Antileishmanial Activity of the Antiulcer Agent Omeprazole

Jiang, Suping; Meadows, Juliana W.; Anderson, Steven A.; Mukkada, Antony J.

doi:10.1128/aac.46.8.2569-2574.2002

Cited by 40 publications

(26 citation statements)

References 17 publications

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“…Therefore, it seemed conceivable that PPI may specifically get to the tumor site, being an additional acidic compartment in cancer patients. We reasoned that any effect of PPI on tumor cells in vitro would be potentiated by the degree of acidity of the surrounding microenvironment, as already shown for its antimicrobial activity (47,48). Indeed, although the doses at which PPI induced cell death in vitro are higher than plasma concentrations reached in humans at standard dosage, we believe that PPI may achieve higher local concentrations at tumor site.…”

Section: Discussionmentioning

confidence: 97%

Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species

et al. 2007

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Proton pumps like the vacuolar-type H + ATPase (V-ATPase) are involved in the control of cellular pH in normal and tumor cells. Treatment with proton pump inhibitors (PPI) induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients. It is also known that low pH is the most suitable condition for a full PPI activation. Here, we tested whether PPI treatment in unbuffered culture conditions could affect survival and proliferation of human B-cell tumors. First, we showed that PPI treatment increased the sensitivity to vinblastine of a pre-B acute lymphoblastic leukemia (ALL) cell line. PPI, per se, induced a dose-dependent inhibition of proliferation of tumor B cells, which was associated with a dose-and time-dependent apoptotic-like cytotoxicity in B-cell lines and leukemic cells from patients with pre-B ALL. The effect of PPI was mediated by a very early production of reactive oxygen species (ROS), that preceded alkalinization of lysosomal pH, lysosomal membrane permeabilization, and cytosol acidification, suggesting an early destabilization of the acidic vesicular compartment. Lysosomal alterations were followed by mitochondrial membrane depolarization, release of cytochrome c, chromatin condensation, and caspase activation. However, inhibition of caspase activity did not affect PPI-induced cell death, whereas specific inhibition of ROS by an antioxidant (N-acetylcysteine) significantly delayed cell death and protected both lysosomal and mitochondrial membranes. The proapoptotic activity of PPI was consistent with a clear inhibition of tumor growth following PPI treatment of B-cell lymphoma in severe combined immunodeficient mice. This study further supports the importance of acidity and pH gradients in tumor cell homeostasis and suggests new therapeutic approaches for human B-cell tumors based on PPI. [Cancer Res 2007;67(11):5408-17]

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Section: Discussionmentioning

confidence: 97%

Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species

et al. 2007

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“…The results show that only one tested compound, omeprazole, significantly disrupted asymmetric Ci-Pitx expression ( Fig. 2A) (Mukherjee et al, 2001;Jiang et al, 2002;Levin et al, 2002). The specificity of action has made omeprazole a popular clinical treatment for targeting gastric H ϩ K ϩ ATPase activity in the con- …”

Section: Dechorionation Disrupts Asymmetric Gene Expression In Ciona mentioning

confidence: 99%

Evidence for the regulation of left-right asymmetry inCiona intestinalis by ion flux

Shimeld

Levin

2006

Dev. Dyn.

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Vertebrate embryos develop distinct left-right asymmetry under the control of a conserved pathway involving left-sided deployment of the nodal and Pitx2 genes. The mechanism that initiates asymmetric expression of these genes is less clear, with cilia, ion flux, and signalling molecules all implicated. Vertebrates share the chordate phylum with urochordates such as the sea squirt Ciona intestinalis. We have explored the role of ion flux in regulating left-right asymmetry in Ciona, using an assay in which perturbation of left-sided Ci-Pitx expression provides a read-out for the disruption of asymmetry. Our data show that omeprazole, which specifically inhibits H

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“…We therefore investigated whether lysosomal enzymes playa role in OM-induced apoptosis. A number of studies have evidenced the lysosomotropic properties of OM and have indicated that following activation by protonation, it can also affect the activity of proton pumps, such as the vacuolar H+-ATPase (5,6,8,49) in part responsible for the internal acid milieu of! ysosomes (9-10).…”

Section: Fl3mentioning

confidence: 99%

Omeprazole Induces Apoptosis in Jurkat Cells

Scaringi

Cornacchione

Ayroldi

et al. 2004

Int J Immunopathol Pharmacol

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We report for the first time a potent apoptotic effect of omeprazole (OM). Apoptosis was induced in Jurkat cells in a time and concentration-dependent mode. Caspase 3 and PARP were rapidly cleaved in response to OM, but apoptosis was only partially inhibited by the caspase 3 inhibitor DEVD-CHO. OM also induced an early lysosomal destabilization which increased progressively and was correlated with a parallel increase in apoptotic cells. The cysteine protease inhibitor E64d gave strong protection against apoptosis thus proving the involvement oflysosomal enzymes in OM-induced apoptosis whereas, it did not impede the caspase 3 cleavage. Instead ZVAD-fmk, a general caspase inhibitor, also able to inhibit cathepsin activity, protected cells completely from OM-induced apoptosis. It therefore seems that both caspases and cysteine cathepsins are involved in the execution stage of OM-induced apoptosis.

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Antileishmanial Activity of the Antiulcer Agent Omeprazole

Cited by 40 publications

References 17 publications

Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species

Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species

Evidence for the regulation of left-right asymmetry inCiona intestinalis by ion flux

Omeprazole Induces Apoptosis in Jurkat Cells

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