Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs.
BACKGROUND
Resistance to antitumor agents is a major cause of treatment failure in patients with cancer. Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. We investigated whether proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents.


METHODS
We pretreated cell lines derived from human melanomas, adenocarcinomas, and lymphomas with the PPIs omeprazole, esomeprazole, or pantoprazole and tested their response to cytotoxic drugs in cell death assays. We also evaluated extracellular and intracellular pH and vacuolar-H+-ATPase (V-H+-ATPase) expression, distribution, and activity in PPI-pretreated cells by using western blot analyses, immunocytochemistry, laser scanning confocal analysis, and bioluminescence assays. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice.


RESULTS
PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles. PPI pretreatment induced a marked increase in the cytoplasmic retention of the cytotoxic drugs, with clear targeting to the nucleus in the case of doxorubicin. In in vivo experiments, oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin.


CONCLUSIONS
Our results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs.
Luciani
Francesca
F
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Nazionale dei Tumori, Milan, Italy.
Spada
Massimo
M
De Milito
Angelo
A
Molinari
Agnese
A
Rivoltini
Licia
L
Montinaro
Annalisa
A
Marra
Manuela
M
Lugini
Luana
L
Logozzi
Mariantonia
M
Lozupone
Francesco
F
Federici
Cristina
C
Iessi
Elisabetta
E
Parmiani
Giorgio
G
Arancia
Giuseppe
G
Belardelli
Filippo
F
Fais
Stefano
S
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004591:Electrophoresis, Polyacrylamide Gel; D064098:Esomeprazole; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D008223:Lymphoma / Q000188:drug therapy*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors; D013454:Sulfoxides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014747:Vinblastine / Q000494:pharmacology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D013454:Sulfoxides; D014747:Vinblastine; D000077402:Pantoprazole; D009853:Omeprazole; D064098:Esomeprazole; D002945:Cisplatin; D005472:Fluorouracil