Effects of 1,2-naphthoquinones on human tumor cell growth and lack of cross-resistance with other anticancer agents

M. Eileen Dolan, Benjamin Frydman, Craig B. Thompson, Alan M. Diamond, Bonnie J. Garbiras, Ahmad R. Safa, William T. Beck, Laurence J. Marton

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

The sensitivity of human tumor and rat prostate tumor cells to a series of naphthoquinones, including tricyclic compounds of the β-lapachone and dunnione families as well as 4-alkoxy-1,2-naphthoquinones, was evaluated. To better understand the mechanism of cytotoxicity of 1,2-naphthoquinones, the roles of various resistance mechanisms Including P-glycoprotein, multidrug resistant associated protein, glutathione (GSH) and related enzymes, altered topoisomerase activity, and overexpression of genes that control apoptosis (bcl-2 and bcl-x(L)) were studied. MCF7 cells were most sensitive to the naphthoquinones with IC50 values ranging from 1.1 to 10.8 μM, as compared to 2.5 to >32 μM for HT29 human colon, A549 human lung, CEM leukemia and AT3.1 rat prostate cancer cells. MCF7 ADR cells, selected for resistance to adriamycin (ADR), displayed cross-resistance to the tricyclic 1,2-naphthoquinones. Drug efflux via a P-glycoprotein mechanism was ruled out as a mechanism of resistance to 1,2-naphthoquinones, since KB-V1 cells expressing high levels of P-glycoprotein and the KB-3.1 parent line were equally sensitive to these compounds. Any resistance of the tricyclic naphthoquinones noted in ADR-resistant cells appeared to relate to the GSH redox cycle and could be circumvented by exposure to buthionine sulfoximine or by changing the structure from a tricyclic derivative to a 4-alkoxy-1,2-naphthoquinone. The 1,2-naphthoquinones were found to be cytotoxic against CEM/VM-1 and CEM/M70-B1 cells that were selected for resistance to teniposide or merbarone, respectively. In addition, cells overexpressing bcl-2 or bcl-x(L) proteins were as sensitive to 1,2-naphthoquinones as were control cells. Because of their effectiveness in drug-resistant cells, these agents appear to hold promise as effective chemotherapeutic agents.

Original languageEnglish (US)
Pages (from-to)437-448
Number of pages12
JournalAnti-Cancer Drugs
Volume9
Issue number5
DOIs
StatePublished - Jun 25 1998
Externally publishedYes

Keywords

  • Anticancer drug
  • Cytotoxicity
  • Glutathione
  • Naphthoquinones
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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    Dolan, M. E., Frydman, B., Thompson, C. B., Diamond, A. M., Garbiras, B. J., Safa, A. R., Beck, W. T., & Marton, L. J. (1998). Effects of 1,2-naphthoquinones on human tumor cell growth and lack of cross-resistance with other anticancer agents. Anti-Cancer Drugs, 9(5), 437-448. https://doi.org/10.1097/00001813-199806000-00011