Inhibition of endosomal sequestration of basic anticancer drugs: influence on cytotoxicity and tissue penetration.
The basic drugs doxorubicin and mitoxantrone are known to be concentrated in acidic endosomes of cells. Here, we address the hypotheses that raising endosomal pH with the modifying agents chloroquine, omeprazole or bafilomycin A might decrease sequestration of anticancer drugs in endosomes, thereby increasing their cytotoxicity and availability for tissue penetration. Chloroquine, omeprazole and bafilomycin A showed concentration-dependent effects to raise endosomal pH, and to inhibit sequestration of doxorubicin in endosomes. Chloroquine and omeprazole but not bafilomycin A decreased the net uptake of doxorubicin into cells, but there was no significant effect on uptake of mitoxantrone. Omeprazole and bafilomycin A increased the cytotoxicity of the anticancer drugs for cultured cells, as measured in a clonogenic assay, whereas chloroquine had minimal effects on cytotoxicity despite reduced uptake of doxorubicin. Omeprazole but not chloroquine or bafilomycin A increased the penetration of anticancer drugs through multicellular layers of tumour tissue. We conclude that modifiers of endosomal pH might increase therapeutic effectiveness of basic drugs by increasing their toxicity and/or tissue penetration in solid tumours.
Division of Applied Molecular Oncology, Princess Margaret Hospital/University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.
C M
CM
Lee
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Tannock
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics*; D000962:Antimalarials / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000473:pathology; D002738:Chloroquine / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics*; D004347:Drug Interactions; D011992:Endosomes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D018942:Macrolides / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D051379:Mice; D008942:Mitoxantrone / Q000737:chemistry / Q000493:pharmacokinetics*; D009853:Omeprazole / Q000494:pharmacology; D012509:Sarcoma / Q000473:pathology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000962:Antimalarials; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; C057620:bafilomycin A; D004317:Doxorubicin; D002738:Chloroquine; D008942:Mitoxantrone; D009853:Omeprazole