Klopper Joshua P, Sharma Vibha, Berenz Andrew, Hays William R, Loi Michele, Pugazhenthi Umarani, Said Sherif, Haugen Bryan R
Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Aurora, CO, USA.
Mol Cancer. 2009 Mar 6;8:16. doi: 10.1186/1476-4598-8-16.
Metastatic melanoma has a high mortality rate and suboptimal therapeutic options. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid x receptor selective agonist, and thiazolidinediones (TZD), PPARgamma selective ligands, as novel treatments.
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), PPARgamma 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 PPARgamma expression but preserved RXR expression. shRNA knockdown of PPARgamma or RXRgamma 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 RXRgamma resulted in a decreased response to either ligand.
A375 (DRO) melanoma cell growth is inhibited by rexinoid and TZD treatment, and this response is dependent on RXR and PPARgamma 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.
转移性黑色素瘤死亡率高且治疗选择欠佳。使用类视黄醇X受体选择性激动剂类视黄醛LGD1069和过氧化物酶体增殖物激活受体γ（PPARγ）选择性配体噻唑烷二酮（TZD）作为新型治疗方法进行分子靶向治疗可能有益。
用人黑色素瘤细胞系[A375（DRO）或M14（5 - 16）]建立的小鼠异种移植模型，分别每日给予溶媒、RXR激动剂（类视黄醛，LGD1069，30 mg/kg/天）、PPARγ激动剂（TZD，罗格列酮，10 mg/kg/天）或联合用药，治疗4周。单独使用任一配体均可显著抑制A375（DRO）肿瘤生长，联合用药具有相加作用。M14（5 - 16）肿瘤仅对100 mg/kg/天的LGD1069有反应。构建了对类视黄醛、TZD及联合用药耐药的A375（DRO）亚系，所有三个亚系的PPARγ表达均降低，但RXR表达保留。用短发夹RNA（shRNA）敲低PPARγ或RXRγ可减弱类视黄醛、TZD及联合配体介导的A375（DRO）细胞增殖减少。用类视黄醛（LGD1069）和视黄酸（TTNPB）处理M14（5 - 16）细胞导致增殖减少，类视黄醛和视黄酸联合使用具有相加作用。用shRNA敲低RXRγ导致对任一配体的反应减弱。
类视黄醛和TZD治疗可抑制A375（DRO）黑色素瘤细胞生长，且这种反应依赖于RXR和PPARγ受体表达。类视黄醛和视黄酸治疗可抑制M14（5 - 16）黑色素瘤细胞生长，且这种反应依赖于RXR表达。这些发现可能有助于指导黑色素瘤的分子靶向治疗策略，并为某些癌症中对核受体靶向治疗的耐药机制提供见解。
Zotero 插件
