hait WN (1990) Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines. Cancer Res 50:1748–1756

    Google Scholar 

  5. Gosland MP, Lum BL, Sikic BI (1989) Reversal by cefoperazone of resistance to etopside, doxorubicin and vinblastine in multidrug resistant human sarcoma cells. Cancer Res 49:6901–6905

    Google Scholar 

  6. Hofsli E, Nissen-Meyer J (1990) Reversal of multidrug resistance by lipophilic drugs. Cancer Res 50:3997–4002

    Google Scholar 

  7. Inaba M, Maruyama E (1988) Reversal of resistance to vincristine in P388 leukemia by various polycyclic clinical drugs with a special emphasis on quinacrine. Cancer Res 48:2064–2067

    Google Scholar 

  8. Kamiwatari M, Nagata Y, Kikuchi H, Yoshimura A, Sumizawa T, Shudo N, Sakoda R, Seto K, Akiyama S-I (1989) Correlation between reversing of multidrug resistance and inhibiting of [3H]-Azidopine photolabeling of P-glycoprotein by newly synthesized dihydropyridine analogues in a human cell line. Cancer Res 49: 3190–3195

    Google Scholar 

  9. Kessel D, Corbett T (1985) Correlation between anthracycline resistance, drug accumulation and membrane glycoprotein patterns in solid tumors of mice. Cancer Lett 28:187–193

    Google Scholar 

  10. Kiue A, Sano T, Suzuki K-I, Inada H, Kumura M, Kikuchi J, Sato S-I, Kohno K, Kuwano M (1990) Activities of newly synthesized dihydropyridines in overcoming of vincristine resistance, calcium antagonism and inhibition of photoaffinity labeling of P-glycoprotein in rodents. Cancer Res 50:310–317

    Google Scholar 

  11. Klohs WD, Steinkampf RW (1988) The effect of lysomotropic agents and secretory inhibitors on anthracycline retention and activity in multiple drug-resistant cells. Mol Pharmacol 34:180–185

    Google Scholar 

  12. Kodavanti UP, Mehendale HM (1990) Cationic amphiphilic drugs and phospholipid storage disorder. Pharmacol Rev 42:327–354

    Google Scholar 

  13. Nogae I, Kohno K, Kikuchi J, Kuwano M, Akiyama S-I, Kiue A, Suzuki K-I, Yoshida Y, Cornwell MM, Pastan I, Gottesman MM (1989) Analysis of structural features of dihydropyridine analogs needed to reverse multidrug resistance and to inhibit photoaffinity labeling of P-glycoprotein. Biochem Pharmacol 38:519–527

    Google Scholar 

  14. Pearce HL, Safa AR, Bach NJ, Winter MA, Cirtain MC, Beck WT (1989) Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance. Proc Natl Acad Sci USA 86:5128–5132

    Google Scholar 

  15. Ramu A (1989) Structure-activity relationship of compounds that restore sensitivity to doxorubicin in drug-resistant P388 cells. In: Kessel D (ed) Resistance to antineoplastic drugs. CRC. Boca Raton, Florida, pp 63–80

    Google Scholar 

  16. Ramu A, Spanier R, Rahamimoff H, Fuks Z (1984) Restoration of doxorubicin responsiveness in doxorubicin-resistant P388 murine leukemia cells. Br J Cancer 50:501–507

    Google Scholar 

  17. Ramu A, Glaubiger D, Fuks Z (1984) Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by tamoxifen and other triparanol analogues. Cancer Res 44:4392–4395

    Google Scholar 

  18. Ramu A, Pollard HB, Rosario LM (1989) Doxorubicin resistance in P388 leukemia — evidence for reduced drug influx. Int J Cancer 44: 539–547

    Google Scholar 

  19. Ramu A, Ramu N, Rosario LM (1991) Circumvention of multidrug resistance in P388 cells is associated with a rise in the cellular content of phosphatidylcholine. Biochem Pharmacol 41:1455–1461

    Google Scholar 

  20. Ramu N, Ramu A (1989) Circumvention of Adriamycin resistance by dipyridamole analogues: a structure-activity relationship study. Int J Cancer 43:487–491

    Google Scholar 

  21. Sirotnak FM, Yang CH, Mines LS, Oribe E, Biedler JL (1986) Markedly altered membrane transport and intracellular binding of vincristine in multidrug-resistant Chinese hamster cells selected for resistance to vinca alkaloids. J Cell Physiol 126:266–274

    Google Scholar 

  22. Stewart DJ, Evans WK (1989) Non-chemotherapeutic agents that potentiate chemotherapy efficacy. Cancer Treat Rev 16:1–40

    Google Scholar 

  23. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41:1967–1972

    Google Scholar 

  24. Twentyman PR (1988) Modification of cytotoxic drug resistance by non-immuno-suppressive cyclosporins. Br J Cancer 57:254–258

    Google Scholar 

  25. Wallner J, Pirker R, Keilhauer G, Lechner C, Raschack M, Ludwig H (1990) Reversal of multidrug resistance of cell lines by structural analogs of verapamil. Proc Am Assoc Cancer Res 31:379

    Google Scholar 

  26. Yoshinari T, Iwasawa Y, Miura K, Takahashi IS, Fukuroda T, Suzuki K, Okura A (1989) Reversal of multidrug resistance by new dihydropyridines with lower calcium antagonistic activity. Cancer Chemother Pharmacol 24:367–370

    Google Scholar 

  27. Zamora JM, Pearce HL, Beck WT (1988) Physico-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells. Mol Pharmacol 33:454–462

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Hadassah Hospital, P. O. Box 12000, 91 120, Jerusalem, Israel

    Avner Ramu & Nili Ramu

Authors
  1. Avner Ramu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nili Ramu
    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

Ramu, A., Ramu, N. Reversal of multidrug resistance by phenothiazines and structurally related compounds. Cancer Chemother. Pharmacol. 30, 165–173 (1992). https://doi.org/10.1007/BF00686306

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00686306

Keywords

Search

Navigation