An Original Aspirin-Containing Carbonic Anhydrase 9 Inhibitor Overcomes Hypoxia-Induced Drug Resistance to Enhance the Efficacy of Myocardial Protection

Abstract

Purpose Hypoxic microenvironment plays a vital role in myocardial ischemia injury, generally leading to the resistance of chemotherapeutic drugs. This induces an intriguing study on mechanism exploration and prodrug design to overcome the hypoxia induced drug resistance.Methods In this study, we hypothesized that the overexpression of carbonic anhydrase 9 (CAIX) in myocardial cells is closely related to the drug resistance. Herein, bioinformatics analysis, gene knockdown and overexpression assay certi cated the correlation between CAIX overexpression and hypoxia. An original aspirin-containing CAIX inhibitor AcAs has been developed.Results Based on the downregulation of CAIX level, both in vitro and in vivo, AcAs can overcome the acquired resistance, and more effectively attenuate myocardial ischemia and hypoxia injury than that of aspirin. CAIX inhibitor is believed to recover the extracellular pH value so as to ensure the stable effect of aspirin.Conclusion Results indicate great potential of CAIX inhibitor for further application in myocardial hypoxia injury therapy.

Discovery of Efficient Hypoxia-Targeted NO Donor Compounds to Alleviate Hypoxia Cardiac Disease

“…It is recognized as one of the safe modeling agents for the construction of myocardial ischemia models. 28,30 In the blank group, an equal amount of 0.5% sodium carboxymethyl cellulose was injected. In the medicated groups, starting from the third day of modeling, after ISO injection, the drug was given by intraperitoneal injection and again at an interval of 8 h for 3 consecutive days.…”

“…Because the increased electronegativity promotes binding of the NO moiety in the NO donors with heme iron ions in the active center of cytochrome P450 (Cyt-P450), it can facilitate the catalytic release of NO. 30 Therefore, the adjustment of the electronegativity of the −NO terminal at the NO donors can be made to optimize the NO release as expected. It has been reported that the NO release ratio is dependent on the chemical structure of the donor itself and the chemical environment.…”

Hypoxia-Activated Prodrugs with Dual COX-2/CA Inhibitory Effects on Attenuating Cardiac Inflammation under Hypoxia

“…N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)hept-6-ynamide was prepared according to a literature method. 8 NMR spectra were performed on a Bruker 600 MHz Ultra shield spectrometer (Avance AV-500) and reported as parts per million (ppm) from tetramethylsilane (TMS). The final products were characterized by 1 H and 13 C NMR together with ESI-HRMS.…”

“…4-Nitrobenzyl alcohol, 2,6-bis­(hydroxymethyl)-4-methylphenol, 2-azidoacetic acid, and 4-(2-aminoethyl) benzenesulfonamide as well as indomethacin, naproxen, acetazolamide, and benzsulfamide were commercials. N -(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)­hept-6-ynamide was prepared according to a literature method . NMR spectra were performed on a Bruker 600 MHz Ultra shield spectrometer (Avance AV-500) and reported as parts per million (ppm) from tetramethylsilane (TMS).…”

“…In a hypoxic microenvironment, abnormal gene expressions lead to heart injuries . For example, carbonic anhydrase (CA) overexpression induced by hypoxia tends to produce abnormal acidity of cardiomyocytes, causing cardiac acidosis and pH-dependent primary resistance. − By reducing either H + –Na + exchange or HCO 3 – reabsorption, CA inhibitors (CAIs) are capable of regulating acidic pH values, inhibiting acidosis, and overcoming drug resistance. , However, the application of CAIs can cause apparent side effects on normal tissues, owing to the wide distribution of CA in multiple organs and tissues throughout the body. , Similar to CAIs, NSAIDs also have recognized side effects. As NSAIDs inhibit the activity of native enzyme COX-2, the conversion of TXA 2 to PG 2 I in endothelial cells is suppressed, which may induce thrombosis due to the imbalance of PG 2 I/TXA 2 . , Thus, a combination of CAIs and NSAIDs may be meaningful in the treatment of cardiac inflammation along with hypoxic injury for low toxicity and high efficiency.…”