Br J Clin Pharmacol. 2021 Aug 7. doi: 10.1111/bcp.15026. Online ahead of print.

ABSTRACT

In the past decade, direct oral anticoagulants (DOACs) have transformed the world of anti-thrombotic therapy. Edoxaban is the most recently approved DOAC. Though intended for use primarily in stroke prevention, it has found applications in various other conditions including thromboembolic and peripheral arterial disease. This review aims to provide a detailed outline of the growing indications, evidence for use in special populations, pharmacogenetics, and side effect profile of edoxaban.

PMID:34365675 | DOI:10.1111/bcp.15026

Clin Pharmacol Ther. 2021 Aug 8. doi: 10.1002/cpt.2387. Online ahead of print.

ABSTRACT

Clinical decision support (CDS) is an essential part of any pharmacogenomics (PGx) implementation. Increasingly institutions have CDS tools in the clinical setting to bring PGx data into patient care, and several have published their experiences with these implementations. However, barriers remain that limit the ability of some programs to create CDS tools to fit their PGx needs. Therefore, the purpose of this review is to summarize the types, functions, and limitations of PGx CDS currently in practice. Then, we provide an approachable step-by-step how-to guide with a case example to help implementers bring PGx to the front lines of care regardless of their setting. Particular focus is paid to the five 'rights' of CDS as a core around designing PGx CDS tools. Finally, we conclude with a discussion of opportunities and areas of growth for PGx CDS.

PMID:34365648 | DOI:10.1002/cpt.2387

Lasers Med Sci. 2021 Aug 8. doi: 10.1007/s10103-021-03381-3. Online ahead of print.

ABSTRACT

Non-melanoma skin cancer (NMSC) is the most common malignancy. Photodynamic therapy (PDT) is effective for the treatment of certain NMSCs. However, the clinical response rates of some NMSCs to single PDT are still far from ideal. The reason may be that PDT has shown limited efficacy in managing thicker NMSCs. To explore the efficacy and safety of dermabrasion combined with PDT (D-PDT) for the treatment of NMSCs. This was a retrospective, single-arm, multi-centre study. In total, 172 tumours from 40 patients were treated with D-PDT during the study period. The mean follow-up period was 40 months (range 15-110 months). D-PDT was performed with 633-nm red light at 80 m W/cm2 after lesion dermabrasion and 4 h of photosensitizer exposure. Six nodular basal cell carcinomas (nBCCs) from 6 patients, 9 squamous cell carcinomas (SCCs) from 9 patients, 17 Bowen diseases (BDs) from 10 patients and 140 actinic keratoses (AKs) from 15 patients treated with D-PDT were examined in this study. Only two patients with three AKs experienced recurrence over 12 months. The mean final follow-up periods of patients with AKs, BDs, nBCCs and SCCs were 30, 33, 45 and 60 months, respectively. Thirty-four of the 40 patients treated with D-PDT reported excellent or good cosmetic results. The mean Dermatology Life Quality Index (DLQI) scores of the patients improved significantly after treatment (estimated MD 9.72 [95% CI 8.69 to 10.75]; p < 0.001). D-PDT is a safe, cosmetic and effective treatment that could be a new candidate therapeutic for NMSC.

PMID:34365550 | DOI:10.1007/s10103-021-03381-3

Clin Ther. 2021 Aug 4:S0149-2918(21)00251-4. doi: 10.1016/j.clinthera.2021.07.006. Online ahead of print.

NO ABSTRACT

PMID:34364698 | DOI:10.1016/j.clinthera.2021.07.006

Am J Hum Genet. 2021 Aug 3:S0002-9297(21)00276-7. doi: 10.1016/j.ajhg.2021.07.008. Online ahead of print.

ABSTRACT

An individual's genetics can dramatically influence breast cancer (BC) risk. Although clinical measures for prevention do exist, non-invasive personalized measures for reducing BC risk are limited. Commonly used medications are a promising set of modifiable factors, but no previous study has explored whether a range of widely taken approved drugs modulate BC genetics. In this study, we describe a quantitative framework for exploring the interaction between the genetic susceptibility of BC and medication usage among UK Biobank women. We computed BC polygenic scores (PGSs) that summarize BC genetic risk and find that the PGS explains nearly three-times greater variation in disease risk within corticosteroid users compared to non-users. We map 35 genes significantly interacting with corticosteroid use (FDR < 0.1), highlighting the transcription factor NRF2 as a common regulator of gene-corticosteroid interactions in BC. Finally, we discover a regulatory variant strongly stratifying BC risk according to corticosteroid use. Within risk allele carriers, 18.2% of women taking corticosteroids developed BC, compared to 5.1% of the non-users (with an HR = 3.41 per-allele within corticosteroid users). In comparison, there are no differences in BC risk within the reference allele homozygotes. Overall, this work highlights the clinical relevance of gene-drug interactions in disease risk and provides a roadmap for repurposing biobanks in drug repositioning and precision medicine.

