Aldo-Keto Reductases and Cancer Drug Resistance

Penning, T.M.; Jonnalagadda, Sravan K.; Trippier, Paul C.; Rižner, Tea Lanišnik

doi:10.1124/pharmrev.120.000122

Cited by 87 publications

(83 citation statements)

References 132 publications

(197 reference statements)

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“…In addition, other oxidoreductases, especially among the Medium-Chain dehydrogenase/Reductase (MDR) superfamily, could in principle carry out similar oxidation of secondary alcohol-containing substrates ( Persson et al, 2008 ), which could widen the field of application of our findings. Conversely, some carbonyl reductases, especially among the Aldo-Keto Reductase (AKR) superfamily ( Oppermann, 2007 ; Penning et al, 2021 ), could theoretically antagonize DACones cytotoxicity by reverting the reactive ketone into the corresponding alcohol, which could be further conjugated and eliminated. However, the fact that modulating glutathione levels or GST activity in cells only had a very small impact on ( S )-DAC cytotoxicity ( Figure 3—figure supplement 3D ,E ) indicates that, once produced, DACones immediately react with nearby proteins which limits the activity of general detoxification mechanisms.…”

Section: Discussionmentioning

confidence: 99%

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Demange

Joly

Marcoux

et al. 2022

eLife

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Hundreds of cytotoxic natural or synthetic lipidic compounds contain chiral alkynylcarbinol motifs, but the mechanism of action of those potential therapeutic agents remains unknown. Using a genetic screen in haploid human cells, we discovered that the enantiospecific cytotoxicity of numerous terminal alkynylcarbinols, including the highly cytotoxic dialkynylcarbinols, involves a bioactivation by HSD17B11, a short-chain dehydrogenase/reductase (SDR) known to oxidize the C-17 carbinol center of androstan-3-alpha,17-beta-diol to the corresponding ketone. A similar oxidation of dialkynylcarbinols generates dialkynylketones, that we characterize as highly protein-reactive electrophiles. We established that, once bioactivated in cells, the dialkynylcarbinols covalently modify several proteins involved in protein-quality control mechanisms, resulting in their lipoxidation on cysteines and lysines through Michael addition. For some proteins, this triggers their association to cellular membranes and results in endoplasmic reticulum stress, unfolded protein response activation, ubiquitin-proteasome system inhibition and cell death by apoptosis. Finally, as a proof-of-concept, we show that generic lipidic alkynylcarbinols can be devised to be bioactivated by other SDRs, including human RDH11 and HPGD/15-PGDH. Given that the SDR superfamily is one of the largest and most ubiquitous, this unique cytotoxic mechanism-of-action could be widely exploited to treat diseases, in particular cancer, through the design of tailored prodrugs.

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Section: Discussionmentioning

confidence: 99%

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Demange

Joly

Marcoux

et al. 2022

eLife

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“…Surprisingly, AKR1B1 and AKR1B10 were not associated with different responses to chemotherapy although most of the patients included in our study received paclitaxel and carboplatin chemotherapy and both AKR1B1 and AKR1B10 have previously been implicated in the resistance to platinum-based drugs [56]. However, we have to point out that no BRCA mutation status or HRD status were available to stratify these patients or to perform a survival analysis accordingly, which represents a weakness of this study.…”

Section: Discussionmentioning

confidence: 83%

AKR1B1 as a Prognostic Biomarker of High-Grade Serous Ovarian Cancer

Hojnik

Šuster

Smrkolj

et al. 2022

Cancers

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Although aldo-keto reductases (AKRs) have been widely studied in cancer, no study to date has examined the roles of AKR family 1 members B1 (AKR1B1) and B10 (AKR1B10) in a large group of ovarian cancer patients. AKR1B1 and AKR1B10 play a significant role in inflammation and the metabolism of different chemotherapeutics as well as cell differentiation, proliferation, and apoptosis. Due to these functions, we examined the potential of AKR1B1 and AKR1B10 as tissue biomarkers. We assessed the immunohistochemical levels of AKR1B1 and AKR1B10 in tissue paraffin sections from 99 patients with high-grade serous ovarian cancer (HGSC) and compared these levels with clinicopathological characteristics, survival, and response to chemotherapy. A higher immunohistochemical AKR1B1 expression correlated with a better overall and disease-free survival of HGSC patients whereas AKR1B10 expression did not show any significant differences. A multivariant Cox analysis demonstrated that a high AKR1B1 expression was an important prognostic factor for both overall and disease-free survival. However, AKR1B1 and AKR1B10 were not associated with different responses to chemotherapy. Our data suggest that AKR1B1 is involved in the pathogenesis of HGSC and is a potential prognostic biomarker for this cancer.

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“…This phenomenon is related to the positive regulation of human aldo-keto reductases (AKRs) by Nrf2. AKRs directly participate in drug metabolism or eliminate the cell stress caused by drugs, especially ROS and lipid peroxidation, and promote tumor resistance to these drugs ( Penning et al, 2021 ).…”

Section: Crosstalk Between Ferroptosis and Tumor Drug Resistancementioning

confidence: 99%

Ferroptosis and Tumor Drug Resistance: Current Status and Major Challenges

et al. 2022

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Ferroptosis is a novel type of regulated cell death, whose unique metabolic characteristics are commonly used to evaluate the conditions of various diseases especially in tumors. Accumulating evidence supports that ferroptosis can regulate tumor development, metastasis, and therapeutic responses. Considering to the important role of chemotherapy in tumor treatment, drug resistance has become the most serious challenge. Revealing the molecular mechanism of ferroptosis is expected to solve tumor drug resistance and find new therapies to treat cancers. In this review, we discuss the relationship between ferroptosis and tumor drug resistance, summarize the abnormal ferroptosis in tissues of different cancer types and current research progress and challenges in overcoming treatment resistance, and explore the concept of targeting ferroptosis to improve tumor treatment outcomes.

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Aldo-Keto Reductases and Cancer Drug Resistance

Abstract: Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer chemotherapeutic agents either because they are directly involved in their metabolism or help eradicate

Cited by 87 publications

References 132 publications

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

AKR1B1 as a Prognostic Biomarker of High-Grade Serous Ovarian Cancer

Ferroptosis and Tumor Drug Resistance: Current Status and Major Challenges

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