Markatos Christos, Biniari Georgia, Karageorgos Vlasios, Chepurny Oleg G, Venihaki Maria, Holz George G, Tselios Theodore, Liapakis George
Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Greece.
Department of Chemistry, University of Patras, 26504 Rion, Greece.
Curr Mol Pharmacol. 2024;17:e18761429343090. doi: 10.2174/0118761429343090250121052955.
Endometrial cancer is one of the most common gynecological malignancies. Endometrial cancer cells express the gonadotropin-releasing hormone (GnRH) and its receptor (GnRH-R). Among the various therapeutic approaches for the treatment of endometrial cancer is the use of GnRH conjugates, such as the AN-152, created by linking the [D-Lys6] GnRH with the cytotoxic doxorubicin through an ester bond. An undesirable property of these conjugates is their vulnerability to plasma carboxylesterases, which cleave the ester bond to release doxorubicin before reaching the cancer cells.
To overcome this problem, we recently developed the Con-3 and Con-7, which are GnRH analogs conjugated through a disulfide bond with the cytotoxic mitoxantrone. In this study, we determined the cytotoxic properties of the Con-3 and Con-7 on the Ishikawa endometrial cancer cells, assuming that their interaction with the GnRH-R of cells exposes the conjugated mitoxantrone to the cellular thioredoxin. The cellular thioredoxin reduces the disulfide bond of Con-3 & Con-7 to release mitoxantrone, which accumulates in the cancer cells and exerts its cytotoxic actions.
Indeed, treatment of Ishikawa cells with Con-3, Con-7, or the free unconjugated mitoxantrone increased their apoptosis and decreased their proliferation in a dose- and time-dependent manner, displaying half-maximal inhibitory concentrations (IC50) of 0.64 - 1.15 μM. In specific, the IC50 values on days 2, 3, and 4 were 1.45, 0.64, and 0.83 μΜ, respectively, for Con-3, 0.91, 0.82 μΜ, and 1.00 μΜ, respectively for Con-7 and 1.15, 0.98, 0.78 μM, respectively for mitoxantrone.
In contrast, the free, mitoxantrone-unconjugated peptides did not affect the proliferation of Ishikawa cells. The Con-3 and Con-7 could put the basis for the development of a new class of anticancer drugs for endometrial cancer, which will act as "prodrugs" that deliver the cytotoxic mitoxantrone in a GnRH-R-specific manner.
子宫内膜癌是最常见的妇科恶性肿瘤之一。子宫内膜癌细胞表达促性腺激素释放激素（GnRH）及其受体（GnRH-R）。治疗子宫内膜癌的各种方法中包括使用GnRH偶联物，例如AN-152，它是通过酯键将[D-Lys6]GnRH与细胞毒性药物阿霉素连接而成。这些偶联物的一个不良特性是它们易受血浆羧酸酯酶的作用，该酶会裂解酯键，在到达癌细胞之前释放出阿霉素。
为克服这一问题，我们最近开发了Con-3和Con-7，它们是通过二硫键与细胞毒性药物米托蒽醌偶联的GnRH类似物。在本研究中，我们测定了Con-3和Con-7对石川子宫内膜癌细胞的细胞毒性特性，假定它们与细胞的GnRH-R相互作用会使偶联的米托蒽醌暴露于细胞硫氧还蛋白。细胞硫氧还蛋白会还原Con-3和Con-7的二硫键以释放米托蒽醌，米托蒽醌在癌细胞中蓄积并发挥其细胞毒性作用。
确实，用Con-3、Con-7或游离的未偶联米托蒽醌处理石川细胞会以剂量和时间依赖性方式增加其凋亡并降低其增殖，半数最大抑制浓度（IC50）为0.64 - 1.15μM。具体而言，Con-3在第2、3和4天的IC50值分别为1.45、0.64和0.83μM，Con-7分别为0.91、0.82μM和1.00μM，米托蒽醌分别为1.15、0.98和0.78μM。
相比之下，游离的、未偶联米托蒽醌的肽对石川细胞的增殖没有影响。Con-3和Con-7可为开发一类新型子宫内膜癌抗癌药物奠定基础，这类药物将作为“前药”以GnRH-R特异性方式递送细胞毒性米托蒽醌。
