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Indian Journal of Experimental Biology (IJEB) >
IJEB Vol.49 [2011] >
IJEB Vol.49(11) [November 2011] >
| Title: | Inhibition of mercapturic acid pathway-mediated disposal of 4-hydroxynonenal causes complete and sustained remission of human cancer xenografts in nude mice |
| Authors: | Kumar, Sushil
Kokate, Rutika A
Sahu, Mukesh
Chaudhary, Pankaj
Sharma, Rajendra
Awasthi, Sanjay
Awasthi, Yogesh C |
| Keywords: | Cancer
Chemo-prevention
Glutathione S-transferase
4-Hydroxynonenal
Mercapturic acid pathway
RLIP76
Xenobiotics |
| Issue Date: | Nov-2011 |
| Publisher: | NISCAIR-CSIR, India |
| 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. |
| Page(s): | 817-825 |
| CC License: |  CC Attribution-Noncommercial-No Derivative Works 2.5 India |
| ISSN: | 0975-1009 (Online); 0019-5189 (Print) |
| Source: | IJEB Vol.49(11) [November 2011]
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