PMID- 24525589 OWN - NLM STAT- MEDLINE DCOM- 20141021 LR - 20211021 IS - 1473-5741 (Electronic) IS - 0959-4973 (Print) IS - 0959-4973 (Linking) VI - 25 IP - 4 DP - 2014 Apr TI - Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB. PG - 433-46 LID - 10.1097/CAD.0000000000000079 [doi] AB - 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. FAU - Wecksler, Aaron T AU - Wecksler AT AD - Departments of aEntomology and Nematology bNeurobiology, Physiology and Behavior, University of California Davis, Davis cUC Davis Comprehensive Cancer Center dDepartment of Internal Medicine, Davis Medical Center, Division of Nephrology, University of California eDepartment of Biochemistry and Molecular Medicine, University of California Davis School of Medicine fUS Department of Veterans' Affairs Medical Center, Sacramento, California, USA. FAU - Hwang, Sung Hee AU - Hwang SH FAU - Wettersten, Hiromi I AU - Wettersten HI FAU - Gilda, Jennifer E AU - Gilda JE FAU - Patton, Amy AU - Patton A FAU - Leon, Leonardo J AU - Leon LJ FAU - Carraway, Kermit L 3rd AU - Carraway KL 3rd FAU - Gomes, Aldrin V AU - Gomes AV FAU - Baar, Keith AU - Baar K FAU - Weiss, Robert H AU - Weiss RH FAU - Hammock, Bruce D AU - Hammock BD LA - eng GR - R01 DK082690/DK/NIDDK NIH HHS/United States GR - P30 CA093373/CA/NCI NIH HHS/United States GR - ES02710/ES/NIEHS NIH HHS/United States GR - R01 HL059699/HL/NHLBI NIH HHS/United States GR - 1R01 CA135401-01A1/CA/NCI NIH HHS/United States GR - U01 CA086402/CA/NCI NIH HHS/United States GR - R01 ES002710/ES/NIEHS NIH HHS/United States GR - 1R01 DK082690-01A1/DK/NIDDK NIH HHS/United States GR - P42 ES004699/ES/NIEHS NIH HHS/United States GR - R01 CA135401/CA/NCI NIH HHS/United States GR - 5U01 CA86402/CA/NCI NIH HHS/United States GR - HL096819/HL/NHLBI NIH HHS/United States GR - R37 ES002710/ES/NIEHS NIH HHS/United States GR - R01 HL096819/HL/NHLBI NIH HHS/United States GR - P42 ES04699/ES/NIEHS NIH HHS/United States GR - HL059699/HL/NHLBI NIH HHS/United States GR - T32 CA108459/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. PL - England TA - Anticancer Drugs JT - Anti-cancer drugs JID - 9100823 RN - 0 (4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)-N-methylbenzamide) RN - 0 (Antineoplastic Agents) RN - 0 (Apoptosis Inducing Factor) RN - 0 (Benzamides) RN - 0 (N-methyl-4-(4-(3-(4-trifluoromethoxyphenyl)ureido)cyclohexyloxy)benzamide) RN - 0 (Phenylurea Compounds) RN - 0 (Protein Kinase Inhibitors) RN - 25X51I8RD4 (Niacinamide) RN - 8W8T17847W (Urea) RN - 9ZOQ3TZI87 (Sorafenib) RN - EC 3.4.22.- (Caspases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) RN - PJY633525U (Adamantane) SB - IM MH - Adamantane/*analogs & derivatives/pharmacology MH - Antineoplastic Agents/*pharmacology MH - Apoptosis/drug effects MH - Apoptosis Inducing Factor/metabolism MH - Autophagy/drug effects MH - Benzamides/*pharmacology MH - Caspases/metabolism MH - Cell Cycle/drug effects MH - Cell Line, Tumor MH - Drug Screening Assays, Antitumor MH - Humans MH - Mitochondrial Membranes/physiology MH - Niacinamide/*analogs & derivatives/pharmacology MH - Oxidative Stress MH - Phenylurea Compounds/*pharmacology MH - Proteasome Endopeptidase Complex/metabolism MH - Protein Kinase Inhibitors/*pharmacology MH - Sorafenib MH - Urea/*analogs & derivatives/pharmacology PMC - PMC3947856 MID - NIHMS558141 COIS- Conflict of Interest None declared. EDAT- 2014/02/15 06:00 MHDA- 2014/10/22 06:00 PMCR- 2015/04/01 CRDT- 2014/02/15 06:00 PHST- 2014/02/15 06:00 [entrez] PHST- 2014/02/15 06:00 [pubmed] PHST- 2014/10/22 06:00 [medline] PHST- 2015/04/01 00:00 [pmc-release] AID - 10.1097/CAD.0000000000000079 [doi] PST - ppublish SO - Anticancer Drugs. 2014 Apr;25(4):433-46. doi: 10.1097/CAD.0000000000000079.