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

Filomeni, Giuseppe; Turella, Paola; Dupuis, Maria Luisa; Forini, Olindo; Ciriolo, Maria Rosa; Cianfriglia, Maurizio; Pezzola, Silvia; Federici, Giorgio; Caccuri, Anna Maria

doi:10.1158/1535-7163.mct-07-0487

Cited by 53 publications

(57 citation statements)

References 39 publications

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“…NBDHEX is known to cause the release of JNK from the complex with GSTP1-1 and to promote a JNK-mediated apoptosis. [9][10][11][12][13][14] Our study confirms this mechanism in human osteosarcoma cell lines and shows that the activation of the MAPK signaling pathway causes different effects. In order to get deeper insights into the NBDHEX action mechanism, we performed a comparative proteomic investigation of the U-2OS untreated cell line and cells treated with the drug by label-free nLC-MS E .…”

Section: Introductionsupporting

confidence: 78%

Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines

Filomeni

Pezzola

et al. 2012

Mol. BioSyst.

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The effect of the glutathione transferase P1-1 (GSTP1-1) targeting has been investigated in both sensitive (U-2OS) and cisplatin-resistant (U-2OS/CDDP4 mg) human osteosarcoma cell lines. Despite the different enzyme's content, inhibition of GSTP1-1 by 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) causes the activation of c-Jun N-terminal kinase (JNK) and apoptosis in both cell lines. However, different time courses of JNK activation and cell responses are observed. Whereas in the U-2OS/CDDP4 mg cell line drug treatment results in an early increase of caspase activity and secondary necrosis, in the U-2OS cells it mainly causes an early cell cycle arrest followed by apoptosis. In order to elucidate the action mechanism of NBDHEX we performed a proteomic investigation by label-free nLC-MS E . The high-throughput analysis associated with a bioinformatic tool suggested the involvement of the TNF receptor associated factor (TRAF) family in the cellular response to the drug treatment. We report experimental evidence of the interaction between GSTP1-1 and TRAF2 and we demonstrate that NBDHEX is able to dissociate the GSTP1-1 : TRAF2 complex. This restores the TRAF2 : ASK1 signaling, thereby leading to the simultaneous and prolonged activation of JNK and p38. These mitogenactivated protein kinases (MAPKs) mediate different effects: JNK is crucial for apoptosis, whereas p38 causes an increase in the p21 level and a concomitant cell cycle arrest. Our study shows that GSTP1-1 plays an important regulatory role in TRAF signaling of osteosarcoma and discloses new features of the action mechanism of NBDHEX that suggest potentially practical consequences of these findings.

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Section: Introductionsupporting

confidence: 78%

Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines

Filomeni

Pezzola

et al. 2012

Mol. BioSyst.

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“…Moreover, the NBDHEX antitumor efficacy in these mesothelioma cell lines was comparable to that observed in other tumor cells. (31)(32)(33)(34)(35)(36) Analysis of the cell death induced by 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol. The growth curves of each cell line, incubated in the absence and in the presence of equitoxic concentrations of NBDHEX, are shown in Figure 2(a).…”

Section: Resultsmentioning

confidence: 99%

“…(29,30) An important property of this compound is that it is not recognized as a substrate by the ABC transporters P-glycoprotein and MRP1 and is highly cytotoxic against tumor cells that overexpress these transporters. (31)(32)(33) Given the promising results already observed in several different tumors, (31)(32)(33)(34)(35)(36)(37)(38) in the present study we evaluate the effect of NBDHEX in four human malignant mesothelioma cell lines, MSTO-211H, MPP89, MM-B1 and Mero 48a, featuring the two most common phenotypes, epithelioid and biphasic. The mechanism of cell death triggered by NBDHEX and the in vitro efficacy of NBDHEX in combination with CDDP are investigated.…”

