Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression
| Autor: | Michele M Loi, Vibha Sharma, Umarani Pugazhenthi, Bryan R. Haugen, Sherif Said, Andrew Berenz, Joshua P. Klopper, William R. Hays |
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| Jazyk: | angličtina |
| Předmět: |
Agonist
Cancer Research Tetrahydronaphthalenes medicine.drug_class Receptor expression Receptors Cytoplasmic and Nuclear Retinoid X receptor Pharmacology Biology Ligands Benzoates lcsh:RC254-282 Rosiglitazone Mice Retinoids 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Retinoid RNA Small Interfering Thiazolidinedione Receptor Melanoma Cell Proliferation 030304 developmental biology 0303 health sciences Research lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Xenograft Model Antitumor Assays 3. Good health PPAR gamma Retinoid X Receptors Nuclear receptor Oncology Bexarotene Drug Resistance Neoplasm 030220 oncology & carcinogenesis Molecular Medicine Thiazolidinediones medicine.drug |
| Zdroj: | Molecular Cancer, Vol 8, Iss 1, p 16 (2009) Molecular Cancer |
| ISSN: | 1476-4598 |
| DOI: | 10.1186/1476-4598-8-16 |
| Popis: | Background Metastatic melanoma has a high mortality rate and suboptimal therapeutic options. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid × receptor selective agonist, and thiazolidinediones (TZD), PPARγ selective ligands, as novel treatments. Results Mouse xenograft models with human melanoma cell lines [A375(DRO) or M14(5–16)] were treated for 4 weeks with daily vehicle, RXR agonist (rexinoid, LGD1069, 30 mg/kg/d), PPARγ agonist (TZD, rosiglitazone, 10 mg/kg/d) or combination. A375(DRO) tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect. M14(5–16) tumors only responded to LGD1069 100 mg/kg/day. A375(DRO) sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARγ expression but preserved RXR expression. shRNA knockdown of PPARγ or RXRγ attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO) cells. Rexinoid (LGD1069) and retinoid (TTNPB) treatment of M14(5–16) cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRγ resulted in a decreased response to either ligand. Conclusion A375 (DRO) melanoma cell growth is inhibited by rexinoid and TZD treatment, and this response is dependent on RXR and PPARγ receptor expression. M14 (5–16) melanoma cell growth is inhibited by rexinoid and retinoid treatment, and this response is dependent on RXR expression. These findings may help guide molecular-based treatment strategies in melanoma and provide insight for mechanisms of resistance to nuclear receptor targeted therapies in certain cancers. |
| Databáze: | OpenAIRE |
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