CYP11B1 has no role in mitotane action and metabolism in adrenocortical carcinoma cells

PLoS One. 2018 May 7;13(5):e0196931. doi: 10.1371/journal.pone.0196931. eCollection 2018.

Abstract

Mitotane is the reference drug for adrenocortical carcinoma (ACC) and the metabolic activation of the drug is considered as essential for its activity. The aim of this study was to assess the role of CYP11B1 on mitotane action and metabolism in H295R ACC cells to understand whether this enzyme may influence mitotane action. The simultaneous incubation with mitotane and metyrapone, an adrenolytic molecule targeting 11-beta-hydroxylase, did not influence mitotane-mediated cytotoxic effect and metabolism in H295R ACC cells. CYP11B1 silencing confirmed the lack of a significant metyrapone effect on mitotane action. The present findings do not support the view that CYP11B1 catalyzes a crucial step in the metabolic activation of mitotane and that CYP11B1 confers the adrenal specificity to mitotane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocortical Carcinoma / drug therapy*
  • Adrenocortical Carcinoma / metabolism
  • Adrenocortical Carcinoma / pathology
  • Antineoplastic Agents, Hormonal / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Humans
  • Metyrapone / pharmacology
  • Mitotane / pharmacology*
  • Steroid 11-beta-Hydroxylase / antagonists & inhibitors
  • Steroid 11-beta-Hydroxylase / genetics*
  • Steroid 11-beta-Hydroxylase / metabolism

Substances

  • Antineoplastic Agents, Hormonal
  • Mitotane
  • Steroid 11-beta-Hydroxylase
  • Metyrapone

Grants and funding

This work was supported by a research grant from Associazione Italiana per la Ricerca sul Cancro to MT (AIRC grant number 17678); http://www.airc.it/. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.