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  • To further demonstrate the significance of Nrf activation in

    2024-05-14

    To further demonstrate the significance of Nrf2 activation in the prevention of EGF-induced CRC growth by AR inhibitor, we examined the effect of fidarestat on EGF-induced cell viability in Nrf2-ablated cells. Our results suggest that AR inhibitor prevented the EGF-induced cell viability in control DDD107498 but not in Nrf2-ablated cells suggesting that Nrf2-mediated anti-oxidative pathways are required for AR-regulated cell viability. Since Nrf2 also transcribes genes responsible for mitochondrial biogenesis [12], we examined the effect of AR inhibitor on mitochondrial biogenesis in CRC cells. Our results demonstrate that AR inhibitor increased the expression of PGC-1α, a master regulator of the transcriptional network which regulates mitochondrial biogenesis in CRC cells. It is also suggested that PGC-1α causes apoptosis and acts as a tumor suppressor in some cancers [33]. Furthermore, expression of another transcription factor, Nrf1, activated by PGC-1α, acts on nuclear genes coding for proteins necessary for the mitochondrial biogenesis or for mtDNA transcription and replication [13], [14], [15], significantly increased in the cells pretreated with fidarestat. Both PGC-1α and Nrf1 co-activate the expression of TFAM, which is also important for the regulation and maintenance of mtDNA integrity [13]. Our results show that the protein expression of PGC-1α and TFAM associated with mitochondrial biogenesis increased in CRC cells treated with EGF + fidarestat. Further, AR inhibitor prevented DDD107498 the EGF-induced mitochondrial DNA damage. These observations indicate that AR inhibition could prevent CRC cell growth by increasing the mitochondrial biogenesis and expression of tumor suppressor genes such as PGC-1α and p53 and decreasing the DNA damage [34], [35]. Our results also suggest that AMPK plays a significant role in the maintenance of intracellular energy balance, phosphorylates Nrf2 at Ser550, promotes nuclear accumulation of Nrf2, and upregulates PGC-1α and mitochondrial biogenesis [36]. Similarly, tumor suppressor p53 also plays a major role in cellular response to diverse intracellular and extracellular stresses including DNA damage and oncogene expression [37].
    Acknowledgment Supported by NIH grant CA129383.
    The incidence of diabetes mellitus has markedly increased over the last century due to changes in human life style and behavior. Estimates indicate that about 400million patient worldwide are affected by diabetes and by the year 2030, about 10% of world population will suffer from this chronic disease. More importantly, the management of the debilitating complications associated with diabetes costs at least 10% of overall healthcare cost in many countries. For these reasons, the discovery and development of drugs for prevention and treatment of diabetic complications will remain a major challenge to medicinal chemists. In this context, there has been a growing interest over the last few decades in aldose reductase inhibitors as therapeutic candidates for diabetic complications., , , , , , , , , , , , , , , , , , , , , , Aldose reductase (ALR-2) is the key enzyme of the polyol pathway through which glucose is metabolized under conditions of hyperglycemia associated with diabetes. In the polyol pathway, glucose is reduced by aldose reductase to sorbitol with the associated oxidation of NADPH to NADP. The accumulation of sorbitol in cells leads to osmotic stress. The second step in the polyol pathway involves the oxidation of sorbitol to fructose by the enzyme sorbitol dehydrogenase using NAD as a cofactor. Alteration of the proportion of cytosolic NADH to NAD results in oxidative stress which is associated with reduced intracellular concentrations of glutathione, activation of protein kinase C, and non-enzymatic glycation., Aldose reductase inhibitors are categorized into two major classes: acetic acid derivatives and the cyclic imides. The acetic acid derivatives currently available include epalrestat, tolrestat, zenarestat, and ponalrestat. The cyclic imides include the hydantoins and their bioisosteres such as the rhodanines, 2,4-thiazolidinediones, and the succinimides. Sorbinil, fidarestat, and imirestat are hydantoins whereas, ranirestat and minalrestat belong to the succinimides. (). Unfortunately, many of these agents were unsuccessful in clinical trials due to poor pharmacokinetics, adverse effects, or low efficacy. Only epalrestat, which is a rhodanineacetic acid derivative, was approved for clinical use in Japan, China and India. Long-term studies have revealed that epalrestat is generally well tolerated with only mild side effects such as nausea, vomiting, and elevation of liver enzyme levels., , , , , These findings urged us to address novel rhodanineacetic acid derivatives as potential useful therapeutic candidates for the management of diabetic complications. In the present investigation, a series of quinazolinone-based rhodanineacetic acid derivatives was designed, synthesized, and tested for aldose reductase inhibitory activity. Another series of representative rhodanines lacking the acetic acid moiety was also tested for comparison purposes.