Source:http://linkedlifedata.com/resource/pubmed/id/10543887
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
21
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| pubmed:dateCreated |
1999-11-22
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| pubmed:abstractText |
A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10(7) SCC-38 cells, groups of 5 nu/nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-trans-retinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0. 05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RARalpha, RXRalpha, and RXRbeta were similar in the two cell lines, while RARbeta expression was higher in SCC-2 over SCC-38, and RARgamma expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Benzamides,
http://linkedlifedata.com/resource/pubmed/chemical/Bicyclo Compounds, Heterocyclic,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Retinoic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoid X Receptors,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoids,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor AP-1,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/retinoic acid receptor alpha,
http://linkedlifedata.com/resource/pubmed/chemical/retinoic acid receptor gamma
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| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
0022-2623
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| pubmed:author |
pubmed-author:BenbrookD MDM,
pubmed-author:BerlinK DKD,
pubmed-author:BrownC WCW,
pubmed-author:ClementFF,
pubmed-author:DharAA,
pubmed-author:FountainK RKR,
pubmed-author:GoldM AMA,
pubmed-author:HouckJ RJRJr,
pubmed-author:KlucikJJ,
pubmed-author:LiuSS,
pubmed-author:MadlerM MMM,
pubmed-author:PJ,
pubmed-author:SubramanianSS,
pubmed-author:WeerasekareG MGM,
pubmed-author:ZacheisDD
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| pubmed:issnType |
Print
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| pubmed:day |
21
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| pubmed:volume |
42
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
4434-45
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| pubmed:dateRevised |
2007-11-14
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| pubmed:meshHeading |
pubmed-meshheading:10543887-Animals,
pubmed-meshheading:10543887-Antineoplastic Agents,
pubmed-meshheading:10543887-Benzamides,
pubmed-meshheading:10543887-Bicyclo Compounds, Heterocyclic,
pubmed-meshheading:10543887-Carcinoma, Squamous Cell,
pubmed-meshheading:10543887-Cell Division,
pubmed-meshheading:10543887-Drug Screening Assays, Antitumor,
pubmed-meshheading:10543887-Head and Neck Neoplasms,
pubmed-meshheading:10543887-Humans,
pubmed-meshheading:10543887-Mice,
pubmed-meshheading:10543887-Mice, Nude,
pubmed-meshheading:10543887-Neoplasm Transplantation,
pubmed-meshheading:10543887-Receptors, Retinoic Acid,
pubmed-meshheading:10543887-Retinoid X Receptors,
pubmed-meshheading:10543887-Retinoids,
pubmed-meshheading:10543887-Structure-Activity Relationship,
pubmed-meshheading:10543887-Transcription, Genetic,
pubmed-meshheading:10543887-Transcription Factor AP-1,
pubmed-meshheading:10543887-Transcription Factors,
pubmed-meshheading:10543887-Tumor Cells, Cultured
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| pubmed:year |
1999
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| pubmed:articleTitle |
Heteroarotinoids inhibit head and neck cancer cell lines in vitro and in vivo through both RAR and RXR retinoic acid receptors.
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| pubmed:affiliation |
Departments of Otorhinolaryngology, Obstetrics and Gynecology, and Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, Oklahoma 73190, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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