The PI3Kδ inhibitor idelalisib suppresses liver and lung cellular respiration

Suleiman Al Hammadi, Saeeda Almarzooqi, Hidaya Mohammed Abdul-Kader, Dhanya Saraswathiamma, Abdul Kader Souid

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Idelalisib (an inhibitor of phosphatidylinositol-3-kinase-delta) is approved for treatment of B-cell malignancies, with a Boxed Warning concerning potentially fatal hepatic, lung, and intestinal toxicities. The mechanisms of these tissue-specific adverse events have yet to be elucidated. This in vitro study investigated whether these effects could be attributed, at least in part, to altered cellular bioenergetics. A phosphorescence analyzer was used to measure cellular mitochondrial O2 consumption (kc, μM O2 min-1 mg-1) in C57BL/6 mouse organs in the presence of 10 μM idelalisib or dimethyl-sulfoxide. Idelalisib significantly reduced the rate of cellular respiration in liver and lung fragments by 20% and 27%, respectively. Respiration in intestinal, thymic, and kidney fragments was unaffected. Idelalisib did not alter respiratory chain activities in mitochondria isolated from the liver and did not induce hepatocyte death. Thus, the drug mildly lowers liver and lung cellular respiration, an effect that may contribute to toxicities observed in these organs.

Original languageEnglish
Pages (from-to)115-125
Number of pages11
JournalInternational Journal of Physiology, Pathophysiology and Pharmacology
Volume7
Issue number3
Publication statusPublished - Jan 1 2015

Keywords

  • Cellular bioenergetics
  • Cellular respiration
  • Idelalisib
  • Liver toxicity
  • Lung toxicity
  • Mitochondrial function
  • Oxidative phosphorylation
  • PI3K delta
  • PI3K inhibitors

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Physiology
  • Physiology (medical)

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