title: Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors.
abstract: Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors.
authors.affiliation: Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Man
authors.initials: M
authors.lastname: Yu
authors.affiliation: Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Lee
authors.affiliation: Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Marina
authors.initials: M
authors.lastname: Wang
authors.affiliation: Ontario Cancer Institute, Toronto, Ontario, Canada.|Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D064747:Lansoprazole / Q000494:pharmacology*; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D004317:Doxorubicin
keywords: Doxorubicin; drug distribution; lansoprazole; pharmacodynamic markers; solid tumor