A new pyridazinone exhibits potent cytotoxicity on human cancer cells via apoptosis and poly-ubiquitinated protein accumulation.
Cell Biol Toxicol, 2019/12;35(6):503-519.
Gutierrez DA[1], DeJesus RE[1], Contreras L[1], Rodriguez-Palomares IA[1], Villanueva PJ[1], Balderrama KS[1], Monterroza L[1], Larragoity M[1], Varela-Ramirez A[1], Aguilera RJ[2]
Affiliations
PMID: 30825052DOI: 10.1007/s10565-019-09466-8
Impact factor: 6.819
Abstract
In the last 15 years, pyridazinone derivatives have acquired extensive attention due to their widespread biological activities and pharmacological applications. Pyridazinones are well known for their anti-microbial, anti-viral, anti-inflammatory, anti-cancer, and cardiovascular activities, among others. In this study, we evaluated the anti-cancer activity of a new pyridazinone derivative and propose it as a potential anti-neoplastic agent in acute promyelocytic leukemia cells. Pyr-1 cytotoxicity was assessed on several human cancer and two non-cancerous cell lines by the DNS assay. Pyr-1 demonstrated potent cytotoxicity against 22 human cancer cell lines, exhibiting the most favorable selective cytotoxicity on leukemia (CEM and HL-60), breast (MDA-MB-231 and MDA-MB-468), and lung (A-549) cancer cell lines, when compared with non-cancerous breast epithelial MCF-10A cells. Analyses of apoptosis/necrosis pathways, reactive oxygen species (ROS) production, mitochondria health, caspase-3 activation, and cell cycle profile were performed via flow cytometry. Both hmox-1 RNA and protein expression levels were evaluated by quantitative real-time PCR and Western blotting assays, respectively. Pyr-1 induced apoptosis in acute promyelocytic leukemia cells as confirmed by phosphatidylserine externalization, mitochondrial depolarization, caspase-3 activation, DNA fragmentation, and disrupted cell cycle progression. Additionally, it was determined that Pyr-1 generates oxidative and proteotoxic stress by provoking the accumulation of ROS, resulting in the overexpression of the stress-related hmox-1 mRNA transcripts and protein and a marked increase in poly-ubiquitinated proteins. Our data demonstrate that Pyr-1 induces cell death via the intrinsic apoptosis pathway by accumulating ROS and by impairing proteasome activity.
Keywords: Anti-cancer; Apoptosis; Proteasome inhibition; Pyridazinone; ROS; hmox-1
MeSH terms
Antineoplastic Agents; Apoptosis; Caspase 3; Caspases; Cell Line, Tumor; Cell Survival; DNA Fragmentation; Humans; Membrane Potential, Mitochondrial; Mitochondria; Necrosis; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyridazines; Reactive Oxygen Species; Signal Transduction; Ubiquitinated Proteins; bcl-2-Associated X Protein
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