Phosphatidylinositol-3-kinase as a putative target for anticancer action of clotrimazole

The International Journal of Biochemistry & Cell Biology
Cristiane M FurtadoPatricia Zancan

Abstract

Clotrimazole (CTZ) has been proposed as an antitumoral agent because of its properties that inhibit glycolytic enzymes and detach them from the cytoskeleton. However, the broad effects of the drug, e.g., acting on different enzymes and pathways, indicate that CTZ might also affect several signaling pathways. In this study, we show that CTZ interferes with the human breast cancer cell line MCF-7 after a short incubation period (4 h), thereby diminishing cell viability, promoting apoptosis, depolarizing mitochondria, inhibiting key glycolytic regulatory enzymes, decreasing the intracellular ATP content, and permeating plasma membranes. CTZ treatment also interferes with autophagy. Moreover, when the incubation is performed under hypoxic conditions, certain effects of CTZ are enhanced, such as phosphatidylinositol-3-phosphate kinase (PI3K), which is inhibited upon CTZ treatment; this inhibition is potentiated under hypoxia. CTZ-induced PI3K inhibition is not caused by upstream effects of CTZ because the drug does not affect the interaction of the PI3K regulatory subunit and the insulin receptor substrate (IRS)-1. Additionally, CTZ directly inhibits human purified PI3K in a dose-dependent and reversible manner. Pharmacologic and in...Continue Reading

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Citations

Oct 30, 2016·Journal of Cellular Biochemistry·Thyago Rubens Cardim PiresPatricia Zancan
Mar 23, 2017·Scientific Reports·Aldo Segura-CabreraKakajan Komurov
Aug 10, 2021·The Journal of Nutritional Biochemistry·Jessica Ristow BrancoMauro Sola-Penna
Apr 25, 2018·Molecular and Cellular Endocrinology·Daniel Escorsim MachadoPatricia Zancan

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