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ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells
dc.contributor.authorBurns, Veronica Elizabeth
dc.contributor.authorKerppola, Tom Klaus
dc.date.accessioned2017-10-05T18:17:32Z
dc.date.available2019-01-07T18:34:36Zen
dc.date.issued2017-10
dc.identifier.citationBurns, Veronica Elizabeth; Kerppola, Tom Klaus (2017). "ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells." British Journal of Pharmacology 174(19): 3315-3332.
dc.identifier.issn0007-1188
dc.identifier.issn1476-5381
dc.identifier.urihttps://hdl.handle.net/2027.42/138270
dc.description.abstractBackground and PurposeTo 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 ApproachWe 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 ResultsATR‐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 ImplicationsInhibition 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.
dc.publisherWiley Periodicals, Inc.
dc.titleATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells
dc.typeArticleen_US
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelPharmacy and Pharmacology
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/1/bph13951-sup-0001-supplementary_material.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/2/bph13951_am.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/3/bph13951.pdf
dc.identifier.doi10.1111/bph.13951
dc.identifier.sourceBritish Journal of Pharmacology
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