Calmodulin inhibitor trifluoperazine selectively enhances cytotoxic effects of strong vs weak DNA binding antitumor drugs in doxorubicin-resistant P388 mouse leukemia cells.
Doxorubicin-resistant P388 mouse leukemia cells are cross-resistant to anthracycline and non-anthracycline DNA intercalators as well as to natural and semisynthetic anthracyclines which bind weakly or not at all to DNA. In the presence of a non-lethal concentration of 5 microM trifluoperazine cytotoxic effects of the strong DNA binding drugs actinomycin-D, mitoxantrone and m-AMSA were enhanced less than 2 fold in doxorubicin-sensitive cells and up to 50 fold in doxorubicin-resistant cells. Additionally, trifluoperazine induced a greater than 2-fold enhancement in the cytotoxic effects (but not accumulation and retention) of the strong DNA binder N,N-dimethyladriamycin-14-valerate only in doxorubicin resistant cells. In contrast, cell kill, drug accumulation and retention in P388/S and P388/DOX cells treated with the weak DNA binders N-benzyl-adriamycin-14-valerate and 7(R)-O-methylnogarol, and DNA-nonbinding N,N-dibenzyldaunorubicin was similar with or without trifluoperazine treatment. The study demonstrates that the calmodulin inhibitor trifluoperazine induces a specific and marked enhancement in the cytotoxic effects of strong vs weak DNA binding antitumor drugs in doxorubicin-resistant cells.
Ganapathi
R
R
Grabowski
D
D
Schmidt
H
H
Seshadri
R
R
Israel
M
M
D000609:Aminoacridines / Q000627:therapeutic use; D000677:Amsacrine; D000818:Animals; D000880:Anthraquinones / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D003609:Dactinomycin / Q000627:therapeutic use; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000627:therapeutic use; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D004347:Drug Interactions; D004351:Drug Resistance; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D017290:Menogaril; D051379:Mice; D008942:Mitoxantrone; D009279:Naphthacenes / Q000378:metabolism; D009621:Nogalamycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D014268:Trifluoperazine / Q000494:pharmacology*
D000609:Aminoacridines; D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D009279:Naphthacenes; D000677:Amsacrine; D003609:Dactinomycin; D014268:Trifluoperazine; D004317:Doxorubicin; C037526:N,N-dibenzyldaunorubicin; D017290:Menogaril; D004247:DNA; C046807:N,N-dimethyladriamycin-14-valerate; C046808:N-benzyladriamycin-14-valerate; D008942:Mitoxantrone; D009621:Nogalamycin; D003630:Daunorubicin