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Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of...
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Context 1
... and others have demonstrated a significant role of CYP1B1 in the pathogenesis of cardiovascular diseases, most remarkably in cardiac hypertrophy and hypertension (Table 1). El-Kadi and colleagues demonstrated that cardiac CYP1B1 expression was up-regulated in different models of cardiac hypertrophy induced by isoproterenol [82][83][84], pressure overload [85,86], angiotensin II [73], and polycyclic aromatic hydrocarbons [42,87]. ...Citations
... 23,24 In contrast, CYP1A1 and CYP1B1 are primarily expressed by extrahepatic tissues, including the lungs, heart, gastrointestinal tract, kidney and uterus. [25][26][27][28][29][30] Notably, CYP1B1 is the most abundantly expressed CYP gene in human hearts. 31 Cyp1b1 has been reported to contribute to the development of hypertension and renal dysfunction in male mice. ...
Background
Anthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy and heart failure. Our laboratory previously reported that induction of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute Dox cardiotoxicity in zebrafish and in mice, and that potent Cyp1 inhibitors prevent cardiotoxicity. However, the role of Cyp1 enzymes in chronic Dox cardiomyopathy, as well as the mechanisms underlying cardioprotection associated with Cyp1 inhibition, have not been fully elucidated.
Methods
The Cyp1 pathway was evaluated using a small molecule Cyp1 inhibitor in wild-type (WT) mice, or Cyp1-null mice ( Cyp1a1/1a2 -/- , Cyp1b1 -/- , and Cyp1a1/1a2/1b1 -/- ). Low-dose Dox was administered by serial intraperitoneal or intravenous injections, respectively. Expression of Cyp1 isoforms was measured by RT-qPCR, and myocardial tissue was isolated from the left ventricle for RNA sequencing. Cardiac function was evaluated by transthoracic echocardiography.
Results
In WT mice, Dox treatment was associated with a decrease in Cyp1a2 and increase in Cyp1b1 expression in the heart and in the liver. Co-treatment of WT mice with Dox and the novel Cyp1 inhibitor YW-130 protected against cardiac dysfunction compared to Dox treatment alone. Cyp1a1/1a2 -/- and Cyp1a1/1a2/1b1 -/- mice were protected from Dox cardiomyopathy compared to WT mice. Male, but not female, Cyp1b1 -/- mice had increased cardiac dysfunction following Dox treatment compared to WT mice. RNA sequencing of myocardial tissue showed upregulation of Fundc1 and downregulation of Ccl21c in Cyp1a1/1a2 -/- mice treated with Dox, implicating changes in mitophagy and chemokine-mediated inflammation as possible mechanisms of Cyp1a-mediated cardioprotection.
Conclusions
Taken together, this study highlights the potential therapeutic value of Cyp1a inhibition in mitigating anthracycline cardiomyopathy.
... Some of the known shared target genes between EREs and RARs are related with EMT, ECM, focal adhesion, and antioxidant response 28,65-68 . Therefore it is interesting that CYP1B1 is involved in the metabolism of both 17β-oestradiol and all-trans retinoic acid 69 . Importantly, Cyp1b1 is among the NRF2-target genes 32 , suggesting that NRF2, via transcriptional modulation of Cyp1b1, may alter 17β-oestradiol and all-trans retinoic acid levels, with consequences on neuroprotection and regulation of ECM, EMT and focal adhesion, as discussed above. ...
Abstractdispe
Loss-of-function mutations in PARK7 , encoding for DJ-1, can lead to early onset Parkinson’s disease (PD). In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies. To understand the early molecular changes upon loss of DJ-1, we performed transcriptomic profiling of midbrain sections from young mice. Interestingly, while at 3 months the transcriptomes of both male and female mice were unchanged compared to their wildtype littermates, an extensive deregulation was observed specifically in 8-month-old males. The affected genes are involved in processes such as focal adhesion, extracellular matrix interaction, and epithelial-to-mesenchymal transition (EMT), and enriched for primary target genes of Nuclear factor erythroid 2-related factor 2 (NRF2). Consistently, the antioxidant response was altered specifically in the midbrain of male DJ-1 deficient mice. Many of the misregulated genes are known target genes of estrogen and retinoic acid signaling and show sex-specific expression in wildtype mice. Depletion of DJ-1 or NRF2 in male, but not female primary astrocytes recapitulated many of the in vivo changes, including downregulation of cytochrome P450 family 1 subfamily B member 1 (CYP1B1), an enzyme involved in estrogen and retinoic acid metabolism. Interestingly, knock-down of CYP1B1 led to gene expression changes in focal adhesion and EMT in primary male astrocytes. Finally, male iPSC-derived astrocytes with loss of function mutation in the PARK7 gene also showed changes in the EMT pathway and NRF2 target genes. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes specifically in males through astrocytic alterations in the NRF2-CYP1B1 axis. These findings suggest higher sensitivity of males to loss of DJ-1 and might help to better understand variation in the reported Park7 −/− phenotypes.
