Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression.
Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression.
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DOI：
10.1186/1476-4598-8-16
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发表时间：
2009-03-06
期刊：
影响因子：
37.3
通讯作者：
Haugen BR
中科院分区：
文献类型：
--
作者：
Klopper JP;Sharma V;Berenz A;Hays WR;Loi M;Pugazhenthi U;Said S;Haugen BR
转移性黑色素瘤具有高死亡率和次优的治疗选择。使用rexinoid LGD 1069（一种类维生素A ×受体选择性激动剂）和噻唑烷二酮类（TZD）（一种PPARγ选择性配体）作为新的治疗方法，分子靶向可能是有益的。使用人黑色素瘤细胞系[A375（DRO）或M14（5-16）]的小鼠异种移植物模型，每天用溶剂、RXR激动剂（rexinoid，LGD 1069，30 mg/kg/d）、PPARγ激动剂（TZD，罗格列酮，10 mg/kg/d）或组合治疗4周。A375（DRO）肿瘤生长显着抑制任一配体单独和组合具有累加效应。M14（5-16）肿瘤仅对LGD 1069 100 mg/kg/天有反应。产生了对rexinoid、TZD和组合具有抗性的A375（DRO）亚系，并且所有三个亚系均具有降低的PPARγ表达，但保留了RXR表达。shRNA敲低PPARγ或RXRγ可减弱rexinoid、TZD和组合配体介导的A375（DRO）细胞增殖降低。Rexinoid（LGD 1069）和类维生素A（TTNPB）处理M14（5-16）细胞导致增殖降低，这与Rexinoid和类维生素A两者的组合相加。RXRγ的shRNA敲低导致对任一配体的应答降低。A375（DRO）黑色素瘤细胞生长受到rexinoid和TZD处理的抑制，并且这种反应依赖于RXR和PPARγ受体表达。M14（5-16）黑色素瘤细胞生长被rexinoid和retinoid处理抑制，并且该应答依赖于RXR表达。这些发现可能有助于指导黑色素瘤的分子治疗策略，并为某些癌症对核受体靶向治疗的耐药机制提供见解。
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. 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. 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.
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