Effect of the calmodulin inhibitor trifluoperazine on phosphorylation of P-glycoprotein and topoisomerase II: relationship to modulation of subcellular distribution, DNA damage and cytotoxicity of doxorubicin in multidrug resistant L1210 mouse leukemia cells.
The results from the present study using the sensitive and progressively DOX resistant L1210 model system demonstrated that the effects of TFP are not due to redistribution of DOX to the nucleus, and modulation of cytotoxicity is related to effects on DOX-induced DNA strand breaks. Although TFP affects phosphorylation of PGP and TOPO II (R2 greater than R1), the comparable DNA strand breaks at lower DOX levels with TFP in the resistant sublines suggest that modulation of TOPO II function related to drug-induced DNA damage by calmodulin-mediated events may be an important mode of action.
Research Institute, Cleveland Clinic Foundation, OH 44195.
R
R
Ganapathi
N
N
Kamath
A
A
Constantinou
D
D
Grabowski
J
J
Ford
A
A
Anderson
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D003720:Densitometry; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D004351:Drug Resistance; D015151:Immunoblotting; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002147:Calmodulin; D008562:Membrane Glycoproteins; D014268:Trifluoperazine; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II