title: Two repeated low doses of doxorubicin are more effective than a single high dose against tumors overexpressing P-glycoprotein.
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.
authors: Department of Oncology, University of Torino, via Santena 5/bis, Torino 10126, Italy.
authors: Chiara
authors: C
authors: Riganti
authors: Department of Oncology, University of Torino, via Santena 5/bis, Torino 10126, Italy.
authors: Elena
authors: E
authors: Gazzano
authors: Department of Oncology, University of Torino, via Santena 5/bis, Torino 10126, Italy.
authors: Giulia Rossana
authors: GR
authors: Gulino
authors: Department of Oncology, University of Torino at San Luigi Hospital, Regione Gonzole 10, Orbassano 10043, Italy.
authors: Marco
authors: M
authors: Volante
authors: Department of Oncology, University of Torino, via Santena 5/bis, Torino 10126, Italy. Electronic address: dario.ghigo@unito.it.
authors: Dario
authors: D
authors: Ghigo
authors: Department of Oncology, University of Torino, via Santena 5/bis, Torino 10126, Italy.
authors: Joanna
authors: J
authors: Kopecka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9
keywords: Doxorubicin; Mitochondria; P-glycoprotein; Reactive oxygen species