Biological Activity and Apoptotic Signaling Pathway of C11- Functionalized Cephalostatin 1 Analogues

Publication date: Available online 22 February 2020Source: SteroidsAuthor(s): Mansour M. Nawasreh, Elham I. Alzyoud, Zainab A. Al-Mazaydeh, Majdoleen S. Rammaha, Salim R. Yasin, Lubna H. TahtamouniAbstractCephalostatin 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 C11-functionalized cephalostatin 1 analogues (CAs) to evaluate their biological activity. For the cytotoxic compounds, the induced apoptotic pathway was investigated. The C11-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 mitoch...
Source: Steroids - Category: Drugs & Pharmacology Source Type: research