ATR-101 disrupts mitochondrial functions in adrenocortical carcinoma cells and in vivo

Cheng, Yunhui; Kerppola, Raili Emilia; Kerppola, Tom K.

doi:10.1530/erc-15-0527

Cited by 23 publications

(23 citation statements)

References 56 publications

(67 reference statements)

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“…Here we have investigated the adrenalytic compound ATR-101, also known as PD132301-02, as a prospective agent for the treatment of adrenocortical carcinoma (ACC). We focused on ATR-101 because of its cytotoxicity in ACC-derived cells and its antixenograft and adrenalytic activities (Cheng et al, 2016). ACC is a rare cancer that has few treatment options.…”

Section: Introductionmentioning

confidence: 99%

“…The differences in the genetic and epigenetic changes among different ACC tumours suggest that different molecular mechanisms underlie the malignancy of different ACC tumours (Assie et al, 2014;Zheng et al, 2016). Adrenalytic compounds can potentially be used for the treatment of ACCs that have different determinants of malignancy.ATR-101 inhibits the establishment and impedes the growth of ACC cell xenografts in nude mice (Cheng et al, 2016). The inhibition of xenograft growth in animals that are treated with ATR-101 correlates with increased apoptosis of xenograft cells.…”

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“…The inhibition of xenograft growth in animals that are treated with ATR-101 correlates with increased apoptosis of xenograft cells. ATR-101 causes mitochondrial dysfunction in ACC-derived cells and toxicity due to reactive oxygen species (ROS) in cultured cells and in the zona fasciculata layer of the guinea pig adrenal cortex (Cheng et al, 2016).The tissue-specific toxicity of adrenalytic compounds correlates with cholesterol accumulation. The cholesterol level of guinea pig adrenal glands rises within an hour after ATR-101 administration and increases threefold in 24 h (Wolfgang et al, 1995).…”

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confidence: 99%

“…The differences in cytotoxicity among different combinations of ABC transporter inhibitors could be due to the distinct distributions of cholesterol or to effects that are independent of cholesterol accumulation. The many molecular and cellular mechanisms that mediate ATR-101 cytotoxicity can account for the tissue and cell type specificity of its adrenalytic activity.ATR-101 inhibits mitochondrial oxidative phosphorylation and causes the release of ROS in ACC-derived cells (Cheng et al, 2016). Both cholesterol accumulation and mitochondrial dysfunctions are necessary for ATR-101 cytotoxicity, as compounds that prevent either of these effects suppress ATR-101 cytotoxicity.…”

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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

Burns

Kerppola

2017

British J Pharmacology

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BACKGROUND 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. IntroductionControl of the levels of cholesterol (The term "cholesterol" is used to denote unesterified cholesterol in this paper) is essential for cell functions and viability (see Maxfield and Van Meer, 2010). The cholesterol levels in adrenocortical cells are affected by many pathways, some of which are unique to the adrenal cortex. Studies of anti-atherosclerosis agents have identified compounds that cause selective degeneration of the adrenal cortex (adrenalytic activity) in several species (Dominick et al., 1993;Reindel et al., 1994;Matsuo et al., 1996;Sliskovic et al., 1998;Tanaka et al., 1998). Here we have investigated the adrenalytic compound ATR-101, also known as PD132301-02, as a prospective agent for the treatment of adrenocortical carcinoma (ACC). We focused on ATR-101 because of its cytotoxicity in ACC-derived cells and its antixenograft and adrenalytic activities (Cheng et al., 2016). ACC is a rare cancer that has few treatment options. The adrenalytic compound mitotane is a first-line drug for ACC treatment despite its poor efficacy, unfavourable pharmacokinetics, severe side effects and potential drug interactions (Maiter et al., 2016). Clinical trials of molecularly targeted agents...

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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

Burns

Kerppola

2017

British J Pharmacology

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“…In vitro, in H295R cells, ATR-101 induced mitochondria hyperpolarization, increased the ROS formation within 1 h of exposure [46]. ATR-101 treatment of H295R cells led to the accumulation of free fatty acids and cholesterol that induces ER stress [47].…”

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