Inhibition of endosomal sequestration of basic anticancer drugs: influence on cytotoxicity and tissue penetration

Abstract

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.

Use of the Proton Pump Inhibitor Pantoprazole to Modify the Distribution and Activity of Doxorubicin: A Potential Strategy to Improve the Therapy of Solid Tumors

“…We hypothesized that preventing sequestration of drug in acidic endosomes would improve extracellular drug distribution. In support of this hypothesis, modest improvements in drug distribution have been observed in multilayered cell cultures (MCC) pretreated with chloroquine or the PPI, omeprazole (21). As well, PPIs have been shown to increase chemotherapy efficacy in vitro and improve tumor control in vivo (22)(23)(24).…”

ClC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment

“…Several studies have implied a link between drug resistance and intravesicular acidity either by comparison of drugsensitive and drug-resistant cell lines (3,4) or through treatment with agents disrupting organellar pH (5). A recent study showed that omeprazole, a proton pump inhibitor used in antiacid treatment of peptic disease, and the vacuolar proton pump (v-H + -ATPase) inhibitor bafilomycin A increased cytotoxicity of the basic chemotherapeutic drugs doxorubicin and mitoxantrone (6). Similarly, in vivo studies of human melanoma xenografts in severe combined immunodeficient mice showed that proton pump inhibitors affected sensitivity to cisplatin (7).…”

The use of Nanocarriers for Drug Delivery in Cancer Therapy David R. Khan

“…those that target receptors which undergo receptor-mediated endocytosis), another challenge associated with this type of delivery is the release of the drug from the nanocarrier. This is due to the fact that cellular internalization of these nanocarriers generally results in them being sequestered to acidic endosomes (Lee and Tannock, 2006), which can result in drug protonation of weakly basic drugs such as doxorubicin (Gerweck et al, 2006). The result is that the encapsulated drug is unable to undergo nanocarrier/endosomal escape.…”