Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia.

Autor: Song S; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea., Lee JY; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea., Ermolenko L; Département SNCM (Substances Naturelles et Chimie Médicinale), ICSN-CNRS, LabEx LERMIT, Centre de Recherche de Gif-sur-Yvette, Avenue de la Terrasse (Bat. 27), 91190, Gif-sur-Yvette, France., Mazumder A; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea., Ji S; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea., Ryu H; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea., Kim H; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea., Kim DW; Catholic University, Seoul St. Mary's Hospital, Banpo dong 505, Seocho Gu, Seoul, Korea., Lee JW; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea., Dicato M; Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg., Christov C; Service d'Histologie, Faculté de Médicine, Université de Lorraine, and INSERM U1256 NGERE, 54000, Nancy, France., Schnekenburger M; Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg., Cerella C; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea.; Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg., Gérard D; Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg., Orlikova-Boyer B; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea.; Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540, Luxembourg, Luxembourg., Al-Mourabit A; Département SNCM (Substances Naturelles et Chimie Médicinale), ICSN-CNRS, LabEx LERMIT, Centre de Recherche de Gif-sur-Yvette, Avenue de la Terrasse (Bat. 27), 91190, Gif-sur-Yvette, France. ali.almourabit@cnrs.fr., Diederich M; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08626, Korea. marcdiederich@snu.ac.kr.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2020 Feb 07; Vol. 11 (2), pp. 109. Date of Electronic Publication: 2020 Feb 07.
DOI: 10.1038/s41419-020-2304-8
Abstrakt: 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 Ca 2+ 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.
Databáze: MEDLINE
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