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Lipoprotein-free mitotane exerts high cytotoxic activity in adrenocortical carcinoma

Abstract : Context: Mitotane (o,p’-DDD), the only approved drug for advanced adrenocortical carcinoma (ACC), is a lipophilic agent that accumulates into circulating lipoprotein fractions and high lipid-containing tissues. Objective: The aim of our study was to evaluate the in vivo and in vitro biological implication of serum lipoproteins on pharmacological action of mitotane. Distribution and concentration of mitotane were studied in plasma and adrenal tissue samples from mitotane-treated patients. The impact of lipoprotein-bound or free (LP-F) mitotane was analyzed on proliferation and apoptosis of human adrenocortical H295R cells. A retrospective study of ACC patients treated or not with statins was also performed. Results: o,p’-DDD distribution among VLDL, LDL, HDL and lipoprotein-free (LP-F) fractions obtained after ultracentrifugation of 23 plasmas of mitotane-treated patients was widely distributed in each subfraction. A positive correlation was observed between mitotane levels in plasma and in LDL, HDL but also LP-F compartment. Intra-tumor o,p’-DDD concentrations in 5 ACC samples of mitotane-treated patients were found independent of cholesterol transporter expression, scavenger receptors (SrB1) and LDL-Receptors. In vitro studies showed significant higher anti-proliferative and pro-apoptotic effects and higher cell and mitochondrial uptake of mitotane when H295R cells were grown in LP-F medium. Finally, retrospective study of an ACC cohort of 26 mitotane-treated patients revealed that statin therapy was significantly associated with a higher rate of tumor control. Conclusions: Altogether, our in vitro and in vivo studies provided compelling evidence for a greater efficacy of lipoprotein-free mitotane. ACC patients may thus benefit from therapeutic strategies that aim to increase LP-F mitotane fraction.
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https://www.hal.inserm.fr/inserm-01175477
Contributor : Marc Lombes <>
Submitted on : Friday, July 10, 2015 - 3:17:20 PM
Last modification on : Wednesday, September 16, 2020 - 5:48:52 PM
Long-term archiving on: : Monday, October 12, 2015 - 11:32:18 AM

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  • HAL Id : inserm-01175477, version 1
  • PUBMED : 26120791

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Ségolène Hescot, Atmane Seck, Maryse Guerin, Florence Cockenpot, Thierry Huby, et al.. Lipoprotein-free mitotane exerts high cytotoxic activity in adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism, Endocrine Society, 2015, pp.22. ⟨inserm-01175477⟩

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