Suppression of P-glycoprotein expression and multidrug resistance by DNA cross-linking agents.
Overexpression of the trans-membrane drug efflux pump P-glycoprotein is one of the major mechanisms by which cancer cells develop multidrug resistance. We demonstrated previously that noncytotoxic doses of various genotoxic chemicals, particularly DNA cross-linking agents, preferentially altered expression of inducible genes. These effects occurred principally at the transcriptional level and were closely correlated temporally with DNA damage. Because the mdr1 gene coding for P-glycoprotein has been reported to be highly inducible, we were interested in the effects of genotoxic cancer chemotherapy agents on its expression. We report that the DNA cross-linking agent mitomycin C significantly suppressed mRNA and protein expression of P-glycoprotein and decreased the rate of drug efflux. Mitomycin C pretreatment also significantly increased the sensitivity of cancer cells to subsequent killing by the P-glycoprotein substrate doxorubicin, decreasing the ED50 by 5- to 10-fold. Suppression of P-glycoprotein expression was also observed with subtoxic doses of the DNA cross-linking agents cisplatin, BMS181174, and chromium(VI). These effects occurred in both human and rodent cell lines; in cell lines derived from colon, breast, leukemia, neuroblastoma, and hepatoma tumors; and under both monolayer and "spheroid" culture conditions. These results suggest the basis for novel clinical cancer chemotherapy regimens aimed at drug-resistant tumors, in which a sub-chemotherapeutic dose of a DNA cross-linking agent is used to modulate the multidrug resistance phenotype prior to treatment with a second cytotoxic agent.
Ihnat
M A
MA
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755-3835, USA.
Lariviere
J P
JP
Warren
A J
AJ
La Ronde
N
N
Blaxall
J R
JR
Pierre
K M
KM
Turpie
B W
BW
Hamilton
J W
JW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity; D001943:Breast Neoplasms; D006528:Carcinoma, Hepatocellular; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D003110:Colonic Neoplasms; D003432:Cross-Linking Reagents / Q000633:toxicity*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005260:Female; D006801:Humans; D020014:K562 Cells; D008113:Liver Neoplasms; D016685:Mitomycin / Q000633:toxicity; D008937:Mitomycins / Q000633:toxicity; D009447:Neuroblastoma; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D008937:Mitomycins; D012333:RNA, Messenger; D016685:Mitomycin; D004317:Doxorubicin; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C; D014700:Verapamil; D002945:Cisplatin