PMID:34363748 | DOI:10.1016/j.ajhg.2021.07.008

J Clin Med. 2021 Jul 21;10(15):3200. doi: 10.3390/jcm10153200.

ABSTRACT

There is a growing number of evidence-based indications for pharmacogenetic (PGx) testing. We aimed to evaluate clinical relevance of a 16-gene panel test for PGx-guided pharmacotherapy. In an observational cohort study, we included subjects tested with a PGx panel for variants of ABCB1, COMT, CYP1A2, CYP2B6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, CYP4F2, DPYD, OPRM1, POR, SLCO1B1, TPMT and VKORC1. PGx-guided pharmacotherapy management was supported by the PGx expert system SONOGEN XP. The primary study outcome was PGx-based changes and recommendations regarding current and potential future medication. PGx-testing was triggered by specific drug-gene pairs in 102 subjects, and by screening in 33. Based on PharmGKB expert guidelines we identified at least one "actionable" variant in all 135 (100%) tested patients. Drugs that triggered PGx-testing were clopidogrel in 60, tamoxifen in 15, polypsychopharmacotherapy in 9, opioids in 7, and other in 11 patients. Among those, PGx variants resulted in clinical recommendations to change PGx-triggering drugs in 33 (32.4%), and other current pharmacotherapy in 23 (22.5%). Additional costs of panel vs. single gene tests are moderate, and the efficiency of PGx panel testing challenges traditional cost-benefit calculations for single drug-gene pairs. However, PGx-guided pharmacotherapy requires specialized expert consultations with interdisciplinary collaborations.

PMID:34361984 | DOI:10.3390/jcm10153200

Int J Mol Sci. 2021 Jul 30;22(15):8221. doi: 10.3390/ijms22158221.

ABSTRACT

CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.

PMID:34360999 | DOI:10.3390/ijms22158221

Int J Mol Sci. 2021 Jul 28;22(15):8090. doi: 10.3390/ijms22158090.

ABSTRACT

Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.

PMID:34360853 | DOI:10.3390/ijms22158090

Int J Mol Sci. 2021 Jul 27;22(15):8041. doi: 10.3390/ijms22158041.

ABSTRACT

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF--5FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the (1) induction of cell cycle arrest in the S phase and (2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both the c-mesenchymal-epithelial transition (MET)/Kirsten rat sarcoma virus (KRAS)/extracellular signal-regulated kinase (ERK) and the c-MET/phosphatidyl-inositol 3-kinases (PI3K)/protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required in order to validate the results of the present study.

PMID:34360807 | DOI:10.3390/ijms22158041

Int J Mol Sci. 2021 Jul 21;22(15):7786. doi: 10.3390/ijms22157786.

ABSTRACT

Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigated the impact of such variants on protein structure to assess their functional importance. We used genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability seemed to act on the plasticity of the protein. The impact on drug binding might be drug dependant. We concluded that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.

PMID:34360551 | DOI:10.3390/ijms22157786

Cells. 2021 Jul 1;10(7):1657. doi: 10.3390/cells10071657.

ABSTRACT

Cancer is a disorder characterized by an uncontrollable overgrowth and a fast-moving spread of cells from a localized tissue to multiple organs of the body, reaching a metastatic state. Throughout years, complexity of cancer progression and invasion, high prevalence and incidence, as well as the high rise in treatment failure cases leading to a poor patient prognosis accounted for continuous experimental investigations on animals and cellular models, mainly with 2D- and 3D-cell culture. Nowadays, these research models are considered a main asset to reflect the physiological events in many cancer types in terms of cellular characteristics and features, replication and metastatic mechanisms, metabolic pathways, biomarkers expression, and chemotherapeutic agent resistance. In practice, based on research perspective and hypothesis, scientists aim to choose the best model to approach their understanding and to prove their hypothesis. Recently, 3D-cell models are seen to be highly incorporated as a crucial tool for reflecting the true cancer cell microenvironment in pharmacokinetic and pharmacodynamics studies, in addition to the intensity of anticancer drug response in pharmacogenomics trials. Hence, in this review, we shed light on the unique characteristics of 3D cells favoring its promising usage through a comparative approach with other research models, specifically 2D-cell culture. Plus, we will discuss the importance of 3D models as a direct reflector of the intrinsic cancer cell environment with the newest multiple methods and types available for 3D-cells implementation.

