Abstract |
By comparing imatinib-sensitive and -resistant chronic myeloid leukemia (CML) cell models, we investigated the molecular mechanisms by which tetrahydrobenzimidazole derivative TMQ0153 triggered caspase-dependent apoptosis at low concentrations accompanied by loss of mitochondrial membrane potential ( MMP) and increase of cytosolic free Ca2+ levels. Interestingly, at higher concentrations, TMQ0153 induced necroptotic cell death with accumulation of ROS, both preventable by N-acetyl-L-cysteine (NAC) pretreatment. At necroptosis-inducing concentrations, we observed increased ROS and decreased ATP and GSH levels, concomitant with protective autophagy induction. Inhibitors such as bafilomycin A1 (baf-A1) and siRNA against beclin 1 abrogated autophagy, sensitized CML cells against TMQ0153 and enhanced necroptotic cell death. Importantly, TMQ153-induced necrosis led to cell surface exposure of calreticulin (CRT) and ERp57 as well as the release of extracellular ATP and high mobility group box ( HMGB1) demonstrating the capacity of this compound to release immunogenic cell death (ICD) markers. We validated the anti- cancer potential of TMQ0153 by in vivo inhibition of K562 microtumor formation in zebrafish. Taken together, our findings provide evidence that cellular stress and redox modulation by TMQ0153 concentration-dependently leads to different cell death modalities including controlled necrosis in CML cell models.
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Authors | Sungmi Song, Jin-Young Lee, Ludmila Ermolenko, Aloran Mazumder, Seungwon Ji, Heeju Ryu, HyeJin Kim, Dong-Wook Kim, Jung Weon Lee, Mario Dicato, Christo Christov, Michael Schnekenburger, Claudia Cerella, Déborah Gérard, Barbora Orlikova-Boyer, Ali Al-Mourabit, Marc Diederich |
Journal | Cell death & disease
(Cell Death Dis)
Vol. 11
Issue 2
Pg. 109
(02 07 2020)
ISSN: 2041-4889 [Electronic] England |
PMID | 32034134
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Benzimidazoles
- Reactive Oxygen Species
- Calcium
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Autophagy
(drug effects)
- Benzimidazoles
(pharmacology)
- Calcium
(metabolism)
- Dose-Response Relationship, Drug
- Energy Metabolism
(drug effects)
- Gene Expression Regulation, Leukemic
- Humans
- K562 Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(drug therapy, genetics, metabolism, pathology)
- Membrane Potential, Mitochondrial
(drug effects)
- Necroptosis
(drug effects)
- Oxidative Stress
(drug effects)
- Reactive Oxygen Species
(metabolism)
- Signal Transduction
- Zebrafish
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