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

Mirit Argov; Rina Kashi; Dan Peer; Rimona Margalit

doi:10.1016/j.canlet.2008.09.005

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

Cancer Lett. 2009 Feb 8;274(1):118-25. doi: 10.1016/j.canlet.2008.09.005. Epub 2008 Oct 11.

Authors

Mirit Argov¹, Rina Kashi, Dan Peer, Rimona Margalit

Affiliation

¹ Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel.

PMID: 18851896
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.

Publication types

Comparative Study

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / metabolism
Animals
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Bevacizumab
Cell Proliferation / drug effects
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Doxorubicin / administration & dosage
Drug Resistance, Multiple
Drug Resistance, Neoplasm*
Female
Flow Cytometry
Fluoxetine / therapeutic use*
Humans
Mice
Mice, Nude
Multidrug Resistance-Associated Proteins / metabolism
Neoplasm Proteins / metabolism
Selective Serotonin Reuptake Inhibitors / therapeutic use*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
Serotonin Uptake Inhibitors
Fluoxetine
Bevacizumab
Doxorubicin
multidrug resistance-associated protein 1