摘要
过氧化物酶体增殖物激活受体(PPARγ)是一种配体激活的核激素受体功能的转录因子,在脂质代谢和与胰岛素增敏中发挥重要的作用,最近的研究表明,PPARγ在许多类型的肿瘤中过度表达,包括乳腺癌、肺癌、胰腺癌、结肠癌、前列腺癌和胶质母细胞瘤,甲状腺分化/未分化癌,这些数据表明PPARγ在肿瘤发生和/或发展中的作用。PPARγ作为一种新兴的增长极限和促分化因子,具有肿瘤抑制作用。 此外,天然的和合成的PPARγ激动剂促进生长抑制和凋亡。噻唑烷二酮类药物(TZDs)被开发用于治疗II型糖尿病的PPARγ合成激动剂。这些化合物也显示出主要表现为独立的PPARγ激动剂活性的抗癌作用。各种临床前和临床研究表明TZDs单独或组合现有的化疗药物,用于治疗癌症。 诱导分化治疗包括诱导分化细胞失去其能力,即癌细胞,靶向性重新激活终末分化程序的途径,PPARγ 激动剂已被证明可以诱导实体肿瘤如甲状腺分化/未分化癌和肉瘤的分化。 然而,新的数据表明,TZDs长期使用与心血管不良事件的风险增加相关。PPARγ激动剂的新探索能帮助揭开这些药物的作用机制,提供新的分子式。
关键词: 过氧化物酶体增殖物激活受体-γ;噻唑烷二酮类;;PPARγ激动剂;抗肿瘤作用;甲状腺癌;分化型甲状腺癌;甲状腺未分化癌;
Current Medicinal Chemistry
Title:Antineoplastic Effects of PPARγ Agonists, with a Special Focus on Thyroid Cancer
Volume: 23 Issue: 7
Author(s): Silvia Martina Ferrari, Gabriele Materazzi, Enke Baldini, Salvatore Ulisse, Paolo Miccoli, Alessandro Antonelli and Poupak Fallahi
Affiliation:
关键词: 过氧化物酶体增殖物激活受体-γ;噻唑烷二酮类;;PPARγ激动剂;抗肿瘤作用;甲状腺癌;分化型甲状腺癌;甲状腺未分化癌;
摘要: Peroxisome Proliferator-Activated Receptor-γ (PPARγ) is a ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in lipid metabolism and insulin sensitization. Recent studies have shown that PPARγ is overexpressed in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma, prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPARγ in tumor development and/or progression. PPARγ is emerging as a growth-limiting and differentiation-promoting factor, and it exerts a tumor suppressor role.
Moreover, naturally-occurring and synthetic PPARγ agonists promote growth inhibition and apoptosis. Thiazolidinediones (TZDs) are synthetic agonists of PPARγ that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPARγ agonist activity. Various preclinical and clinical studies strongly suggest a role for TZDs both alone and in combination with existing chemotherapeutic agents, for the treatment of cancer.
Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells, targeting pathways capable of re-activating blocked terminal differentiation programs. PPARγ agonists have been shown to induce differentiation in solid tumors such as thyroid differentiated/ anaplastic cancers and sarcomas.
However, emerging data suggest that chronic use of TZDs is associated with increased risk of adverse cardiovascular events. The exploration of newer PPARγ agonists can help in unveiling the underlying mechanisms of these drugs, providing new molecules that are able to treat cancer, without increasing the cardiovascular risk of neoplastic patients.
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Silvia Martina Ferrari, Gabriele Materazzi, Enke Baldini, Salvatore Ulisse, Paolo Miccoli, Alessandro Antonelli and Poupak Fallahi , Antineoplastic Effects of PPARγ Agonists, with a Special Focus on Thyroid Cancer, Current Medicinal Chemistry 2016; 23 (7) . https://dx.doi.org/10.2174/0929867323666160203114607
DOI https://dx.doi.org/10.2174/0929867323666160203114607 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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