Murine monoclonal antibody recognizing a 90‐kDa cell‐surface determinant selectively lost by multi‐drug‐resistant variants of cem cells

Cianfriglia, Maurizio; Cenciarelli, C.; Tombesi, Marina; Barca, Stefano; Mariani, Massimo A.; Morrone, Stefania; Santoni, Angela; Samoggia, Paola; Alessio, Massimo; Malavasi, Fabio

doi:10.1002/ijc.2910450118

Cited by 25 publications

(18 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, omeprazole was able to increase the cytotoxicity of vinblastine in drug-sensitive tumour cells. The effect of PPIs on drug sensitivity was also observed in a cell line (VBL-100) selected in vitro for an MDR phenotype [44]: the pretreatment with PPIs restored the sensitivity of these cells to vinblastine. A possible mechanism explaining the capacity of PPIs to reverse MDR is the accumulation of antitumour drugs (vinblastine and doxorubicin) in vesicle-like structures and the inhibition of the secretion of such vesicles, thus allowing drugs to reach their cellular target.…”

Section: Proton Pump Inhibitors Treat Tumour Resistance To Cytotoxic mentioning

confidence: 93%

Proton pump inhibitors may reduce tumour resistance

Milito¹,

Fais²

2005

Expert Opinion on Pharmacotherapy

View full text Add to dashboard Cite

Resistance to cytotoxic agents is a major problem in treating cancer. The mechanisms underlying this phenomenon appear to take advantage of functions involved in the control of cell homeostasis. A mechanism of resistance may be alteration of the tumour microenvironment via changes in the pH gradient between the extracellular environment and the cell cytoplasm. The extracellular pH of solid tumours is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumours. An option to revert multi-drug resistance is the use of agents that disrupt the pH gradient in tumours by inhibiting the function of pumps generating the pH gradient, such as vacuolar H(+)-ATPases (V-H(+)-ATPases). V-H(+)-ATPases pump protons across the plasma membrane and across the membranes of various intracellular compartments. Some human tumour cells, particularly those selected for multi-drug resistance, exhibit enhanced V-H(+)-ATPase activity. A class of V-H(+)-ATPase inhibitors, called proton pump inhibitors (PPIs), have emerged as the drug class of choice for treating patients with peptic diseases. These drugs inhibit gastric acid secretion by targeting the gastric acid pump, but they also directly inhibit V-H(+)-ATPases. PPIs (including omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole) are protonable weak bases which selectively accumulate in acidic spaces. Recent findings from our group have shown that PPI pretreatment sensitised tumour cell lines to the effect of cisplatin, 5-fluoro-uracil and vinblastine. PPI pretreatment was associated with the inhibition of V-H(+)-ATPase activity and an increase of both extracellular pH and the pH of lysosomal organelles, consistent with a cytoplasmic retention of the cytotoxic drugs and targeting to the nucleus in the case of doxorubicin. In vivo experiments showed that oral pretreatment with omeprazole induced a sensitivity of the human solid tumours to anticancer drugs.

show abstract

Section: Proton Pump Inhibitors Treat Tumour Resistance To Cytotoxic mentioning

confidence: 93%

Proton pump inhibitors may reduce tumour resistance

Milito¹,

Fais²

2005

Expert Opinion on Pharmacotherapy

View full text Add to dashboard Cite

show abstract

“…13 All the cells used in this study were cultured in RPMI 1640 medium enriched with 10% fetal bovine serum and antibiotics (basic medium, BM) in a humidified 5% CO 2 and 95% air atmosphere. P-gp drug efflux was measured by the dye compound VBL-bodipy (50 ng/mL; Molecular Probes, Eugene, OR).…”

Section: Cells and Chemicalsmentioning

confidence: 99%

“…12 In in vitro cell systems, the level of P-gp expression correlates with the final concentration of the anticancer compound used for MDR variant selection. 13 Of interest, some evidence has suggested an important role of the actin cytoskeleton in P-gp-mediated multidrug resistance. In fact, the organization of actin filaments may be involved in the expression of P-gp function in MDR osteosarcoma cells, 14 and cytoskeleton alterations occur in an MDR human breast cancer cell line.…”

