Inhibition of mercapturic acid pathway-mediated disposal of 4-hydroxynonenal causes complete and sustained remission of human cancer xenografts in nude mice

Sushil Kumar, Rutika A. Kokate, Mukesh Sahu, Pankaj Chaudhary, Rajendra Sharma, Sanjay Awasthi, Yogesh C. Awasthi

Research output: Contribution to journalReview article

4 Citations (Scopus)

Abstract

Environmental electrophilic chemical carcinogens are detoxified via mercapturic acid pathway to be excreted as mercapturic acid derivatives. Mercapturic acid pathway is also involved in the metabolism of pro-apoptotic and toxic endogenous electrophiles such as 4-hydroxynonenal (HNE). HNE is a common denominator in stress induced signaling and is a pro-apoptotic second messenger that affects cell cycle signaling in a concentration dependent manner. It can regulate signaling for apoptosis, differentiation, and gene expression by interacting with the transcriptional factors, transcriptional repressors, membrane receptors and other proteins. First two rate limiting enzymes of the mercapturic acid pathway, GSTs that conjugate HNE to glutathione (GSH), and RLIP76 that excludes GHS-HNE conjugate from cells, regulate the intracellular concentration of HNE. Thus GSTs and RLIP76 can have a profound effect on cell cycle signaling. Our studies have established that increased HNE levels in cells promote apoptotic signaling while at decreased levels below its basal constituted levels HNE promote proliferation. A major outcome of these findings is that by blocking the mercapturic acid pathway mediated detoxification of HNE through the inhibition of RLIP76 catalyzed transport of GS-HNE, a complete remission of many human cancer xenografts in mice can be achieved.

Original languageEnglish
Pages (from-to)817-825
Number of pages9
JournalIndian Journal of Experimental Biology
Volume49
Issue number11
StatePublished - 1 Nov 2011

Fingerprint

Acetylcysteine
Heterografts
Nude Mice
Neoplasms
Cell Cycle
4-hydroxy-2-nonenal
Poisons
Second Messenger Systems
Carcinogens
Glutathione
Apoptosis
Gene Expression
Membranes
Enzymes

Keywords

  • 4-Hydroxynonenal
  • Cancer
  • Chemo-prevention
  • Glutathione S-transferase
  • Mercapturic acid pathway
  • RLIP76,Xenobiotics

Cite this

Kumar, Sushil ; Kokate, Rutika A. ; Sahu, Mukesh ; Chaudhary, Pankaj ; Sharma, Rajendra ; Awasthi, Sanjay ; Awasthi, Yogesh C. / Inhibition of mercapturic acid pathway-mediated disposal of 4-hydroxynonenal causes complete and sustained remission of human cancer xenografts in nude mice. In: Indian Journal of Experimental Biology. 2011 ; Vol. 49, No. 11. pp. 817-825.
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Inhibition of mercapturic acid pathway-mediated disposal of 4-hydroxynonenal causes complete and sustained remission of human cancer xenografts in nude mice. / Kumar, Sushil; Kokate, Rutika A.; Sahu, Mukesh; Chaudhary, Pankaj; Sharma, Rajendra; Awasthi, Sanjay; Awasthi, Yogesh C.

In: Indian Journal of Experimental Biology, Vol. 49, No. 11, 01.11.2011, p. 817-825.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Inhibition of mercapturic acid pathway-mediated disposal of 4-hydroxynonenal causes complete and sustained remission of human cancer xenografts in nude mice

AU - Kumar, Sushil

AU - Kokate, Rutika A.

AU - Sahu, Mukesh

AU - Chaudhary, Pankaj

AU - Sharma, Rajendra

AU - Awasthi, Sanjay

AU - Awasthi, Yogesh C.

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AB - Environmental electrophilic chemical carcinogens are detoxified via mercapturic acid pathway to be excreted as mercapturic acid derivatives. Mercapturic acid pathway is also involved in the metabolism of pro-apoptotic and toxic endogenous electrophiles such as 4-hydroxynonenal (HNE). HNE is a common denominator in stress induced signaling and is a pro-apoptotic second messenger that affects cell cycle signaling in a concentration dependent manner. It can regulate signaling for apoptosis, differentiation, and gene expression by interacting with the transcriptional factors, transcriptional repressors, membrane receptors and other proteins. First two rate limiting enzymes of the mercapturic acid pathway, GSTs that conjugate HNE to glutathione (GSH), and RLIP76 that excludes GHS-HNE conjugate from cells, regulate the intracellular concentration of HNE. Thus GSTs and RLIP76 can have a profound effect on cell cycle signaling. Our studies have established that increased HNE levels in cells promote apoptotic signaling while at decreased levels below its basal constituted levels HNE promote proliferation. A major outcome of these findings is that by blocking the mercapturic acid pathway mediated detoxification of HNE through the inhibition of RLIP76 catalyzed transport of GS-HNE, a complete remission of many human cancer xenografts in mice can be achieved.

KW - 4-Hydroxynonenal

KW - Cancer

KW - Chemo-prevention

KW - Glutathione S-transferase

KW - Mercapturic acid pathway

KW - RLIP76,Xenobiotics

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