... CYP1B1 is a member of the CYP1 subfamily and encodes CYP1B1 enzyme which is involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids 26 . While many studies reported the role of CYP1B1 in glaucoma and cancer 27,28 , recent studies have indicated that CYP1B1 is involved in cardiac pathophysiological changes. For example, CYP1B1 has been found to mediate angiotensin II-induced aortic smooth muscle cell migration, proliferation, and protein synthesis in rats 29 , as well as to contribute to cardiac hypertrophy induced by uremic toxin in mice 30 . ...
Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.
... This gene has attracted attention because of its unusual properties and characteristics (19). The CYP1B1 gene belongs to the CPYP1 gene family, including the CYP1A1 and CYP1A2 genes (20). It is expressed in the liver and extrahepatic tissue and is located on chromosome 2 (21). ...
... This enzyme aids in the conversion of oestradiol and oestrone to their hydroxylated catechol oestrogens through oxidative metabolism (23). Previous research, observed a possible role for intracellular CY1PB1 levels in the risk of carcinogenity (19,20). CYP1B1 is regulated by several key transcription factors, such as the aryl hydrocarbon receptor (AhR) (24). ...
The pathogenesis of frontal fibrosing alopecia has been linked to specific genetic variants. CYP1B1 codes for a component of the cytochrome p450 machinery that is involved in the metabolism of xenobiotic oestrogens. The study of the prevalence of polymorphisms in this gene may help to understand their role in the development of frontal fibrosing alopecia. The aim of this study is to describe the frequency of genetic variations in the alleles HLA-B*07:02 and CYP1B1 in patients with frontal fibrosing alopecia. A cross-sectional study was designed to evaluate blood samples from patients with frontal fibrosing alopecia who attended the Dermatology Department at University Hospital Ramón y Cajal (Madrid, Spain), in search of the polymorphisms rs9258883 and rs1800440 in the alleles HLA-B*07:02 and CYP1B1, respectively. A total of 223 patients were included in the study. Among the 83.8% of patients who carried the rs9258883 polymorphism in HLA-B*07:02, 58.7% were heterozygous for this variant and it was not present in 14.8% of the cases. The majority of patients with frontal fibrosing alopecia lacked the protective rs1800440 polymorphism in CYP1B1 (75.2%). This suggests a relevant role of this variant in development of frontal fibrosing alopecia. The genetic approach to this condition might influence patient prognosis and therapy options.
... 53 Although it is possible that CYP1B1 may play different roles in regulating drug resistance in different cancer types, the inhibition of CYP1B1 activity has been considered to be a therapeutic target for improving chemotherapy. 54 Although lacking high selectivity, phytochemicals are the most common source of CYP1B1 inhibitors, including stilbene, flavonoids, coumarins, anthraquinones, and alkaloids. [55][56][57] By modifying the structures of phytochemicals, highly potent and selective inhibitors of CYP1B1 have been developed and under preclinical evaluation, such as TMS ((E)-2,3′,4,5′-tetramethoxystilbene) 58 and αnaphthoflavone derivatives. ...
Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.
... This extrahepatic enzyme transforms estrogen into DNA mutagens and is overexpressed in several types of tumors. Additionally, point mutations and CYP1B1 overexpression make many chemotherapeutics ineffective in cancer treatment (Carrera, Alexa N et al., 2020). The results of Docking have resulted in respective binding affinity ΔG (kcal/mol) shown in Table 4. ...
