Institute of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Hungary.
Department of Inorganic, Organic and Analytical Chemistry, University of Szeged, H-6720 Szeged, Hungary.
Int J Mol Sci. 2023 Apr 1;24(7):6625. doi: 10.3390/ijms24076625.
Cervical carcinoma is one of the most frequent malignant gynecological cancers in women of reproductive age. Because of the poor tolerability of currently available chemotherapeutic agents, efforts have been focused on developing innovative molecules, including steroids, that exert antineoplastic effects with a better safety profile. In addition to their endocrine properties, certain estrogens exhibit additional biological activities, such as antiangiogenic and anticancer effects. Based on previous studies, the antineoplastic properties of 13α-estrone sulfamate derivatives (13AES1-3) were investigated, and the mechanism of action for the most promising compound 13AES3 was explored. Based on their effects on the viability of different human adherent gynecological cancer cells, the SiHa cervical cell line was used for mechanistic experiments. The most active analog 13AES3 was shown to exert considerable proapoptotic effects, as evidenced by a colorimetric caspase-3 assay and fluorescent double staining. It also elicited antimigratory and anti-invasive effects in a concentration-dependent manner, as evidenced by wound healing and Boyden chamber assays, respectively. Regarding their mechanism of action, 13AES derivatives were shown to inhibit tubulin polymerization, and computer simulations provided a possible explanation for the importance of the presence of the chlorophenyl ring on the estrane skeleton. 13AES3 is considered to be the first 13α-estrone derivative with a significant antineoplastic potency against SiHa cancer cells. Therefore, it might serve as a valuable lead molecule for the design of anticancer agents targeting cervical carcinomas.
宫颈癌是生育年龄妇女最常见的妇科恶性肿瘤之一。由于目前可用的化疗药物耐受性差，因此人们致力于开发创新分子，包括甾体，以具有更好的安全性特征发挥抗肿瘤作用。除了它们的内分泌特性外，某些雌激素还具有其他生物学活性，如抗血管生成和抗癌作用。基于先前的研究，研究了 13α-雌酮磺酸盐衍生物（13AES1-3）的抗肿瘤特性，并探索了最有前途的化合物 13AES3 的作用机制。基于它们对不同人贴壁妇科癌细胞活力的影响，使用 SiHa 宫颈细胞系进行了机制实验。最活跃的类似物 13AES3 表现出相当大的促凋亡作用，这一点通过比色法 caspase-3 测定和荧光双重染色得到证明。它还以浓度依赖性方式表现出抗迁移和抗侵袭作用，分别通过划痕愈合和 Boyden 室测定证明。关于它们的作用机制，13AES 衍生物被证明抑制微管聚合，并且计算机模拟为雌烷骨架上存在氯苯基环的重要性提供了可能的解释。13AES3 被认为是第一个对 SiHa 癌细胞具有显著抗肿瘤活性的 13α-雌酮衍生物。因此，它可能成为针对宫颈癌的抗癌药物设计的有价值的先导分子。
