Two repeated low doses of doxorubicin are more effective than a single high dose against tumors overexpressing P-glycoprotein

• Published in: Cancer letters Vol. 360; no. 2; pp. 219 - 226
• Main Authors: Riganti, Chiara, Gazzano, Elena, Gulino, Giulia Rossana, Volante, Marco, Ghigo, Dario, Kopecka, Joanna
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.05.2015; Elsevier Limited
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cancer therapies; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell cycle; Chemotherapy; Colleges & universities; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Cytochromes c - metabolism; Cytotoxicity; DNA repair; Dose-Response Relationship, Drug; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Drug Administration Schedule; Drug dosages; Drug resistance; Drug Resistance, Neoplasm; Female; Hematology, Oncology and Palliative Medicine; HT29 Cells; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Medical research; Metabolism; Mice; Mice, Inbred BALB C; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Oxidative Stress - drug effects; P-glycoprotein; Random Allocation; Reactive oxygen species; Tumors; Xenograft Model Antitumor Assays; NO; Reactive oxygen species; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; alanine aminotransferase; ALT; MTT; Doxorubicin; relative light unit; LDH; Mitochondria; DCFDA-AM; analysis of variance; ANOVA; RLU; nitric oxide synthase; RFU; AST; nitric oxide; creatine phosphokinase; 5-(and-6)-chloromethyl-2′,7′-dichlorodihydro-fluorescein diacetate-acetoxymethyl ester; relative fluorescence unit; lactate dehydrogenase; thiobarbituric acid reactive substances; TBARS; aspartate aminotransferase; P-glycoprotein; NOS; ROS; Pgp; CPK
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2015.02.008

Abstract Standard chemotherapeutic protocols, based on maximum tolerated doses, do not prevent nor overcome chemoresistance caused by the efflux transporter P-glycoprotein (Pgp). We compared the effects of two consecutive low doses versus a single high dose of doxorubicin in drug-sensitive Pgp-negative and drug-resistant Pgp-positive human and murine cancer cells. Two consecutive low doses were significantly more cytotoxic in vitro and in vivo against drug-resistant tumors, while a single high dose failed to do so. The greater efficacy of two consecutive low doses of doxorubicin could be linked to increased levels of intracellular reactive oxygen species. These levels were produced by high electron flux from complex I to complex III of the mitochondrial respiratory chain, unrelated to the synthesis of ATP. This process induced mitochondrial oxidative damage, loss of mitochondrial potential and activation of the cytochrome c/caspase 9/caspase 3 pro-apoptotic axis in drug-resistant cells. Our work shows that the “apparent” ineffectiveness of doxorubicin against drug-resistant tumors overexpressing Pgp can be overcome by changing the timing of its administration and its doses.