In the present work, we have investigated the antitumor activity of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on aggressive small cell lung cancer. NBDHEX not only is cytotoxic toward the parental small cell lung cancer H69 cell line (LC50 of 2.3 +/- 0.6 mu mol/L) but also overcomes the multidrug resistance of its variant, H69AR, which overexpresses the ATP-binding cassette transporter multidrug resistance-associated protein 1 (MRP1; LC50 of 4.5 +/- 0.9 mu mol/L). Drug efflux experiments, done in the presence of a specific inhibitor of MRP1, confirmed that NBDHEX is not a substrate for this export pump. Interestingly, NBDHEX triggers two different types of cell death: a caspase-dependent apoptosis in the H69AR cells and a necrotic phenotype in the parental H69 cells. The apoptotic pathway triggered by NBDHEX in H69AR cells is associated with c-Jun NH2-terminal kinase and c-Jun activation, whereas glutathione oxidation and activation of p38(MAPK) is observed in the NBDHEX-treated H69 cells. In contrast to the parental cells, the higher propensity to die through apoptosis of the H69AR cell line may be related to the lower expression of the antiapoptotic protein Bcl-2. Therefore, down-regulation of a factor crucial for cell survival makes H69AR cells more sensitive to the cytotoxic action of NBDHEX, which is not a MRP1 substrate. We have previously shown that NBDHEX is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines. Therefore, NBDHEX seems a very promising compound in the search for new molecules able to overcome the ATP-binding cassette family of proteins, one of the major mechanisms of multidrug resistance in cancer cells.

Filomeni, G., Turella, P., Dupuis, M., Forini, O., Ciriolo, M.r., Cianfriglia, M., et al. (2008). 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)-associated protein 1-mediated MDR in small cell lung cancer. MOLECULAR CANCER THERAPEUTICS, 7(2), 371-379 [10.1158/1535-7163.MCT-07-0487].

6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)-associated protein 1-mediated MDR in small cell lung cancer

FILOMENI, GIUSEPPE;CIRIOLO, MARIA ROSA;FEDERICI, GIORGIO;CACCURI, ANNA MARIA
2008-01-01

Abstract

In the present work, we have investigated the antitumor activity of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on aggressive small cell lung cancer. NBDHEX not only is cytotoxic toward the parental small cell lung cancer H69 cell line (LC50 of 2.3 +/- 0.6 mu mol/L) but also overcomes the multidrug resistance of its variant, H69AR, which overexpresses the ATP-binding cassette transporter multidrug resistance-associated protein 1 (MRP1; LC50 of 4.5 +/- 0.9 mu mol/L). Drug efflux experiments, done in the presence of a specific inhibitor of MRP1, confirmed that NBDHEX is not a substrate for this export pump. Interestingly, NBDHEX triggers two different types of cell death: a caspase-dependent apoptosis in the H69AR cells and a necrotic phenotype in the parental H69 cells. The apoptotic pathway triggered by NBDHEX in H69AR cells is associated with c-Jun NH2-terminal kinase and c-Jun activation, whereas glutathione oxidation and activation of p38(MAPK) is observed in the NBDHEX-treated H69 cells. In contrast to the parental cells, the higher propensity to die through apoptosis of the H69AR cell line may be related to the lower expression of the antiapoptotic protein Bcl-2. Therefore, down-regulation of a factor crucial for cell survival makes H69AR cells more sensitive to the cytotoxic action of NBDHEX, which is not a MRP1 substrate. We have previously shown that NBDHEX is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines. Therefore, NBDHEX seems a very promising compound in the search for new molecules able to overcome the ATP-binding cassette family of proteins, one of the major mechanisms of multidrug resistance in cancer cells.
2008
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/10 - BIOCHIMICA
English
Con Impact Factor ISI
6 (7 nitro 2,1,3 benzoxadiazol 4 ylthio)hexanol; ABC transporter; caspase; glutathione; glutathione transferase; glycoprotein P; mitogen activated protein kinase p38; multidrug resistance protein 1; protein bcl 2; protein c jun; stress activated protein kinase; transferase inhibitor; antineoplastic activity; apoptosis; article; cancer resistance; cell survival; controlled study; down regulation; drug cytotoxicity; drug specificity; drug transport; enzyme activation; enzyme substrate; human; human cell; LC 50; lung small cell cancer; multidrug resistance; oxidation; phenotype; priority journal; protein expression; protein family; tumor cell line; Antineoplastic Agents; Apoptosis; Carcinoma, Small Cell; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Activation; Glutathione; Glutathione Transferase; Hexanols; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Necrosis; Oxadiazoles; Oxidation-Reduction; P-Glycoprotein; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-jun; Substrate Specificity
Filomeni, G., Turella, P., Dupuis, M., Forini, O., Ciriolo, M.r., Cianfriglia, M., et al. (2008). 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)-associated protein 1-mediated MDR in small cell lung cancer. MOLECULAR CANCER THERAPEUTICS, 7(2), 371-379 [10.1158/1535-7163.MCT-07-0487].
Filomeni, G; Turella, P; Dupuis, M; Forini, O; Ciriolo, Mr; Cianfriglia, M; Pezzola, S; Federici, G; Caccuri, Am
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/30690
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