PMID:34359827 | DOI:10.3390/cells10071657

Cancers (Basel). 2021 Jul 25;13(15):3738. doi: 10.3390/cancers13153738.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a non-immunogenic tumor poorly responsive to immune checkpoint inhibitors. This study investigates the effect of 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX), and gemcitabine plus nab-paclitaxel (GEMnPAC) regimens on PD-L1 mRNA expression in plasma-derived microvesicles (MVs) in 50 PDAC patients. Plasma was collected before starting chemotherapy and after 3 months of treatment. mRNA was extracted from MVs, and PD-L1 expression was measured by digital droplet PCR. Twenty-eight patients were PD-L1 positive in MVs at baseline, of which 18 were in the GEMnPAC cohort and 10 in the FOLFIRINOX one. The amount of PD-L1 expression in MVs increased from baseline to 3 months of treatment in patients receiving GEMnPAC (median value 0.002 vs. 0.005; p = 0.01) compared to those treated with FOLFIRINOX (median 0.003 vs. 0.004; p = 0.97). The increase in PD-L1 mRNA expression in MVs was not related to tumor response (PR + SD: p = 0.08; PD: p = 0.28). Our findings demonstrate that GEMnPAC can increase PD-L1 mRNA expression in patient-derived circulating MVs, providing a rationale for testing the efficacy of this regimen in sequential or simultaneous combinations with immunotherapy in PDAC patients.

PMID:34359638 | DOI:10.3390/cancers13153738

Gastroenterology. 2021 Aug 3:S0016-5085(21)03338-2. doi: 10.1053/j.gastro.2021.07.043. Online ahead of print.

ABSTRACT

BACKGROUND/AIM: Helicobacter pylori infects approximately 50% of individuals worldwide. Successful H. pylori eradication is associated with reduced risk of gastric cancer and peptic ulcer disease, among other conditions. We hypothesized that host genetic determinants, especially those affecting gastric pH, might contribute to eradication therapy failure, particularly when treatment adherence and antibiotic susceptibility are confirmed. We aimed to conduct a meta-analysis of host genetic variants associated with H. pylori eradication failure.

METHODS: We searched the literature for studies comparing post-treatment H. pylori eradication failure vs success (outcome) according to host genetic polymorphisms (exposure). Reference groups were defined according to genotypes (or corresponding phenotypes) hypothesized to be associated with successful eradication. We pooled estimates using a random-effects model, and performed comprehensive sensitivity analyses.

RESULTS: We analyzed 57 studies from 11 countries; the vast majority analyzed CYP2C19 polymorphisms. Among individuals prescribed eradication regimens with PPIs predominantly CYP2C19-metabolized, enhanced vs poor metabolizer phenotypes were associated with a 2.52-fold significantly higher likelihood of eradication failure, and 4.44-fold significantly higher likelihood when treatment adherence and H. pylori clarithromycin susceptibility (if relevant) were confirmed. There was no association between CYP2C19 variants and eradication failure if PPIs less metabolized by or which bypass CYP2C19 metabolism were used. IL-1B polymorphisms that are vs. are not associated with less gastric acid suppression were associated with 1.72-fold significantly higher likelihood of eradication failure. There was no association between MDR1 polymorphisms and H. pylori eradication failure. The certainty of evidence was moderate.

CONCLUSION: Based on meta-analysis, we identified host genetic polymorphisms significantly associated with H. pylori eradication failure; host genetics might underlie eradication failure among treatment-adherent individuals with confirmed H. pylori antibiotic susceptibility.

PMID:34358488 | DOI:10.1053/j.gastro.2021.07.043

Mol Diagn Ther. 2021 Aug 6. doi: 10.1007/s40291-021-00549-z. Online ahead of print.