Section: Introductionmentioning

confidence: 99%

P-glycoprotein–actin association through ERM family proteins: a role in P-glycoprotein function in human cells of lymphoid origin

Luciani

Molinari

Lozupone

et al. 2002

Blood

135

140

View full text Add to dashboard Cite

P-glycoprotein is a 170-kd glycosylated transmembrane protein, expressed in a variety of human cells and belonging to the adenosine triphosphate-binding cassette transporter family, whose membrane expression is functionally associated with the multidrug resistance phenotype. However, the mechanisms underlying the regulation of P-glycoprotein functions remain unclear. On the basis of some evidence suggesting P-glycoprotein-actin cytoskeleton interaction, this study investigated the association of Pglycoprotein with ezrin, radixin, and moesin, a class of proteins that cross-link actin filaments with plasma membrane in a human cell line of lymphoid origin and that have been shown to link other ionpump-related proteins. To this purpose, a multidrug-resistant variant of CCRF-CEM cells (CEM-VBL100) was used as a model to investigate the following: (1) the cellular localizations of P-glycoprotein and ezrin, radixin, and moesin and their molecular associations; and (2) the effects of ezrin, radixin, and moesin antisense oligonucleotides on multidrug resistance and P-glycoprotein function. The results showed that: (1) P-glycoprotein colocalized and coimmunoprecipitated with ezrin, radixin, and moesin; and (2) treatment with antisense oligonucleotides for ezrin, radixin, and moesin restored drug susceptibility consistently with inhibition of both drug efflux and actin-P-glycoprotein association and induction of cellular redistribution of P-glycoprotein. These data suggest that P-glycoprotein association with the actin cytoskeleton through ezrin, radixin, and moesin is key in conferring to human lymphoid cells a multidrug resistance phenotype. Strategies aimed at inhibiting P-glycoprotein-actin association may be helpful in increasing the efficiency of both antitumor and antiviral therapies. (Blood. 2002;99:641-648)

show abstract

“…P-gp overexpressing variants, CEM-VBL10 and CEM-VBL100, which show different relative resistance levels to vinblastine (CEM-VBL10 Ͻ10 4 and CEM-VBL100 Ͼ10 6 P-gp molecules per cell) (10,11), and U-2 OS/DX 580 cell lines resistant to doxorubicin (12).…”

Section: Methodsmentioning

confidence: 99%

A Strong Glutathione S-Transferase Inhibitor Overcomes the P-glycoprotein-mediated Resistance in Tumor Cells

Turella

Filomeni

Dupuis

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

The new glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines, i.e. CEM-VBL10, CEM-VBL100, and U-2 OS/DX 580 . The mechanism of cell death triggered by NBDHEX has been deeply investigated in leukemia cell lines. Kinetic data indicate a similar NBDHEX membrane permeability between multidrug resistance cells and their sensitive counterpart revealing that NBDHEX is not a substrate of the P-glycoprotein export pump. Unexpectedly, this molecule promotes a caspase-dependent apoptosis that is unusual in the P-glycoprotein-overexpressing cells. The primary event of the apoptotic pathway is the dissociation of glutathione S-transferase P1-1 from the complex with c-Jun N-terminal kinase. Interestingly, leukemia MDR1-expressing cells show lower LC 50 values and a higher degree of apoptosis and caspase-3 activity than their drug-sensitive counterparts. The increased susceptibility of the multidrug resistance cells toward the NBDHEX action may be related to a lower content of glutathione S-transferase P1-1. Given the low toxicity of NBDHEX in vivo, this compound may represent an attractive basis for the selective treatment of MDR1 P-glycoproteinpositive tumors.

show abstract

Murine monoclonal antibody recognizing a 90‐kDa cell‐surface determinant selectively lost by multi‐drug‐resistant variants of cem cells

Cited by 25 publications

References 41 publications

Proton pump inhibitors may reduce tumour resistance

Proton pump inhibitors may reduce tumour resistance

P-glycoprotein–actin association through ERM family proteins: a role in P-glycoprotein function in human cells of lymphoid origin

A Strong Glutathione S-Transferase Inhibitor Overcomes the P-glycoprotein-mediated Resistance in Tumor Cells

Contact Info

Product

Resources

About