Applied Sciences Department, Faculty of Engineering Technology, Al-Balqa Applied University, Amman 11134, Jordan.
Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa 13115, Jordan; Department of Genetics, University of Szeged, H-6720 Szeged, Hungary.
Steroids. 2020 Jun;158:108602. doi: 10.1016/j.steroids.2020.108602. Epub 2020 Feb 22.
Cephalostatin 1, a potent anti-cancer agent, is a natural bis-steroidal alkaloid that causes cell death in the subnanomolar to picomolar ranges via an atypical apoptosis pathway. Although cephalostatin 1 is a highly effective anticancer drug, its availability limits its utilization. We previously reported the synthesis of two 12'α-hydroxy derivatives of cephalostatin 1 that induce cell death by activating the ER stress apoptosis signaling pathway. For the current work, we synthesized six C-functionalized cephalostatin 1 analogues (CAs) to evaluate their biological activity. For the cytotoxic compounds, the induced apoptotic pathway was investigated. The C-functionalized cephalostatin 1 analogues 5 and 6 (CA5 and CA6) were found to exhibit cytotoxic activity against K-562 leukemia cells, MCF-7 breast cancer cells and DU-145 prostate cancer cells, while the remaining four analogues did not show anti-tumor activities against any of the cell lines. Our results indicated that CA5 and CA6 induced cell death via the atypical ER-dependent apoptosis pathway; they increased the expression of Smac/DIABLO, an inhibitor of inhibitors of apoptosis (IAPs), which in turn facilitated the activation of different caspases including the ER-caspase 4 without cytochrome c release from mitochondria. CA5 and CA6 are promising anticancer agents due to their low GI, the remarkable apoptosis pathway they induce which can overcome chemoresistance, and their very low toxicity to normal cells making them cephalostatin 1 utilizable alternatives.
头抱斯他汀 1 是一种强效的抗癌剂，是一种天然的双甾体生物碱，通过一种非典型的细胞凋亡途径，在亚纳摩尔到皮摩尔范围内引起细胞死亡。尽管头抱斯他汀 1 是一种非常有效的抗癌药物，但由于其可用性有限，限制了它的利用。我们之前报道了两种 12'α-羟基头抱斯他汀 1 的合成，它们通过激活内质网应激凋亡信号通路诱导细胞死亡。在目前的工作中，我们合成了六个 C-功能化头抱斯他汀 1 类似物（CAs）来评估它们的生物学活性。对于细胞毒性化合物，研究了诱导凋亡的途径。C-功能化头抱斯他汀 1 类似物 5 和 6（CA5 和 CA6）被发现对 K-562 白血病细胞、MCF-7 乳腺癌细胞和 DU-145 前列腺癌细胞具有细胞毒性活性，而其余四个类似物对任何细胞系均无抗肿瘤活性。我们的结果表明，CA5 和 CA6 通过非典型的内质网依赖性细胞凋亡途径诱导细胞死亡；它们增加了 Smac/DIABLO 的表达，Smac/DIABLO 是凋亡抑制剂（IAPs）的抑制剂，这反过来又促进了不同半胱天冬酶的激活，包括内质网半胱天冬酶 4，而没有线粒体细胞色素 c 的释放。CA5 和 CA6 是很有前途的抗癌药物，因为它们的 GI 低，诱导的显著凋亡途径可以克服化疗耐药性，而且对正常细胞的毒性非常低，使它们成为头抱斯他汀 1 的可替代物。
