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New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation
- Source :
- Chemical research in toxicology, vol 34, iss 12, Chem Res Toxicol
- Publication Year :
- 2021
- Publisher :
- ACS Publications, 2021.
-
Abstract
- The usage of cisplatin, a highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH) inhibitors were shown to ameliorate this dose-limiting side effect, but both approaches have some pharmacological limitations. Analogues of EETs are an alternative avenue with unique benefits, but the current series of analogues face concerns regarding their structure and mimetic functionality. Hence, in this study, regioisomeric mixtures of four new ARA alkyl ethers were synthesized, characterized, and assessed as EET analogues against the concentration- and time-dependent toxicities of cisplatin in porcine proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy- (1), good for n-propoxy- (4), and excellent for ethoxy- (2) and i-propoxy- (3). Compounds 2 and 3 displayed cytoprotective effects comparable to that of an EET regioisomeric mixture (5) against high, acute cisplatin exposures but were more potent against low to moderate, chronic exposures. Compounds 2 and 3 (and 5) acted through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and caspase-3. This study demonstrates that alkoxy- groups are potent and more metabolically stable bioisostere alternatives to the epoxide within EETs that enable sEH-independent activity. It also illustrates the potential of ether-based mimics of EETs and other epoxy fatty acids as promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin without compromising its antineoplastic function.
- Subjects :
- 14-Eicosatrienoic Acid
Swine
030204 cardiovascular system & hematology
Pharmacology
medicine.disease_cause
Toxicology
Kidney Tubules, Proximal
chemistry.chemical_compound
0302 clinical medicine
8,11,14-Eicosatrienoic Acid
Cells, Cultured
chemistry.chemical_classification
0303 health sciences
Cultured
biology
Molecular Structure
Kinase
Caspase 3
Proximal
General Medicine
Caspase 9
Mitochondria
Kidney Tubules
5.1 Pharmaceuticals
Mitogen-activated protein kinase
cardiovascular system
lipids (amino acids, peptides, and proteins)
Mitogen-Activated Protein Kinases
Drug
Development of treatments and therapeutic interventions
medicine.drug
Signal Transduction
Biotechnology
Epoxide hydrolase 2
p38 mitogen-activated protein kinases
Cells
Antineoplastic Agents
Article
Dose-Response Relationship
Inorganic Chemistry
03 medical and health sciences
Medicinal and Biomolecular Chemistry
medicine
Animals
Humans
030304 developmental biology
Cisplatin
Reactive oxygen species
Dose-Response Relationship, Drug
Organic Chemistry
Epithelial Cells
Oxidative Stress
chemistry
biology.protein
Bioisostere
Oxidative stress
Subjects
Details
- ISSN :
- 0893228X
- Database :
- OpenAIRE
- Journal :
- Chemical research in toxicology, vol 34, iss 12, Chem Res Toxicol
- Accession number :
- edsair.doi.dedup.....2f7f68115736339b6e6f7b24f46bf0b4