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Review
. 2024 Jul 17;32(8):1287-1308.
doi: 10.32604/or.2024.049918. eCollection 2024.

Aldo-keto reductases: Role in cancer development and theranostics

Siddavaram Nagini  1 , Prathap Reddy Kallamadi  2 , Kranthi Kiran Kishore Tanagala  3 , Geereddy Bhanuprakash Reddy  2
Affiliations
Review

Aldo-keto reductases: Role in cancer development and theranostics

Siddavaram Nagini et al. Oncol Res. .

Abstract

Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized.

Keywords: Aldo-keto reductase (AKR) inhibitors; Aldo-keto reductases (AKRs); Cancer; Drug-resistance; Xenobiotics.

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Conflict of interest statement

All authors declare no conflicts of interest whatsoever.

Figures

Figure 1A
Figure 1A. A schematic representation of AKR1B1 gene structure.
Figure 1B
Figure 1B. Crystal structures of AKR1B1 and AKR1B10 (Source: RCSB PDB).
Figure 2
Figure 2. Role of AKRs in the acquisition of hallmarks and scope for therapeutic targeting (LPS-lipopolysaccharide, ROS-reactive oxygen species, HNE-4-hydroxytrans-2-nonenal, GSH-reduced glutathione, PLC-phosphatidylcholine by phospholipase C, PKC-protein kinase C, PI3K-phosphoinositide 3-kinase, MAPK-mitogen-activated protein kinases, NF-κB-nuclear factor-κB, AP1-activator protein-1, HIF1α-hypoxia-inducible factor-1α).
Figure 3
Figure 3. Under normal conditions, there is a basal level of NRF2 expression, while its expression is transiently increased upon exposure to toxic chemicals and ROS as a part of detoxification. However, sustained NRF2 activation confers resistance on cancer cells to anticancer drugs and radiation (SDH-sorbitol dehydrogenase, NADP-nicotinamide-adenine dinucleotide phosphate, NAD-nicotinamide-adenine dinucleotide, ROS-reactive oxygen species, Keap1-Kelch-like ECH-associated protein 1, NRF2-nuclear factor erythroid 2 p45-related factor 2, ARE-antioxidant response element).
Figure 4
Figure 4. 2D structures of major AR inhibitors.
See this image and copyright information in PMC

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