Université de Toulouse, Université Paul Sabatier Toulouse, France.
Front Endocrinol (Lausanne). 2013 Apr 29;4:50. doi: 10.3389/fendo.2013.00050. eCollection 2013.
G protein-coupled receptors (GPCRs) constitute a large family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and cellular responses. GPCR are involved in a wide variety of physiological processes, including in the neuroendocrine system. GPCR are also involved in many diseases and are the target of 30% of marketed medicinal drugs. Whereas the majority of the GPCR-targeting drugs have proved their therapeutic benefit, some of them were associated with undesired effects. We develop two examples of used drugs whose therapeutic benefits are tarnished by carcinogenesis risks. The chronic administration of glucagon-like peptide-1 (GLP-1) analogs widely used to treat type-2 diabetes was associated with an increased risk of pancreatic or thyroid cancers. The long-term treatment with the estrogen antagonist tamoxifen, developed to target breast cancer overexpressing estrogen receptors ER, presents agonist activity on the G protein-coupled estrogen receptor which is associated with an increased incidence of endometrial cancer and breast cancer resistance to hormonotherapy. We point out and discuss the need of pharmacological studies to understand and overcome the undesired effects associated with the chronic administration of GPCR ligands. In fact, biological effects triggered by GPCR often result from the activation of multiple intracellular signaling pathways. Deciphering which signaling networks are engaged following GPCR activation appears to be primordial to unveil their contribution in the physiological and physiopathological processes. The development of biased agonists to elucidate the role of the different signaling mechanisms mediated by GPCR activation will allow the generation of new therapeutic agents with improved efficacy and reduced side effects. In this regard, the identification of GLP-1R biased ligands promoting insulin secretion without inducing pro-tumoral effects would offer therapeutic benefit.
G 蛋白偶联受体（GPCR）是一大类受体家族，它们能够感知细胞外的分子，并激活细胞内的信号转导途径和细胞反应。GPCR 参与了广泛的生理过程，包括神经内分泌系统。GPCR 也与许多疾病有关，是 30%上市药物的靶点。虽然大多数针对 GPCR 的药物已经证明了它们的治疗益处，但其中一些药物与不良作用有关。我们举出两个已使用药物的例子，它们的治疗益处因致癌风险而受到损害。广泛用于治疗 2 型糖尿病的胰高血糖素样肽-1（GLP-1）类似物的长期给药与胰腺或甲状腺癌的风险增加有关。长期使用雌激素拮抗剂他莫昔芬治疗雌激素受体 ER 过表达的乳腺癌，表现出对 G 蛋白偶联雌激素受体的激动活性，这与子宫内膜癌和乳腺癌对激素治疗的耐药性增加有关。我们指出并讨论了进行药理学研究的必要性，以了解和克服与 GPCR 配体的慢性给药相关的不良作用。事实上，GPCR 触发的生物学效应通常源于多种细胞内信号通路的激活。阐明 GPCR 激活后哪些信号网络被激活似乎对于揭示它们在生理和病理生理过程中的贡献至关重要。开发偏向激动剂以阐明 GPCR 激活介导的不同信号机制的作用将允许生成具有改善疗效和降低副作用的新型治疗剂。在这方面，确定促进胰岛素分泌而不诱导促肿瘤作用的 GLP-1R 偏向配体将提供治疗益处。