The current study was done on the whole plant Oxalis corniculata Linn (commonly known as creeping wood sorrel) which belongs to the genus Oxalis, and it is one of 500 species in the family Oxalidaceae, distributed in America, Africa, Europe, and Asia. This study focuses on the Phytochemical and antioxidant analysis of whole plant methanolic extract obtained through the Microwave-assisted extraction (MAE) method and evaluation of the molecular docking simulation, drug-likeness assessment, and pharmacokinetic study of bioactive compounds from Oxalis corniculata Linn against Cytochrome P450 (CYP) variants. Of all the time duration of MAE, 4 min extraction time is found to be the most ideal as it showed the highest antioxidant activity. The SwissADME analysis has shown that almost all tested ligands have good penetration for the brain and intestine. Via Swiss Prediction, it was detected that three ligands, namely Acacetin, Apigenin 7,4'-dimethyl ether, and Apigenin found to be good targets for Cytochrome P450 (CYP) variants, CYP450 1B1 and CYP450 19A1. Finally, of all the ligands that were chosen for molecular docking with cytochrome P450 variants, acacetin has shown the highest binding affinity. Therefore, suggesting that it might be a good potent inhibitor of CYP450 1B1.
... The CYP1 family enzymes are long been of interest to researchers due to their dominant role in the hydroxylation of pro-carcinogens such as polycyclic aromatic hydrocarbons [PAHs] and amines to cytotoxic and mutagenic chemicals [5]. Among these, the CYP1B1 is recognized as an intriguing therapeutic target for the following reasons (1) Its overexpression in extra-hepatic tissues, such as ovarian, lung, brain, lymph, breast, and colon cancer tissues, whereas no measurable level of CYP1B1 has been identified in neighboring normal tissues [6]; (2) Ability to trigger carcinogenic action of estradiol by converting 17-estradiol (E2) into 4-hydroxyestradiol a mutagenic compound [7]; (3) Its physiological role is found to be in various metabolic disorders, cardio-oncology, and metastasis [8][9][10]; (4) Its involvement in inactivation of structurally diverse anti-cancer drugs like docetaxel, paclitaxel, cisplatin, and imatinib that ultimately confers drug resistance [11,12]. These resistant drugs are the frontline anti-cancer drugs that are maximally prescribed among cancer patients. ...
Cytochrome P4501B1 (CYP1B1) is reported to be overexpressed in various malignancies including ovarian, lung, lymph, and breast cancers. The overexpression of this enzyme is accountable for the biotransformation-based inactivation of some anti-cancer drugs i.e. Docetaxel, Paclitaxel, and Cisplatin. To circumvent solutions to this issue, the current study reports some optimized derivatives of benzochalcone as selective CYP1B1 inhibitors. The optimized derivatives were screened using some structure-based drug-designing approaches including molecular docking and molecular dynamics. The implemented approaches revealed that all the designed molecules demonstrated not only essential interactions with key amino acid residues but also maintained stability within the active site of CYP1B1. Furthermore, to validate the in-silico results and develop a SAR, the designed molecules were subsequently synthesized and tested for their ability to selectively inhibit CYP1B1 over CYP1A1 using well established EROD assay. This assay results suggested that compounds 1(c), 1(d), and 1(e) are eightfold more selective CYP1B1 inhibitors over CYP1A1 with IC50 values ranging from 0.06 to 0.09 μM respectively. Among these, compound 1(d) manifested potent inhibitory activity i.e. IC50 of 0.06 μM with 24 folds selectivity over 1A1. To have a better insight into the binding pattern of 1(d) within CYP1B1 and precisely compute binding affinity for 1(d)-CYP1B1 complex, one of the advanced QM/MM approaches i.e. ONIOM has been implemented. Where 1(d)-CYP1B1 complex conferred comparable binding affinity in terms of ΔG (kcal/mol) with that of ANF-CYP1B1 complex. This research could provide a suitable starting point for the development of more potent multi-functional compounds with CYP1B1 inhibitory activity.
... Thus, CYP1B1 modulation may affect multiple mechanisms that provide chemotherapeutic benefit in breast cancer treatment. Chemical inhibitors of CYP1B1 are reported to increase the sensitivity of TNBC cell lines to CPT [42] and other compounds in several tumor types [43]. ...
... Such inhibition is also reported to impart cardioprotective effects [43] indicating that there may be added benefits to chemotherapy approaches that include CYP1B1 inhibitors. ...
