Novel sorafenib-based structural analogues

Abstract

In the current study, we performed a mechanistic study on the cytotoxicity of two compounds, t-AUCMB and t-MTUCB, that are structurally similar to sorafenib. These compounds display strong cytotoxic responses in various cancer cell lines, despite significant differences in the induction of apoptotic events such as caspase activation and lactate dehydrogenase release in hepatoma cells. Both compounds induce autophagosome formation and LC3I cleavage, but there was little observable effect on mTORC1 or the downstream targets, S6K1 and 4E-BP1. In addition, there was an increase in activity of upstream signaling through the IRS1/PI3K/Akt signaling pathway, suggesting that unlike sorafenib, both compounds induce mTOR-independent autophagy. The observed autophagy correlates with mitochondrial membrane depolarization, AIF release, and oxidative stress-induced glutathione depletion. However, there were no observable changes in the ER-stress markers such as, Bip, IREα, p-eIP2, and the lipid peroxidation marker, 4-HNE, suggesting ER-independent oxidative stress. Finally, these compounds do not possess the multikinase inhibitory activity of sorafenib, which may be reflected in their difference in ability to halt cell cycle progression compared to sorafenib. Our findings indicate that both compounds have anti-cancer effects comparable to sorafenib in multiple cell line, but they induce significant differences in apoptotic responses and appear to induce mTOR-independent autophagy. t-AUCMB and t-MTUCB, represent novel chemical probes that are capable of inducing mTOR-independent autophagy and apoptosis to differing degrees, and thus may be potential tools for further understanding the link between these two cellular stress responses.

Modulation of Autophagy by Sorafenib: Effects on Treatment Response

“…Regorafenib, a structural analog of sorafenib, induces autophagosome formation in HCC cells similarly than sorafenib (Carr et al, 2013 ; Tavallai et al, 2015 ). In another study, two different sorafenib analogs, t-MTUCB and AUCMB, caused autophagosome formation and LC3 lipidation in various HCC cell lines (Wecksler et al, 2014 ). Finally, sc-59, a kinase-independent derivate of sorafenib showed a higher autophagy induction characterized by an increased ability to induce LC3-lipidation and acid vesicles formation (Tai et al, 2013 ).…”

“…Sorafenib analogs have a different ability to abolish mTOR in cultured cell lines in vitro . Some of them, such as regorafenib or SK-01105, are able to induce mTOR dephosphorylation similarly to sorafenib, whereas other compounds, like t-AUCMB or t-MTUCB, cannot inhibit mTOR activity, so autophagy induction mediated by those sorafenib analogs is not modulated by mTORC1 activity (Wecksler et al, 2014 ; Tavallai et al, 2015 ).…”