P-Glycoprotein is not a key target for the chemosensitizing effect of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol in HepG2 cells exposed to doxorubicin.
Chemosensitization of HepG2 cells to doxorubicin by 1-phenyl-2-decanoylamino-3-morpholino-1-propanol neither impinged on downregulation of P-glycoprotein expression nor on severe impairment of its activity. Moreover, differently from verapamil, a potent P-glycoprotein inhibitor, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitized HepG2 cells in a fashion that was insensitive to the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. At concentrations exceeding the one employed for chemosensitization, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol was by itself strongly toxic to HepG2 cells, and also this effect was insensitive to the pancaspase inhibitor. These results suggest that 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, at subtoxic concentrations, might synergize with scarcely toxic doxorubicin doses to propagate a caspase-independent cytotoxic response, such that P-glycoprotein-dependent drug resistance is circumvented.
Di Bartolomeo
Sabrina
S
Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, I-00133 Rome, Italy.
Luly
Paolo
P
Spinedi
Angelo
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D009025:Morpholines; C033110:RV 538; D004317:Doxorubicin; D014700:Verapamil