title: ATR-101 disrupts mitochondrial functions in adrenocortical carcinoma cells and in vivo.
abstract: Adrenocortical carcinoma (ACC) generally has poor prognosis. Existing treatments provide limited benefit for most patients with locally advanced or metastatic tumors. We investigated the mechanisms for the cytotoxicity, xenograft suppression, and adrenalytic activity of ATR-101 (PD132301-02), a prospective agent for ACC treatment. Oral administration of ATR-101 inhibited the establishment and impeded the growth of ACC-derived H295R cell xenografts in mice. ATR-101 induced H295R cell apoptosis in culture and in xenografts. ATR-101 caused mitochondrial hyperpolarization, reactive oxygen release, and ATP depletion within hours after exposure, followed by cytochrome c release, caspase-3/7 activation, and membrane permeabilization. The increase in mitochondrial membrane potential occurred concurrently with the decrease in cellular ATP levels. When combined with ATR-101, lipophilic free radical scavengers suppressed the reactive oxygen release, and glycolytic precursors prevented the ATP depletion, abrogating ATR-101 cytotoxicity. ATR-101 directly inhibited F1F0-ATPase activity and suppressed ATP synthesis in mitochondrial fractions. ATR-101 administration to guinea pigs caused oxidized lipofuscin accumulation in the zona fasciculate layer of the adrenal cortex, implicating reactive oxygen release in the adrenalytic effect of ATR-101. These results support the development of ATR-101 and other adrenalytic compounds for the treatment of ACC.
authors: Department of Biological ChemistryUniversity of Michigan, Ann Arbor, MI, USA.
authors: Yunhui
authors: Y
authors: Cheng
authors: Atterocor Inc.Ann Arbor, MI, USA.
authors: Raili Emilia
authors: RE
authors: Kerppola
authors: Department of Biological ChemistryUniversity of Michigan, Ann Arbor, MI, USA kerppola@umich.edu.
authors: Tom Klaus
authors: TK
authors: Kerppola
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D017382:Reactive Oxygen Species; C079534:N-(2,6-bis(1-methylethyl)phenyl)-N'-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride
keywords: adrenalytic activity; adrenocortical carcinoma; experimental therapy; mitochondrial oxidative phosphorylation; reactive oxygen release