Wecksler_2014_Anticancer.Drugs_25_433

Reference

Title : Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB - Wecksler_2014_Anticancer.Drugs_25_433
Author(s) : Wecksler AT , Hwang SH , Wettersten HI , Gilda JE , Patton A , Leon LJ , Carraway KL, 3rd , Gomes AV , Baar K , Weiss RH , Hammock BD
Ref : Anticancer Drugs , 25 :433 , 2014
Abstract :

In the current work, we carried out a mechanistic study on the cytotoxicity of two compounds, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-N-methyl-benzamide (t-AUCMB) and trans-N-methyl-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzamide (t-MTUCB), that are structurally similar to sorafenib. These compounds show 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-binding protein. In addition, there was an increase in the activity of upstream signaling through the IRS1/PI3K/Akt-signaling pathway, suggesting that, unlike sorafenib, both compounds induce mammalian target of rapamycin (mTOR)-independent autophagy. The autophagy observed correlates with mitochondrial membrane depolarization, apoptosis-inducing factor release, and oxidative stress-induced glutathione depletion. However, there were no observable changes in the endoplasmic reticulum-stress markers such as binding immunoglobulin protein, inositol-requiring enzyme-alpha, phosphorylated eukaryotic initiation factor 2, and the lipid peroxidation marker, 4-hydroxynonenal, suggesting endoplasmic reticulum-independent oxidative stress. Finally, these compounds do not have the multikinase inhibitory activity of sorafenib, which may be reflected in their difference in the ability to halt cell cycle progression compared with sorafenib. Our findings indicate that both compounds have anticancer effects comparable with sorafenib in multiple cell lines, 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 may thus be potential tools for further understanding the link between these two cellular stress responses.

PubMedSearch : Wecksler_2014_Anticancer.Drugs_25_433
PubMedID: 24525589

Related information

Inhibitor t-AUCMB    t-MTUCB-NH    t-MTUCB

Citations formats

Wecksler AT, Hwang SH, Wettersten HI, Gilda JE, Patton A, Leon LJ, Carraway KL, 3rd, Gomes AV, Baar K, Weiss RH, Hammock BD (2014)
Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB
Anticancer Drugs 25 :433

Wecksler AT, Hwang SH, Wettersten HI, Gilda JE, Patton A, Leon LJ, Carraway KL, 3rd, Gomes AV, Baar K, Weiss RH, Hammock BD (2014)
Anticancer Drugs 25 :433