Abstract
Purpose
There has been an ever growing interest in the search for new anti-tumor compounds that do not interact with MDR1-Pgp and MRP1 drug transporters and so circumvent the effect of these proteins conferring multidrug resistance (MDR) and poor prognosis in AML patients. We have investigated the cytotoxic activity of the strong glutathione S-transferase (GST) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on AML (HL60) cell lines.
Methods
Functional drug efflux studies and cell proliferation assays were performed on both sensitive and MDR AML (HL60) cells after incubation with NBDHEX. Moreover, the mode of cell death (apoptosis vs. necrosis) as well as the correlation between NBDHEX susceptibility and GST activity or Bcl-2 expression was investigated.
Results
NBDHEX is not a substrate of either MDR1-Pgp or MRP1 efflux pumps; in fact, it is not only cytotoxic toward the parental HL60 cell line, but also overcomes the MDR phenotype of its HL60/DNR and HL60/ADR variants.
Conclusions
The data herein reported show that NBDHEX mediates efficient killing of both MDR1-Pgp and MRP1 over-expressing AML cells. Therefore, this drug can potentially be used as an effective agent for treating MDR in AML patients.
This is a preview of subscription content, log in via an institution to check access.
References
van der Kolk DM, de Vries EG, Müller M, Vellenga E (2002) The role of drug efflux pumps in acute myeloid leukemia. Leuk Lymphoma 43:685–701
Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58
Legrand O, Simonin G, Zittoun R, Marie JP (1998) Both P-gp and MRP contribute to drug resistance in AML. Leukemia 12:1327–1328
Benderra Z, Faussat AM, Sayada L, Perrot JY, Tang R, Chaoui D, Morjani H, Marzac C, Marie JP, Legrand O (2005) MRP3, BCRP, and P-glycoprotein activities are prognostic factors in adult acute myeloid leukemia. Clin Cancer Res 11:7764–7772
Ross DD (2000) Novel mechanisms of drug resistance in leukemia. Leukemia 14:467–473
Ricci G, De Maria F, Antonini G, Turella P, Bullo A, Stella L, Filomeni G, Federici G, Caccuri AM (2005) 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs. J Biol Chem 280:26397–26405
Bakos E, Homolya L (2007) Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1). Eur J Physiol 453:621–641
Turella P, Cerella C, Filomeni G, Bullo A, De Maria F, Ghibelli L, Ciriolo MR, Cianfriglia M, Mattei M, Federici G, Ricci G, Caccuri AM (2005) Proapoptotic activity of new glutathione S-transferase inhibitors. Cancer Res 65:3751–3761
Turella P, Filomeni G, Dupuis ML, Ciriolo MR, Molinari A, De Maria F, Tombesi M, Cianfriglia M, Federici G, Ricci G, Caccuri AM (2006) A strong glutathione S-transferase inhibitor overcomes the P-glycoprotein-mediated resistance in tumor cells. 6-(7-Nitro-2, 1, 3-benzoxadiazol-4-ylthio) hexanol (NBDHEX) triggers a caspase-dependent apoptosis in MDR1-expressing leukemia cells. J Biol Chem 281:23725–23732
Filomeni G, Turella P, Dupuis ML, Forini O, Ciriolo MR, Cianfriglia M, Pezzola S, Federici G, Caccuri AM (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. Mol Cancer Ther 7:371–379
Pasello M, Michelacci F, Scionti I, Hattinger CM, Zuntini M, Caccuri AM, Scotlandi K, Picci P, Serra M (2008) Overcoming glutathione S-transferase P1-related cisplatin resistance in osteosarcoma. Cancer Res 68:6661–6668
Tang R, Faussat AM, Majdak P, Perrot JY, Chaoui D, Legrand O, Marie JP (2004) Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1. Leukemia 18:1246–1251
Cianfriglia M, Willingham MC, Tombesi M, Scagliotti GV, Frasca G, Chersi A (1994) P-glycoprotein epitope mapping. I. Identification of a linear human-specific epitope in the fourth loop of the P-glycoprotein extracellular domain by MM4.17 murine monoclonal antibody to human multidrugresistantcells. Int J Cancer 56:153–160
Hipfner DR, Gao M, Scheffer G, Scheper RJ, Deeley RG, Cole SP (1998) Epitope mapping of monoclonal antibodies specific for the 190-kDa multidrug resistance protein (MRP). Br J Cancer 78:1134–1140
Schultz M, Dutta S, Tew KD (1997) Inhibitors of glutathione S-transferases as therapeutic agents. Adv Drug Deliv Rev 26:91–104
Tew KD, Monks A, Barone L, Rosser D, Akerman G, Montali JA, Wheatley JB, Schmidt DE (1996) Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. Mol Pharmacol 50:149–159
Acknowledgments
This work was supported in part by funds from the ISS-NIH and from ISS-Italian Ministry of Health research projects in Oncology. We thank Maura Cianfriglia for proofreading the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ascione, A., Cianfriglia, M., Dupuis, M.L. et al. The glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol overcomes the MDR1-P-glycoprotein and MRP1-mediated multidrug resistance in acute myeloid leukemia cells. Cancer Chemother Pharmacol 64, 419–424 (2009). https://doi.org/10.1007/s00280-009-0960-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-009-0960-6