Cytochrome P4501B1 (CYP1B1) is elevated in breast cancer. Studies indicate a relationship between CYP1B1 and aggressive cancer phenotypes. Here, we report on in vitro studies in triple-negative breast cancer cell lines, where knockdown (KD) of CYP1B1 was used to determine the influence of its expression on invasive cell phenotypes. CYP1B1 KD in MDA-MB-231 cells resulted in the loss of mesenchymal morphology, altered expression of epithelial–mesenchymal genes, and increased claudin (CLDN) RNA and protein. CYP1B1 KD cells had increased cell-to-cell contact and paracellular barrier function, a reduced rate of cell proliferation, abrogation of migratory and invasive activity, and diminished spheroid formation. Analysis of clinical breast cancer tumor samples revealed an association between tumors exhibiting higher CYP1B1 RNA levels and diminished overall and disease-free survival. Tumor expression of CYP1B1 was inversely associated with CLDN7 expression, and CYP1B1HI/CLDN7LOW identified patients with lower median survival. Cells with CYP1B1 KD had an enhanced chemosensitivity to paclitaxel, 5-fluorouracil, and cisplatin. Our findings that CYP1B1 KD can increase chemosensitivity points to therapeutic targeting of this enzyme. CYP1B1 inhibitors in combination with chemotherapeutic drugs may provide a novel targeted and effective approach to adjuvant or neoadjuvant therapy against certain forms of highly metastatic breast cancer.
... Cardiac failure and hypertrophy are regulated by MAP kinases (MAPKs, (ERK)1/2, JNK, and p38 kinase [49,50]. Kaempferol inhibits the cytochrome P450 1B1 (CYP1B1) and Fc Epsilon RI signaling pathways, according to studies [51,52]; we confirmed this observation. Mast cells stimulated by IgE and FcR1 play a vital role in inflammatory diseases such as atherosclerosis, and the absence of FcR1 reduced inflammation, plaques, and the burden of atherosclerosis [53][54][55]. ...
Cardiovascular disease (CVD) is causing high mortality worldwide (World Health Organization-WHO, 2015). Atherosclerosis, the hardening and narrowing of arteries caused by the accumulation of fatty acids and lipids (cholesterol plaques), is a main reason of stroke, myocardial infarction, and angina. Present therapies for cardiovascular disease basically use statins such as β-Hydroxy β-methylglutaryl-CoA, with <70% efficacy and multiple side effects. An in vitro investigation was conducted to evaluate the impact of kaempferol, a natural medication, in an atherosclerotic cell model. We used cytotoxicity assays, Boyden chamber invasion assays, and quantitative PCR. Affymetrix microarrays were used to profile the entire transcriptome of kaempferol-treated cell lines, and Partek Genomic Suite was used to interpret the results. Kaempferol was not cytotoxic to THP-1 macrophages. In comparison to the control, kaempferol reduced monocyte migration mediated by monocyte chemotactic protein 1 (MCP-1) by 80%. The qPCR results showed a 73.7-fold reduction in MCP-1 and a 2.5-fold reduction in intercellular adhesion molecule 1 (ICAM-1) expression in kaempferol-treated cells. In interferon gamma (IFN-γ) without kaempferol and IFN-γ with kaempferol treated cells, we found 295 and 168 differentially expressed genes (DEGs), respectively. According to DEG pathway analysis, kaempferol exhibits anti-atherosclerosis and anti-inflammatory characteristics. Kaempferol is an effective and safe therapy for atherosclerosis.
... We have an interest in the cancer-associated CYP named CYP1B1. This extrahepatic enzyme is overexpressed in a variety of tumors and converts estrogen to DNA mutagens 17 , so it is considered a target for chemoprevention in hormone-associated cancers. Moreover, CYP1B1 overexpression and point mutations result in resistance to many chemotherapeutics, such as cisplatin 18 , daunorubicin 19 , and taxanes [20][21][22][23] . ...
The cytochrome P450 family of enzymes (CYPs) are important targets for medicinal chemistry. Recently, CYP1B1 has emerged as a key player in chemotherapy resistance in the treatment of cancer. This enzyme is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. However, possible off-target effects, such as inhibition of liver CYPs responsible for first pass metabolism, make selective inhibition a high priority to avoid possible drug-drug interactions and toxicity. Here we describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low energy (660 nm) light. These systems provide a selectivity index of 4,000–100,000 over other off-target CYPs. One key to the design was the development of coordinating CYP1B1 inhibitors, which suppress enzyme activity at pM concentrations in live cells. The metal binding group enforces inhibitor orientation in the active site by anchoring to the iron. The second essential component was the biologically compatible Ru(II) scaffold that cages the inhibitors before photochemical release. These Ru(II) photocages are anticipated to provide similar selectivity and control for any coordinating CYP inhibitors.
