Treatment of resistant human colon cancer xenografts by a fluoxetine–doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen

• Published in: Cancer letters Vol. 274; no. 1; pp. 118 - 125
• Main Authors: Argov, Mirit, Kashi, Rina, Peer, Dan, Margalit, Rimona
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 08.02.2009; Elsevier Limited
• Subjects: ABC transporters; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Bevacizumab; Cancer therapies; Cell culture; Cell Proliferation - drug effects; Chemotherapy; Clinical trials; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Doxorubicin; Doxorubicin - administration & dosage; Drug dosages; Drug resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Flow Cytometry; Fluoxetine; Fluoxetine - therapeutic use; Hematology, Oncology and Palliative Medicine; Humans; Mice; Mice, Nude; Microscopy; Multidrug resistance; Multidrug Resistance-Associated Proteins - metabolism; Neoplasm Proteins - metabolism; P-glycoprotein; Pharmaceuticals; Serotonin Uptake Inhibitors - therapeutic use; Studies; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; ABC; MRP; Doxorubicin; Bevacizumab; BSA; Colon cancer; FBS; multidrug resistance-associated protein; HBS; MDR; BCRP; PBS; multiple drug resistance; breast cancer resistance protein; Fluoxetine; Multidrug resistance; ATP binding cassette; P-glycoprotein. SD, standard deviation; hepes buffered saline; P-glycoprotein; fetal bovine serum; phosphate buffered saline; Pgp; SEM; standard error of the mean; bovine serum albumin
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2008.09.005

Abstract Pre-clinical studies of multidrug resistance (MDR) usually address severe resistance, yet moderate MDR is already clinically-impeding. The purpose of this study was to characterize moderate drug resistance in human colon cancer, and it’s modulation by fluoxetine. In vitro fluoxetine enhanced doxorubicin’s cytotoxicity (10-fold), increased doxorubicin’s intracellular accumulation (32%) and decreased efflux of intracellular doxorubicin (70%). In vivo , mild treatment with a doxorubicin–fluoxetine combination slowed-down tumor progression significantly ( p < 0.001 vs. doxorubicin alone), comparable to aggressive treatment with bevacizumab. Collectively, our results suggest that combinations of fluoxetine with chemotherapeutic drugs (P-glycoprotein substrates) are worthy of further pursuit for moderate MDR in the clinic.