Effects of 1,2-naphthoquinones on human tumor cell growth and lack of cross-resistance with other anticancer agents.
The sensitivity of human tumor and rat prostate tumor cells to a series of naphthoquinones, including tricyclic compounds of the beta-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 bc-xL) were studied. MCF7 cells were most sensitive to the naphthoquinones with IC50 values ranging from 1.1 to 10.8 microM, as compared to 2.5 to >32 microM 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-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.
Dolan
M E
ME
Department of Medicine and Cancer Research Center, University of Chicago, IL 60637, USA.
Frydman
B
B
Thompson
C B
CB
Diamond
A M
AM
Garbiras
B J
BJ
Safa
A R
AR
Beck
W T
WT
Marton
L J
LJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000187:drug effects / Q000502:physiology; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D010544:Peroxidases / Q000187:drug effects / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000502:physiology; D051381:Rats; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D051020:bcl-X Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004317:Doxorubicin; D004791:Enzyme Inhibitors; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009285:Naphthoquinones; D010544:Peroxidases; D019253:Proto-Oncogene Proteins c-bcl-2; D059005:Topoisomerase II Inhibitors; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat