Gonadotropin-releasing hormone (GnRH) analogs (e.g., triptorelin) are developed to treat hormone-dependent reproductive cancers. However, these analogs lack a significant direct antitumor activity to make them suitable for hormone-refractory reproductive cancers. In this study, we examined different biological properties of lipid-modified GnRH analogs, with/without D-amino acid substitution at position 6 in prostate and ovarian cancer cells. We revealed that the improved metabolic stability due to lipid-modification and D-amino acid substitution played a pivotal role in enhancing GnRH receptor-mediated direct antiproliferative activity up to 4.5-fold higher than triptorelin. Furthermore, a comparable FSH release and higher LH release activity in pituitary cells than triptorelin was observed, indicating an improved specificity and/or binding affinity to GnRH receptors. We confirmed the important role of sex steroids in the antitumor activity of the lipopeptides, which were contrasting in prostate and ovarian cancer cells. The superior activity of these GnRH analogs over commercial peptides renders promises for developing new GnRH receptor ligands to treat hormone-dependent and -refractory cancers, as well as emerging new targeting moieties for the delivery of anticancer agents in GnRH receptor-overexpressing cancers.

促性腺激素释放激素 (GnRH) 类似物（例如曲普瑞林）被开发用于治疗激素依赖性生殖癌症。然而，这些类似物缺乏显着的直接抗肿瘤活性，使其适用于激素难治性生殖癌症。在这项研究中，我们检查了脂质修饰的 GnRH 类似物的不同生物学特性，在前列腺和卵巢癌细胞的第 6 位有/没有 D-氨基酸取代。我们发现，由于脂质修饰和 D-氨基酸取代而改善的代谢稳定性在增强 GnRH 受体介导的直接抗增殖活性方面发挥了关键作用，该活性比曲普瑞林高 4.5 倍。此外，与曲普瑞林相比，在垂体细胞中观察到了相当的 FSH 释放和更高的 LH 释放活性，表明对 GnRH 受体的特异性和/或结合亲和力提高。我们证实了性类固醇在脂肽的抗肿瘤活性中的重要作用，这在前列腺癌细胞和卵巢癌细胞中形成对比。这些 GnRH 类似物优于商业肽的活性为开发新的 GnRH 受体配体以治疗激素依赖性和难治性癌症以及在 GnRH 受体过度表达的癌症中递送抗癌剂的新兴靶向部分提供了希望。