Drug-metabolizing enzymes: role in drug resistance in cancer

Kaur, Gagandeep; Gupta, Sonu Kumar; Singh, Priyanka; Ali, Villayat; Kumar, Vinod; Verma, Malkhey

doi:10.1007/s12094-020-02325-7

Cited by 74 publications

(42 citation statements)

References 87 publications

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“…xenobiotic metabolism was predicted to be activated in response to cisplatin (constitutive androstane receptor (CAR) signaling and pregnane X receptor (PXR) signaling pathways with respective zscores of 0.45 and 2.0). These findings are consistent with the observations that cisplatin inhibits eukaryotic translation (51) and, like other chemotherapeutic agents, induces the upregulation of drug metabolism pathways (52,53).…”

Section: Comparative Pathway Analysissupporting

confidence: 92%

“…Our findings reveal the drug metabolism enzymes ALDH3A1, GSTM3 and glutathione S-transferase K1 (GSTK1) as significantly upregulated by cisplatin. Expression of drug detoxification and xenobiotic metabolizing enzymes are linked with patient response to chemotherapy and the onset of drug resistance by clearing reactive and cytotoxic compounds (52,53). For example, ALDH3A1 activity is reported to increase upon cisplatin treatment, suggesting that this enzyme can metabolize cytotoxic aldehydes and confer resistance to cisplatin (68)(69)(70).…”

Section: Discussionmentioning

confidence: 99%

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Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

et al. 2021

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Platinum-based chemotherapy remains the cornerstone of treatment for most people with non-small cell lung cancer (NSCLC), either as adjuvant therapy in combination with a second cytotoxic agent or in combination with immunotherapy. Resistance to therapy, either in the form of primary refractory disease or evolutionary resistance, remains a significant issue in the treatment of NSCLC. Hence, predictive biomarkers and novel combinational strategies are required to improve the effectiveness and durability of treatment response 6for people with NSCLC. The aim of this study was to identify novel biomarkers and/or druggable proteins from deregulated protein networks within non-oncogene driven disease that are involved in the cellular response to cisplatin. Following exposure of NSCLC cells to cisplatin, in vitro quantitative mass spectrometry was applied to identify altered protein response networks. A total of 65 proteins were significantly deregulated following cisplatin exposure. These proteins were assessed to determine if they are druggable targets using novel machine learning approaches and to identify whether these proteins might serve as prognosticators of platinum therapy. Our data demonstrate novel candidates and drug-like molecules warranting further investigation to improve response to platinum agents in NSCLC.

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Section: Comparative Pathway Analysissupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

et al. 2021

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“…However, these genes also show tissue-specific and dynamically-regulated interindividual variation in expression that may have more profound impacts on ADME properties of tissues (including tumours) than genetic variance. ADME genes are highly expressed in the liver, the major organ for systemic drug metabolism and clearance, but are also expressed extrahepatically and in cancerous tissues where their expression has been associated with cancer progression and anticancer drug resistance [19,[22][23][24]. This knowledge emphasizes the need for a comprehensive analysis of ADME gene expression profiles in tumours, and their impact on cancer patient survival.…”

Section: Introductionmentioning

confidence: 99%

The Expression Profiles of ADME Genes in Human Cancers and Their Associations with Clinical Outcomes

Mackenzie

Nair

et al. 2020

Cancers

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ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival; however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed differential intratumoral expression profiles for ADME genes in 21 different cancer types. Most genes also showed high interindividual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7); sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1), LUAD (SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.

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“…Cytochrome P450 (CYP) is the main enzyme of phase I detoxification, which converts xenobiotics to active intermediates [79]. In tumour tissues, CYP cause resistance by metabolising and, therefore, targetly deactivating the cytostatics [80]. Phase II detoxification enzymes, including glutathione S-transferases (GSTs), NAD(P)H:quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1), catalyze the conjugation of these active intermediates by sulfation or glucuronidation [81].…”

Section: Detoxification Processesmentioning

confidence: 99%

Genoprotective activities of plant natural substances in cancer and chemopreventive strategies in the context of 3P medicine

et al. 2020

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Severe durable changes may occur to the DNA structure caused by exogenous and endogenous risk factors initiating the process of carcinogenesis. By evidence, a large portion of malignancies have been demonstrated as being preventable. Moreover, the targeted prevention of cancer onset is possible, due to unique properties of plant bioactive compounds. Although genoprotective effects of phytochemicals have been well documented, there is an evident lack of articles which would systematically present the spectrum of anticancer effects by phytochemicals, plant extracts, and plant-derived diet applicable to stratified patient groups at the level of targeted primary (cancer development) and secondary (cancer progression and metastatic disease) prevention. Consequently, clinical implementation of knowledge accumulated in the area is still highly restricted. To stimulate coherent co-development of the dedicated plant bioactive compound investigation on one hand and comprehensive cancer preventive strategies on the other hand, the current paper highlights and deeply analyses relevant evidence available in the area. Key molecular mechanisms are presented to detail genoprotective and anticancer activities of plants and phytochemicals. Clinical implementation is discussed. Based on the presented evidence, advanced chemopreventive strategies in the context of 3P medicine are considered.

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Drug-metabolizing enzymes: role in drug resistance in cancer

Cited by 74 publications

References 87 publications

Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

The Expression Profiles of ADME Genes in Human Cancers and Their Associations with Clinical Outcomes

Genoprotective activities of plant natural substances in cancer and chemopreventive strategies in the context of 3P medicine

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