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

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Abstract
The sensitivity of human tumor and rat prostate tumor cells to a series of naphthoqulnones, including tricyclic compounds of the 03B2Lapachone and dunnlone 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 apoptosls (bcl-2 and bcl-xL were studied. MCF7 cells were most sensitive to the naphthoquinones with IC50 values ranging from 1.1 to 10.8 U03BCM1 as compared to 2.5 to >32 U03BCM 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 ADRresistant cells appeared to relate to the GSH redox cycle and could be circumvented by exposure to buthlonine sulfox- Imine 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 bcf-2 or bcf-xL 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

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