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Cellular resistance to a nitric oxide releasing glutathione S-transferase P-activated prodrug, PABA/NO.

Abstract
PABA/NO is a diazeniumdiolate selectively activated by glutathione S-transferase P (GSTP) to release nitric oxide (NO) and is a potent inducer of protein S-glutathionylation, a redox-sensitive post-translational modification of cysteine residues. Using a procedure that incrementally increased exposure of cells to PABA/NO, an acquired drug resistant human promyelocytic leukemia HL60 cell line (HL60(PABA)) that exhibited 1.9-fold resistance to the drug (IC(50) 15 μM vs ~8 μM for wild-type) was created. HL60(PABA) cells had a decreased growth rate attributable to altered cellular differentiation, as measured by increased expression of CD11b; decreased expression of CD14; decreased nuclear to cytoplasmic ratios and a condensation of nuclear chromatin. This was accompanied by alterations in both plasma and mitochondrial membrane potentials. Both GSTP expression and nitric oxide release were reduced two-fold, while increased expression levels of genes involved in the unfolded protein response (UPR) were evident in HL60(PABA) cells. Wild type cells treated with PABA/NO had increased levels of protein S-glutathionylation and JNK activation, while JNK was constitutively active in HL60(PABA) cells and these cells had reduced levels of S-glutathionylation. By removing PABA/NO from the growth medium, HL60(PABA) cells reverted to sensitivity within 21 days suggesting that resistance was not genetically stable. Mechanistically, PABA/NO resistance is mediated through reduced levels of GSTP resulting in reduced NO release and its subsequent alterations in cellular response to nitrosative stress.
AuthorsSteven Hutchens, Yefim Manevich, Lin He, Kenneth D Tew, Danyelle M Townsend
JournalInvestigational new drugs (Invest New Drugs) Vol. 29 Issue 5 Pg. 719-29 (Oct 2011) ISSN: 1573-0646 [Electronic] United States
PMID20232108 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Azo Compounds
  • O(2)-(2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate
  • Prodrugs
  • para-Aminobenzoates
  • Nitric Oxide
  • Glutathione Transferase
  • JNK Mitogen-Activated Protein Kinases
  • Glutathione
  • 4-Aminobenzoic Acid
Topics
  • 4-Aminobenzoic Acid (chemistry, pharmacology)
  • Azo Compounds (chemistry, pharmacology)
  • Cell Death (drug effects)
  • Cell Differentiation (drug effects)
  • Cell Proliferation (drug effects)
  • Cell Shape (drug effects)
  • Cell Survival (drug effects)
  • Drug Resistance, Neoplasm (drug effects)
  • Glutathione (metabolism)
  • Glutathione Transferase (metabolism)
  • HL-60 Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Membrane Potential, Mitochondrial (drug effects)
  • Nitric Oxide (metabolism)
  • Prodrugs (chemistry, pharmacology)
  • Unfolded Protein Response (drug effects, genetics)
  • para-Aminobenzoates

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