Abstract
Almost all heat shock protein 90 inhibitors reported so far, which are natural product derivatives, have problems mainly with toxic side effects, and with bioavailability and solubility. In our earlier studies, we compared the steric conformational structures of substance P[6-11] with our substance P antagonists in silico, and used the diverse biological effects of these compounds as tools in our modeling and design studies for discovering antiproliferative drugs. Here, we present a new synthesized short peptide-derivative compound family that inhibits only the function of the tumor cell's heat shock protein 90 and selectively kills in vitro more cancer cells than normal cells. During the lead generation, we observed that the difference between the most effective inhibitors was only one residue or group that caused diverse effects in vitro on the studied cell lines. According to our in vivo experiments on nude mice bearing lung cancer xenografts, the inhibitors restrained tumor growth, but not caused overt toxicity. We undertook NMR spectroscopy studies to analyze the 3D molecular structural differences of our inhibitors that control their binding to the target molecule. In conclusion, we demonstrated the efficacy of new selective and small molecule anticancerogen heat shock protein 90 inhibitors with peptide nature, without in vivo toxicity on nude mouse xenograft model. Our results also shed light on the mechanism of anticancerogen action of some substance P antagonists and their derivatives.
| Original language | English |
|---|---|
| Pages (from-to) | 1352-1362 |
| Number of pages | 11 |
| Journal | International Journal of Biochemistry and Cell Biology |
| Volume | 38 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2006 |
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Keywords
- 3D molecular structure
- Anticancerogen
- Hsp90 inhibitor
- Peptide-derivative
- Selective activity
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
Cite this
Novel nontoxic heat shock protein 90 inhibitors having selective antiproliferative effect. / Orosz, Antal; Szabo, Andrea; Szeman, Gabriella; Janáky, T.; Somlai, C.; Penke, B.; Bodor, A.; Perczel, A.
In: International Journal of Biochemistry and Cell Biology, Vol. 38, No. 8, 2006, p. 1352-1362.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel nontoxic heat shock protein 90 inhibitors having selective antiproliferative effect
AU - Orosz, Antal
AU - Szabo, Andrea
AU - Szeman, Gabriella
AU - Janáky, T.
AU - Somlai, C.
AU - Penke, B.
AU - Bodor, A.
AU - Perczel, A.
PY - 2006
Y1 - 2006
N2 - Almost all heat shock protein 90 inhibitors reported so far, which are natural product derivatives, have problems mainly with toxic side effects, and with bioavailability and solubility. In our earlier studies, we compared the steric conformational structures of substance P[6-11] with our substance P antagonists in silico, and used the diverse biological effects of these compounds as tools in our modeling and design studies for discovering antiproliferative drugs. Here, we present a new synthesized short peptide-derivative compound family that inhibits only the function of the tumor cell's heat shock protein 90 and selectively kills in vitro more cancer cells than normal cells. During the lead generation, we observed that the difference between the most effective inhibitors was only one residue or group that caused diverse effects in vitro on the studied cell lines. According to our in vivo experiments on nude mice bearing lung cancer xenografts, the inhibitors restrained tumor growth, but not caused overt toxicity. We undertook NMR spectroscopy studies to analyze the 3D molecular structural differences of our inhibitors that control their binding to the target molecule. In conclusion, we demonstrated the efficacy of new selective and small molecule anticancerogen heat shock protein 90 inhibitors with peptide nature, without in vivo toxicity on nude mouse xenograft model. Our results also shed light on the mechanism of anticancerogen action of some substance P antagonists and their derivatives.
AB - Almost all heat shock protein 90 inhibitors reported so far, which are natural product derivatives, have problems mainly with toxic side effects, and with bioavailability and solubility. In our earlier studies, we compared the steric conformational structures of substance P[6-11] with our substance P antagonists in silico, and used the diverse biological effects of these compounds as tools in our modeling and design studies for discovering antiproliferative drugs. Here, we present a new synthesized short peptide-derivative compound family that inhibits only the function of the tumor cell's heat shock protein 90 and selectively kills in vitro more cancer cells than normal cells. During the lead generation, we observed that the difference between the most effective inhibitors was only one residue or group that caused diverse effects in vitro on the studied cell lines. According to our in vivo experiments on nude mice bearing lung cancer xenografts, the inhibitors restrained tumor growth, but not caused overt toxicity. We undertook NMR spectroscopy studies to analyze the 3D molecular structural differences of our inhibitors that control their binding to the target molecule. In conclusion, we demonstrated the efficacy of new selective and small molecule anticancerogen heat shock protein 90 inhibitors with peptide nature, without in vivo toxicity on nude mouse xenograft model. Our results also shed light on the mechanism of anticancerogen action of some substance P antagonists and their derivatives.
KW - 3D molecular structure
KW - Anticancerogen
KW - Hsp90 inhibitor
KW - Peptide-derivative
KW - Selective activity
UR - http://www.scopus.com/inward/record.url?scp=33646190049&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646190049&partnerID=8YFLogxK
U2 - 10.1016/j.biocel.2006.01.015
DO - 10.1016/j.biocel.2006.01.015
M3 - Article
C2 - 16540363
AN - SCOPUS:33646190049
VL - 38
SP - 1352
EP - 1362
JO - International Journal of Biochemistry and Cell Biology
JF - International Journal of Biochemistry and Cell Biology
SN - 1357-2725
IS - 8
ER -