Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells

Journal Article · Fri Aug 01 04:00:00 EDT 2014 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2014.05.021· OSTI ID:22416914

Ristic, Biljana ^[1]; Bosnjak, Mihajlo ^[2]; Arsikin, Katarina ^[1]; Mircic, Aleksandar; Suzin-Zivkovic, Violeta ^[2]; Bogdanovic, Andrija ^[3]; Perovic, Vladimir ^[1]; Martinovic, Tamara; Kravic-Stevovic, Tamara; Bumbasirevic, Vladimir ^[2]; Trajkovic, Vladimir ^[1]; Harhaji-Trajkovic, Ljubica ^[4]

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1. Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia)
2. Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade (Serbia)
3. Clinic for Hematology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade (Serbia)
4. Institute for Biological Research, University of Belgrade, Belgrade, Despot Stefan Blvd. 142, 11000 Belgrade (Serbia)

We investigated if the antileukemic drug idarubicin induces autophagy, a process of programmed cellular self-digestion, in leukemic cell lines and primary leukemic cells. Transmission electron microscopy and acridine orange staining demonstrated the presence of autophagic vesicles and intracellular acidification, respectively, in idarubicin-treated REH leukemic cell line. Idarubicin increased punctuation/aggregation of microtubule-associated light chain 3B (LC3B), enhanced the conversion of LC3B-I to autophagosome-associated LC3B-II in the presence of proteolysis inhibitors, and promoted the degradation of the selective autophagic target p62, thus indicating the increase in autophagic flux. Idarubicin inhibited the phosphorylation of the main autophagy repressor mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase. The treatment with the mTOR activator leucine prevented idarubicin-mediated autophagy induction. Idarubicin-induced mTOR repression was associated with the activation of the mTOR inhibitor AMP-activated protein kinase and down-regulation of the mTOR activator Akt. The suppression of autophagy by pharmacological inhibitors or LC3B and beclin-1 genetic knockdown rescued REH cells from idarubicin-mediated oxidative stress, mitochondrial depolarization, caspase activation and apoptotic DNA fragmentation. Idarubicin also caused mTOR inhibition and cytotoxic autophagy in K562 leukemic cell line and leukocytes from chronic myeloid leukemia patients, but not healthy controls. By demonstrating mTOR-dependent cytotoxic autophagy in idarubicin-treated leukemic cells, our results warrant caution when considering combining idarubicin with autophagy inhibitors in leukemia therapy. - Highlights: • Idarubicin induces autophagy in leukemic cell lines and primary leukemic cells. • Idarubicin induces autophagy by inhibiting mTOR in leukemic cells. • mTOR suppression by idarubicin is associated with AMPK activation and Akt blockade. • Autophagy is involved in idarubicin-induced apoptotic death of leukemic cells. • Idarubicin does not induce cytotoxic autophagy in normal human leukocytes.

• OSTI ID: 22416914
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 326; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACRIDINE ORANGE
APOPTOSIS
DNA
INHIBITION
LEUKOCYTES
MICROTUBULES
MITOCHONDRIA
MYELOID LEUKEMIA
PHOSPHORYLATION
PROTEINS
PROTEOLYSIS
THERAPY
TRANSMISSION ELECTRON MICROSCOPY