ATR-101 inhibits cholesterol efflux and cortisol secretion by ATP-binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells.

Abstract

BACKGROUND AND PURPOSE:

To further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR-101 (PD132301-02).

EXPERIMENTAL APPROACH:

We compared the effects of ATR-101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC-derived cell lines. We examined the effects of these compounds in combination with methyl-β-cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds.

KEY RESULTS:

ATR-101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC-derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl-β-cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR-101. ATR-101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR-101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR-101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR-101. ATR-101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation.

CONCLUSIONS AND IMPLICATIONS:

Inhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR-101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC.

• Authors: Veronica Elizabeth Burns, Tom Klaus Kerppola
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 174 Issue 19 Pg. 3315-3332 (Oct 2017) ISSN: 1476-5381 [Electronic] England
• PMID: 28710789 (Publication Type: Journal Article)
• Copyright: © 2017 The British Pharmacological Society.

Chemical References

• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Phenylurea Compounds
• Adenosine Triphosphate
• Cholesterol
• CASP3 protein, human
• CASP7 protein, human
• Caspase 3
• Caspase 7
• N-(2,6-bis(1-methylethyl)phenyl)-N'-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride
• Hydrocortisone

Topics

• ATP-Binding Cassette Transporters (metabolism)
• Adenosine Triphosphate (metabolism)
• Adrenocortical Carcinoma (metabolism)
• Antineoplastic Agents (pharmacology)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Line, Tumor
• Cholesterol (metabolism)
• Humans
• Hydrocortisone (metabolism)
• Phenylurea Compounds (pharmacology)