1. An acylhydroquinone derivative produces OXPHOS uncoupling and sensitization to BH3 mimetic ABT-199 (Venetoclax) in human promyelocytic leukemia cells
- Author
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Félix A. Urra, Ramiro Araya-Maturana, Viviana Donoso-Bustamante, Armando Varela-Ramirez, Ignacio Chávez-Báez, Denisse A. Gutierrez, Sebastián Fuentes-Retamal, Edgar A Borrego, Dante Miranda, Yareli Schiaffino-Bustamante, Juan Pablo Millas-Vargas, Ileana Carrillo, Renato J. Aguilera, Pablo Correa, and Rodrigo Pulgar
- Subjects
Acute promyelocytic leukemia ,Programmed cell death ,Antineoplastic Agents ,Apoptosis ,AMP-Activated Protein Kinases ,Mitochondrion ,01 natural sciences ,Biochemistry ,Oxidative Phosphorylation ,Structure-Activity Relationship ,chemistry.chemical_compound ,Leukemia, Promyelocytic, Acute ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Molecular Biology ,Membrane Potential, Mitochondrial ,Sulfonamides ,010405 organic chemistry ,Venetoclax ,Organic Chemistry ,Cell Cycle Checkpoints ,Cell cycle ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Hydroquinones ,Mitochondria ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Leukemia ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Cancer cell ,Cancer research ,Reactive Oxygen Species ,Etomoxir ,Signal Transduction - Abstract
Since cancer cells have different mitochondrial bioenergetic requirements than non-cancerous cells, therapeutic inhibition of its mitochondrial functionality continues to be an important target for anticancer drug discovery. In this study, a series of acylhydroquinones with different acyl-chain length, and their chlorinated derivatives, in the aromatic ring, synthesized by Fries rearrangement under microwave irradiation, were evaluated for their anticancer activity in two leukemia cell lines. Findings from the primary and secondary screening of the 18 acylhydroquinones, tested at 5 µM on acute promyelocytic leukemia HL-60 and acute lymphoblastic leukemia CEM cells lines, identified an acylchlorohydroquinone (12) with a highly selective anti-proliferative effect toward HL-60 cells. This compound induced S-phase arrest in the cell cycle progression of HL-60 cells with insignificant toxicity on leukemic CEM cells and non-cancerous Hs27 cells. In HL-60 leukemic cells, 12 triggered increased mitochondrial NADH oxidation, increased respiration in presence of oligomycin (state 4o), mitochondrial depolarization, and ROS production, suggesting an uncoupling of OXPHOS. This provoked a metabolic adaptation dependent on AMPK/ACC/autophagy axis, having the mitochondrial β-oxidation a pro-survival role since the combination of 12 and etomoxir, a carnitine palmitoyl-transferase (CPT) inhibitor promoted extensive HL-60 cell death. Finally, 12-induced metabolic stress sensitized to HL-60 cells to cell death by the FDA-approved anti-leukemic drug ABT-199, a BH3 mimetic. Therefore, our results suggest that acylchlorohydroquinone is a promising scaffold in anti-promyelocytic leukemia drug research.
- Published
- 2020
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