Mineralocorticoid insufficiency due to suramin therapy

Kobayashi, Ken; Weiss, Roy E.; Vogelzang, Nicholas J.; Vokes, Everett E.; Janisch, Linda; Ratain, Mark J.

doi:10.1002/(sici)1097-0142(19961201)78:11<2411::aid-cncr20>3.0.co;2-2

Cited by 25 publications

(9 citation statements)

References 34 publications

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“…Suramin, a growth factor antagonist often used in the treatment of adrenocortical and prostate cancer, may also suppress adrenal function [111,112].…”

Section: Adrenal Dysfunctionmentioning

confidence: 99%

Endocrine sequelae of cancer and cancer treatments

2007

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“…Suramin, a growth factor antagonist often used in the treatment of adrenocortical and prostate cancer, may also suppress adrenal function [111,112].…”

Section: Adrenal Dysfunctionmentioning

confidence: 99%

Endocrine sequelae of cancer and cancer treatments

2007

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“…ATR-101 administration reduces the levels of circulating steroids in mice with ACC cell xenografts and in dogs stimulated with ACTH (Cheng et al, 2016;Lapensee et al, 2016). Some MDR1 inhibitors reduced circulating corticosteroid levels in clinical trials, suggesting that MDR1 inhibition can reduce steroid secretion in man (Guthrie et al, 1983;Shapiro et al, 1990;Kobayashi et al, 1996). The simultaneous accumulation of cholesterol and inhibition of steroid secretion caused by ATR-101 can potentially provide dual benefits to ACC patients.…”

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confidence: 99%

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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“…Numerous investigators have demonstrated that ketoconazole and suramin may adversely affect adrenal cortical function [9,10]. Conversely phenytoin and rifampin have been similarly implicated, although these medications function to stimulate steroidal metabolism [11].…”

Section: Primary Adrenal Insufficiencymentioning

confidence: 99%

Adrenal insuficiency: Diagnosis and management

Munver

Volfson²

2006

Curr Urol Rep

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Adrenal insufficiency is a disorder characterized by hypoactive adrenal glands resulting in insufficient production of the hormones cortisol and aldosterone by the adrenal cortex. This disorder may develop as a primary failure of the adrenal cortex or be secondary to an abnormality of the hypothalamic-pituitary axis. Patients with adrenal insufficiency often are asymptomatic or they may present with fatigue, muscle weakness, weight loss, low blood pressure, and sometimes darkening of the skin. The presentation of adrenal insufficiency varies dramatically and poses a major diagnostic dilemma. This review focuses on the diagnosis and treatment of primary and secondary adrenal insufficiency.

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Mineralocorticoid insufficiency due to suramin therapy

Cited by 25 publications

References 34 publications

Endocrine sequelae of cancer and cancer treatments

Endocrine sequelae of cancer and cancer treatments

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

Adrenal insuficiency: Diagnosis and management

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