ABSTRACT

Anticoagulant and antiplatelet drugs effectively prevent thrombotic events in patients with cardiovascular diseases, ischemic stroke, peripheral vascular diseases, and other thromboembolic diseases. However, genetic and non-genetic factors affect the response to antithrombotic therapy and can increase the risk of adverse events. This narrative review discusses pharmacogenomic studies on antithrombotic drugs commonly prescribed in Brazil. Multiple Brazilian studies assessed the impact of pharmacokinetic (PK) and pharmacodynamic (PD) gene variants on warfarin response. The reduced function alleles CYP2C9*2 and CYP2C9*3, and VKORC1 rs9923231 (c.-1639G>A) are associated with increased sensitivity to warfarin and a low dose requirement to prevent bleeding episodes, whereas CYP4F2 rs2108622 (p.Val433Met) carriers have higher dose requirements (warfarin resistance). These deleterious variants and non-genetic factors (age, gender, body weight, co-administered drugs, food interactions, and others) account for up to 63% of the warfarin dose variability. Few pharmacogenomics studies have explored antiplatelet drugs in Brazilian cohorts, finding associations between CYP2C19*2, PON1 rs662 and ABCC3 rs757421 genotypes and platelet responsiveness or clopidogrel PK in subjects with coronary artery disease (CAD) or acute coronary syndrome (ACS), whereas ITGB3 contributes to aspirin PK but not platelet responsiveness in diabetic patients. Brazilian guidelines on anticoagulants and antiplatelets recommend the use of a platelet aggregation test or genotyping only in selected cases of ACS subjects without ST-segment elevation taking clopidogrel, and also suggest CYP2C9 and VKORC1 genotyping before starting warfarin therapy to assess the risk of bleeding episodes or warfarin resistance.

PMID:34357562 | DOI:10.1007/s40291-021-00549-z

J Pers Med. 2021 Jul 19;11(7):677. doi: 10.3390/jpm11070677.

ABSTRACT

Purpose: Cytochrome P450 (CYP) is involved in the metabolism of statins; CYP3A5 is the main enzyme responsible for lipophilic statin metabolism. However, the evidence of the association between CYP3A5*3 polymorphism and the risk of statin-induced adverse events remains unclear. Therefore, this study aimed to perform a systematic review and meta-analysis to investigate the relationship between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events. Methods: The PubMed, Web of Science, and EMBASE databases were searched for qualified studies published until August 2020. Observational studies that included the association between statin-induced adverse events and the CYP3A5*3 polymorphism were reviewed. The odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. The Mantel-Haenszel method was used to provide the pooled ORs. Heterogeneity was estimated with I2 statistics and publication bias was determined by Begg's and Egger's test of the funnel plot. Data analysis was performed using Review Manager (version 5.4) and R Studio (version 3.6). Results: In total, data from 8 studies involving 1614 patients were included in this meta-analysis. The CYP3A5*3 polymorphism was found to be associated with the risk of statin-induced adverse events (*3/*3 vs. *1/*1 + *1/*3: OR = 1.40, 95% CI = 1.08-1.82). For myopathy, the pooled OR was 1.30 (95% CI: 0.96-1.75). The subgroup analysis of statin-induced myopathy revealed a trend, which did not achieve statistical significance. Conclusions: This meta-analysis demonstrated that the CYP3A5*3 polymorphism affected statin-induced adverse event risk. Therefore, CYP3A5 genotyping may be useful to predict statin toxicity.

PMID:34357144 | DOI:10.3390/jpm11070677

J Pers Med. 2021 Jul 8;11(7):647. doi: 10.3390/jpm11070647.

ABSTRACT

The complexity of genomic medicine can be streamlined by implementing some form of clinical decision support (CDS) to guide clinicians in how to use and interpret personalized data; however, it is not yet clear which strategies are best suited for this purpose. In this study, we used implementation science to identify common strategies for applying provider-based CDS interventions across six genomic medicine clinical research projects funded by an NIH consortium. Each project's strategies were elicited via a structured survey derived from a typology of implementation strategies, the Expert Recommendations for Implementing Change (ERIC), and follow-up interviews guided by both implementation strategy reporting criteria and a planning framework, RE-AIM, to obtain more detail about implementation strategies and desired outcomes. We found that, on average, the three pharmacogenomics implementation projects used more strategies than the disease-focused projects. Overall, projects had four implementation strategies in common; however, operationalization of each differed in accordance with each study's implementation outcomes. These four common strategies may be important for precision medicine program implementation, and pharmacogenomics may require more integration into clinical care. Understanding how and why these strategies were successfully employed could be useful for others implementing genomic or precision medicine programs in different contexts.

PMID:34357114 | DOI:10.3390/jpm11070647

J Pers Med. 2021 Jul 1;11(7):628. doi: 10.3390/jpm11070628.

