Nitric oxide prodrugs and metallochemotherapeutics: JS-K and CB-3-100 enhance arsenic and cisplatin cytolethality by increasing cellular accumulation

Jie Liu, Chengxiu Li, Wei Qu, Elaine Leslie, Challice Bonifant, Gregory S. Buzard, Joseph E. Saavedra, Larry K. Keefer, Michael P. Waalkes

Research output: Contribution to journalArticle

Abstract

Development of chemotherapeutic resistance is a major cause of pharmacologic failure in cancer treatment. One mechanism of resistance in tumor cells is the overexpression of glutathione S-transferases (GSTs) that serve two distinct roles in the development of drug resistance via the formation of glutathione conjugates with drugs for their cellular efflux, and the inhibition of the mitogen-activated protein kinase pathway. To target GST-based resistance to chemotherapeutics, a series of nitric oxide (NO)-releasing diazeniumdiolates was synthesized and shown to release NO on reaction with GST and/or glutathione. Two diazeniumdiolates, JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate], and CB-3-100 [O2-(2,4-dinitrophenyl) 1-[4-(NN-diethylcarboxamido)piperazin-1-yl]diazen-1-ium-1,2-diolate], were studied on their ability in reversing arsenic and cisplatin resistance in a rat liver cell line that is tumorigenic and shows acquired tolerance to arsenic and cisplatin, with overexpression of GSTs. The enhanced cytolethality produced by the NO donors was accompanied by increased accumulation of arsenic and platinum within cells and by enhanced activation of mitogen-activated protein kinase members c-jun-NH-kinase and extracellular signal-regulated kinase. Our data indicate that JS-K and CB-3-100 are promising lead compounds for the possible development of a novel class of adjuvant chemotherapeutic agents potentially capable of reversing arsenic and cisplatin resistance in certain tumor cells.

Original languageEnglish (US)
Pages (from-to)709-714
Number of pages6
JournalMolecular cancer therapeutics
Volume3
Issue number6
StatePublished - Jun 1 2004
Externally publishedYes

Fingerprint

Prodrugs
Arsenic
Glutathione Transferase
Cisplatin
Nitric Oxide
Mitogen-Activated Protein Kinases
Glutathione
Neoplasms
Nitric Oxide Donors
Extracellular Signal-Regulated MAP Kinases
Platinum
Drug Resistance
Phosphotransferases
Cell Line
O(2)-(2,4-dinitrophenyl) 1-(4-(N,N-diethylcarboxamido)piperazin-1-yl)diazen-1-ium 1,2-diolate
Liver
Pharmaceutical Preparations
diazeniumdiolate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nitric oxide prodrugs and metallochemotherapeutics : JS-K and CB-3-100 enhance arsenic and cisplatin cytolethality by increasing cellular accumulation. / Liu, Jie; Li, Chengxiu; Qu, Wei; Leslie, Elaine; Bonifant, Challice; Buzard, Gregory S.; Saavedra, Joseph E.; Keefer, Larry K.; Waalkes, Michael P.

In: Molecular cancer therapeutics, Vol. 3, No. 6, 01.06.2004, p. 709-714.

Research output: Contribution to journalArticle

Liu, Jie ; Li, Chengxiu ; Qu, Wei ; Leslie, Elaine ; Bonifant, Challice ; Buzard, Gregory S. ; Saavedra, Joseph E. ; Keefer, Larry K. ; Waalkes, Michael P. / Nitric oxide prodrugs and metallochemotherapeutics : JS-K and CB-3-100 enhance arsenic and cisplatin cytolethality by increasing cellular accumulation. In: Molecular cancer therapeutics. 2004 ; Vol. 3, No. 6. pp. 709-714.
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