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confidence: 99%

Glutathione S‐transferase P1‐1 as a target for mesothelioma treatment

Luca

Tregno

et al. 2012

Cancer Science

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Malignant pleural mesothelioma is a poorly responsive tumor known to overexpress the phase II detoxification enzyme glutathione-S-transferase, which catalyzes the conjugation between glutathione and platinum(II)-containing drugs. Therefore, we evaluated the effect of the strong glutathione S-transferase inhibitor NBDHEX on human mesothelioma cell lines (MSTO-211H, MPP89, MM-B1 and Mero 48a) featuring the most common mesothelioma phenotypes: epithelioid and biphasic. Even though a different response to NBDHEX was observed, the molecule was very effective on all cell lines tested, triggering a sustained activation of both JNK and p38, followed by caspase activation and apoptosis. NBDHEX also caused severe oxidative stress in the MPP89 cells and, to a lesser extent, in the MMB1 cells, while it did not cause a significant redox imbalance in the other cell lines. The efficacy of the drug was found to be comparable or even higher than that of cisplatin. Moreover, it showed synergistic or additive effects when used in combination with cisplatin. In conclusion, NBDHEX was effective on mesothelioma cell lines, with IC 50 values in the low micromolar range (IC 50 between 1 and 4 lM). These findings indicate that NBDHEX, alone or in combination with cisplatin, is a promising new strategy for treating this rare and aggressive malignancy. (Cancer Sci 2013; 104: 223-230) M esothelioma is a malignant tumor that arises from pluripotent mesothelial cells of pleura or peritoneum. (1,2) Mesothelioma cells show different phenotypes, including the epithelioid, sarcomatoid and the mixed type. Epithelioid is the most common form (60-70% of cases). The sarcomatoid form represents 10-20% of mesotheliomas, and the mixed (or biphasic) form, with epithelioid and sarcomatoid areas, represents 30-40% of all mesotheliomas.(3) There is strong evidence for a causal relation between the development of mesotelioma and asbestos exposure.(4) Although its use has been widely abandoned in the developed world, the mortality rate will continue to increase over the forthcoming years because of the long latency period between the exposure to asbestos and the onset of tumor.(5) Malignant pleural mesothelioma (MPM) responds poorly to chemotherapy. (6,7) Several clinical studies have been performed using the platinum (II)-containing compound CDDP in combination with antifolates (pemetrexed and raltitrexed), nucleoside analogues (gemcitabine), topoisomerase inhibitors (irinotecan) or mitotic inhibitors (vinorelbine) to improve the response rate of MPM to treatment.(8-12) The combination of pemetrexed plus CDDP is the approved "standard of care" for patients with unresectable MPM; (13)(14)(15)(16) however, only a partial benefit has been shown in terms of survival. (15,17) Among the mechanisms of CDDP resistance, the most studied are those dependent on the elevated expression of glutathione S-transferases (GST) (18,19) and of the export pumps MRP1 and MRP2 (multidrug resistance-associated protein). A coordinated action between these pumps and GST enables e...

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“…The JNK1α2 activity was evaluated by measuring the incorporation of [γ- 33 P] into ATF2 (JNK activity assay kit, Millipore). Briefly, JNK1α2 was phosphoactivated in the first step of the assay by incubating the kinase for 15 min at 30°C in 25 μL (final volume) of 50 mM TrisHCl (pH 7.5) containing 0.1 mM EGTA, 0.1 mM Na 3 VO 4 , 5 mM magnesium acetate, 0.1 mM ATP, and 0.1 μM active MKK7β1 (Millipore).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

The Lipid Dependence of Antimicrobial Peptide Activity Is an Unreliable Experimental Test for Different Pore Models

et al. 2012

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The role played by glutathione transferase P1-1 (GSTP1-1) in modulating the c-Jun N-terminal kinase (JNK) pathway has been extensively investigated using JNK isoforms known to exert opposite effects in the cells. We have expressed isoform JNK1α2, which has been reported to transmit a pro-apoptotic signal, and we have analyzed both the phosphorylation level and the activity of this kinase in the presence of GSTP1-1. Contrary to what previous studies suggest, we found that GSTP1-1 is able to form a complex with the unphosphorylated and inactive JNK1α2 isoform, even in the absence of the substrate. We also analyzed the consequences of this interaction on the activity of both enzymes. The complex strongly reduced the extent of activation of JNK1α2 and preserved GSTP1-1 from inactivation. Unexpectedly, glutathione (GSH) exerted a negative effect on the affinity of GSTP1-1 for JNK1α2, suggesting that the intracellular levels of this thiol may allow a fine-tuning of the MAPK signaling pathway. Moreover, we found that the adduct formed by GSH and the strong GSTP1-1 inhibitor NBDHEX abolishes the interaction between GSTP1-1 and JNK1α2. These data confirm and extend at the molecular level previous evidence obtained in tumor cell lines.

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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

Abstract: In the present work,

Cited by 53 publications

References 39 publications

Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines

Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines

Glutathione S‐transferase P1‐1 as a target for mesothelioma treatment

The Lipid Dependence of Antimicrobial Peptide Activity Is an Unreliable Experimental Test for Different Pore Models

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