ABSTRACT

Data supporting the use of Tocilizumab (TCZ) in COVID-19 are contrasting and inconclusive. This meta-analysis aimed to assess TCZ effectiveness in reducing the mortality rate in COVID-19 patients. PubMed, Scopus, Embase, Cochrane, WILEY, and ClinicalTrials.gov were searched to evaluate observational studies and RCTs. The outcome was the mortality rate. Forty observational studies and seven RCTs, involving 9640 and 5556 subjects treated with Standard Therapy (ST) + TCZ or ST alone, respectively, were included. In patients treated with ST+TCZ, a higher survival (Log odds ratio = -0.41; 95% CI: -0.68 -0.14; p < 0.001) was found. Subgroups analyses were performed to better identify the possible interference of some parameters in modifying the efficacy of TCZ therapy on COVID-19 mortality. Separating observational from RCTs, no statistically significant (p = 0.70) TCZ-related reduction of mortality regarding RCTs was found, while a significant reduction (Log odds ratio = -0.52; 95% CI: -0.82 -0.22, p < 0.001) was achieved regarding the observational studies. Stratifying for the use of Invasive Mechanic Ventilation (IMV), a higher survival was found in patients treated with TCZ in the No-IMV and IMV groups (both p < 0.001), but not in the No-IMV/IMV group. Meta-regression analyses were also performed. The meta-analysis of observational studies reveals that TCZ is associated with reducing the mortality rate in both severe and critically ill patients. Although the largest RCT, RECOVERY, is in line with this result, the meta-analysis of RCTs failed to found any difference between ST + TCZ and ST. It is crucial to personalize the therapy considering the patients' characteristics.

PMID:34357095 | DOI:10.3390/jpm11070628

Life (Basel). 2021 Jul 9;11(7):673. doi: 10.3390/life11070673.

ABSTRACT

In the herein reported case of a 42-year-old woman diagnosed with anxiety and depression, a long history of antidepressant ineffectiveness and adverse drug reactions was decisive for an in-depth medication review including pharmacogenetic panel testing. In detail, treatment attempts with paroxetine and escitalopram were ineffective and discontinued due to subjective gastrointestinal intolerance. Due to the worsening of the depression after the failed treatment attempts, admission to our clinic became necessary. Herein, owing to the collaboration of psychiatrists with clinical pharmacists, individualized incorporation of pharmacogenetic data into the process of antidepressant selection was enabled. We identified vortioxetine as a suitable therapeutic, namely for being most likely pharmacokinetically unaffected as predicted by pharmacogenetic panel testing and taking into account the current comedication, as well as for its favorable action profile. Herein, our collaborative effort proved to be successful and resulted in the patient's depression remission and clinic discharge with the interprofessionally selected pharmacotherapy. This exemplary case not only highlights the potential benefits and challenges of pre-emptive pharmacogenetic testing in antidepressant prescription, but also proposes an approach on how to put pharmacogenetics into practice.

PMID:34357045 | DOI:10.3390/life11070673

Biomedicines. 2021 Jul 1;9(7):766. doi: 10.3390/biomedicines9070766.

ABSTRACT

Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML-targeted therapy.

PMID:34356831 | DOI:10.3390/biomedicines9070766

Biomolecules. 2021 Jul 16;11(7):1042. doi: 10.3390/biom11071042.

ABSTRACT

The emergence of drug resistance is one of the main obstacles to the treatment of lung cancer patients with EGFR inhibitors. Here, to further understand the mechanism of EGFR inhibitors in lung cancer and offer novel therapeutic targets for anti-EGFR-inhibitor resistance via the deep mining of pharmacogenomics data, we associated DNA methylation with drug sensitivities for uncovering the methylation sites related to EGFR inhibitor sensitivity genes. Specifically, we first introduced a grouped regularized regression model (Group Least Absolute Shrinkage and Selection Operator, group lasso) to detect the genes that were closely related to EGFR inhibitor effectiveness. Then, we applied the classical regression model (lasso) to identify the methylation sites associated with the above drug sensitivity genes. The new model was validated on the well-known cancer genomics resource: CTRP. GeneHancer and Encyclopedia of DNA Elements (ENCODE) database searches indicated that the predicted methylation sites related to EGFR inhibitor sensitivity genes were related to regulatory elements. Moreover, the correlation analysis on sensitivity genes and predicted methylation sites suggested that the methylation sites located in the promoter region were more correlated with the expression of EGFR inhibitor sensitivity genes than those located in the enhancer region and the TFBS. Meanwhile, we performed differential expression analysis of genes and predicted methylation sites and found that changes in the methylation level of some sites may affect the expression of the corresponding EGFR inhibitor-responsive genes. Therefore, we supposed that the effectiveness of EGFR inhibitors in lung cancer may be improved by methylation modification in their sensitivity genes.

PMID:34356665 | DOI:10.3390/biom11071042