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Research Articles: Therapeutics, Targets, and Development

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

Departments of ¹ Biology, and ² Chemical Sciences and Technologies, University of Rome "Tor Vergata"; ³ Drug Research and Evaluation, "Istituto Superiore di Sanità"; ⁴ Internal Medicine, University of Rome "Tor Vergata"; ⁵ Research Centre, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana; and ⁶ Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico "Bambin Gesu," Rome, Italy

Requests for reprints: Anna Maria Caccuri, Department of Chemical Sciences and Technologies, University of Rome "Tor Vergata," Via della Ricerca Scientifica, 00133 Rome, Italy. Phone: 39-0672594378; Fax: 39-0672594328. E-mail: caccuri{at}uniroma2.it

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 µmol/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 µmol/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. [Mol Cancer Ther 2008;7(2):371–9]

Grant support: Istituto Superiore di Sanità-NIH research grant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: G. Filomeni and P. Turella contributed equally to this work.

⁷ M.L. Dupuis, in preparation.

Received 7/24/07; revised 11/27/07; accepted 12/20/07.