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Anticancer Potential of Tetrahydrobenzimidazole Derivative in CML

By: Cordi Craig
Posted: Thursday, March 26, 2020

Marc Diederich, PhD, of Seoul National University, Korea, and colleagues, previously found that various tetrahydrobenzimidazole derivatives showed potential against hematopoietic cancer cell lines; in fact, the quinone TMQ0153 exhibited significant cytotoxicity. The researchers reported that TMQ0153 showed potential as an experimental preclinical therapeutic agent and appeared to release immunogenic cell death markers in chronic myeloid leukemia (CML) cell models. The study was published in Cell Death & Disease.

By comparing imatinib-sensitive and imatinib-resistant CML cell models, the research team investigated the molecular mechanisms through which TMQ0153 triggered apoptosis, autophagy, and necroptosis crosstalk. The anticancer potential of TMQ0153 was validated through an in vivo inhibition of K562 microtumor formation in zebrafish.

The researchers found that, at low levels, TMQ0153 caused caspase-dependent apoptosis, the loss of mitochondrial membrane potential, and an increase of cytosolic free Ca2+ levels. At higher concentrations, TMQ0153 triggered necroptotic cell death with the accumulation of reactive oxygen species, increased reactive oxygen species, and decreased ATP and GSH levels. The necrosis induced by TMQ0153 led to cell-surface exposure of calreticulin and ERp57 as well as the release of extracellular ATP and high mobility group box. These findings suggest the compound’s capacity to release immunogenic cell death markers.

“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,” the researchers concluded.

Disclosure: The study authors reported no conflicts of interest.



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