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

• Published in: Chemical research in toxicology 2021-12, Vol.34 (12), p.2579-2591
• Main Authors: Singh, Nalin, Vik, Anders, Lybrand, Daniel B, Morisseau, Christophe, Hammock, Bruce D
• Format: Article
• Language: English
• Subjects: 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - chemical synthesis; 8,11,14-Eicosatrienoic Acid - chemistry; 8,11,14-Eicosatrienoic Acid - pharmacology; Animals; Antineoplastic Agents - toxicity; Caspase 3 - metabolism; Caspase 9 - metabolism; Cells, Cultured; Cisplatin - antagonists & inhibitors; Cisplatin - toxicity; Dose-Response Relationship, Drug; Epithelial Cells - drug effects; Humans; Kidney Tubules, Proximal - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Molecular Structure; Oxidative Stress - drug effects; Signal Transduction - drug effects; Swine
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/acs.chemrestox.1c00347

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.