PMID- 17545622
OWN - NLM
STAT- MEDLINE
DCOM- 20070726
LR  - 20131121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 11
DP  - 2007 Jun 1
TI  - Proton pump inhibitors induce apoptosis of human B-cell tumors through a 
      caspase-independent mechanism involving reactive oxygen species.
PG  - 5408-17
AB  - 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.
FAU - De Milito, Angelo
AU  - De Milito A
AD  - Department of Drug Research and Evaluation, Pharmacogenetic, Drug Resistance, and 
      Experimental Therapeutic Section, Istituto Superiore di Sanita, Rome, Italy. 
      Angelo.demilito@iss.it
FAU - Iessi, Elisabetta
AU  - Iessi E
FAU - Logozzi, Mariantonia
AU  - Logozzi M
FAU - Lozupone, Francesco
AU  - Lozupone F
FAU - Spada, Massimo
AU  - Spada M
FAU - Marino, Maria Lucia
AU  - Marino ML
FAU - Federici, Cristina
AU  - Federici C
FAU - Perdicchio, Maurizio
AU  - Perdicchio M
FAU - Matarrese, Paola
AU  - Matarrese P
FAU - Lugini, Luana
AU  - Lugini L
FAU - Nilsson, Anna
AU  - Nilsson A
FAU - Fais, Stefano
AU  - Fais S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Proton Pump Inhibitors)
RN  - 0 (Reactive Oxygen Species)
RN  - 5V9KLZ54CY (Vinblastine)
RN  - EC 3.4.22.- (Caspases)
RN  - KG60484QX9 (Omeprazole)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Phytogenic/pharmacology
MH  - Apoptosis/*drug effects/physiology
MH  - Caspase Inhibitors
MH  - Caspases/*metabolism
MH  - Cell Growth Processes/drug effects
MH  - Cell Line, Tumor
MH  - Cytosol/metabolism
MH  - Drug Synergism
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Jurkat Cells
MH  - Lymphoma, B-Cell/*drug therapy/enzymology/metabolism/pathology
MH  - Mice
MH  - Mice, SCID
MH  - Omeprazole/pharmacology
MH  - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/*drug 
      therapy/enzymology/pathology
MH  - *Proton Pump Inhibitors
MH  - Reactive Oxygen Species/*metabolism
MH  - Vinblastine/pharmacology
MH  - Xenograft Model Antitumor Assays
EDAT- 2007/06/05 09:00
MHDA- 2007/07/27 09:00
CRDT- 2007/06/05 09:00
PHST- 2007/06/05 09:00 [pubmed]
PHST- 2007/07/27 09:00 [medline]
PHST- 2007/06/05 09:00 [entrez]
AID - 67/11/5408 [pii]
AID - 10.1158/0008-5472.CAN-06-4095 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Jun 1;67(11):5408-17. doi: 10.1158/0008-5472.CAN-06-4095.