Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)

Frasinyuk, M. S.; Zhang, Wen; Wyrebek, Przemyslaw; Yu, Ting; Xu, Xuehe; Sviripa, Vitaliy M.; Bondarenko, S. P.; Xie, Yanqi; Ngo, Huy; Morris, Andrew J.; Mohler, James L.; Fiandalo, Michael V.; Watt, David S.; Liu, Chunming

doi:10.1039/c7ob01584d

Cited by 24 publications

(11 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the specific roles of HSD17B4 seems to be inconsistent in different contexts. For example, its overexpression was associated with the tumor cell proliferation in liver cancer (Lu et al, 2015(Lu et al, , 2019, prostate cancer and colon cancer (Frasinyuk et al, 2017) while exerted tumor suppressive functions in adrenocortical carcinoma (Ding et al, 2017). Here, HSD17B4 was shown to be under-expressed in NSCLC, indicating its diagnostic potential.…”

Section: Discussionmentioning

confidence: 90%

HSD17B4, ACAA1, and PXMP4 in Peroxisome Pathway Are Down-Regulated and Have Clinical Significance in Non-small Cell Lung Cancer

et al. 2020

View full text Add to dashboard Cite

To explore the potential functions and clinical significances of peroxisomes during lung cancer development and progression, we investigated the expressional profiles of peroxisome pathway genes and their correlations with clinical features in nonsmall cell lung cancer (NSCLC). The RNA-seq data of NSCLC including lung squamous carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with their clinical information were downloaded from The Cancer Genome Atlas (TCGA). Gene expression comparisons between tumor and normal samples were performed with edgeR package in R software and the results of the 83 peroxisome pathway genes were extracted. Through Venn diagram analysis, 38 common differentially expressed peroxisome pathway genes (C-DEPGs) in NSCLC were identified. Principal components analysis (PCA) was performed and the 38 C-DEPGs could discriminate NSCLC tumors from the non-tumor controls well. Through Kaplan-Meier survival and Cox regression analyses, 11 of the C-DEPGs were shown to have prognostic effects on NSCLC overall survival (OS) and were considered as key C-DEPGs (K-DEPGs). Through Oncomine, Human Protein Atlas (HPA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), three K-DEPGs (HSD17B4, ACAA1, and PXMP4) were confirmed to be down-regulated in NSCLC at both mRNA and protein level. Their dyregulation mechanisms were revealed through their correlations with their copy number variations and methylation status. Their potential functions in NSCLC were explored through their NSCLC-specific co-expression network analysis, their correlations with immune infiltrations, immunomodulator gene expressions, MKI67 expression and their associations with anti-cancer drug sensitivity. Our findings suggested that HSD17B4, ACAA1, and PXMP4 might be new markers for NSCLC diagnosis and prognosis and might provide new clues for NSCLC treatment.

show abstract

Section: Discussionmentioning

confidence: 90%

HSD17B4, ACAA1, and PXMP4 in Peroxisome Pathway Are Down-Regulated and Have Clinical Significance in Non-small Cell Lung Cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A recent study explored the inhibitory activity of prostate and colon cancer cell proliferation by cytisine-linked isoflavonoids (CLIFs) at C7 through a carbon chain (C2-C6) spacer showing inhibition > 60% at 10 µM [78]. We explored a similar strategy, considering that 1 and 2 were the most potent compounds against the PC-3 cell line (IC 50 < 18.6 µM).…”

Section: Isolation and Identification Of Opls-recognized Anti-prolife...mentioning

confidence: 99%

Identification of Anti-Proliferative Compounds from Genista monspessulana Seeds through Covariate-Based Integration of Chemical Fingerprints and Bioactivity Datasets

2022

View full text Add to dashboard Cite

Genista monspessulana (L.) L.A.S. Johnson (Fabaceae) is a Mediterranean plant introduced to South America and other regions for ornamental purposes. However, it is considered an invasive shrub due to its reproductive vigor in many areas. Unlike other Genista plants, G. monspessulana has few studies disclosing its biologically active components, particularly cytotoxic agents against cancer cells. Thus, as part of our research on anti-proliferative bioactives, a set of ethanolic seed extracts from ten accessions of G. monspessulana, collected in the Bogotá plateau, were evaluated against four cell lines: PC-3 (prostate adenocarcinoma), SiHa (cervical carcinoma), A549 (lung carcinoma), and L929 (normal mouse fibroblasts). Extracts were also analyzed through liquid chromatography coupled with mass spectrometry (LC/MS) to record chemical fingerprints and determine the composition and metabolite variability between accessions. Using multiple covariate statistics, chemical and bioactivity datasets were integrated to recognize patterns and identify bioactive compounds among studied extracts. G. monspessulana seed-derived extracts exhibited dose-dependent antiproliferative activity on PC-3 and SiHa cell lines (>500 µg/mL < IC50 < 26.3 µg/mL). Seven compounds (1–7) were inferred as the compounds most likely responsible for the observed anti-proliferative activity and subsequently isolated and identified by spectroscopic techniques. A tricyclic quinolizidine (1) and a pyranoisoflavone (2) were found to be the most active compounds, exhibiting selectivity against PC-3 cell lines (IC50 < 18.6 µM). These compounds were used as precursors to obtain a quinolizidine-pyranoisoflavone adduct via Betti reaction, improving the activity against PC-3 and comparable to curcumin as the positive control. Results indicated that this composition–activity associative approach is advantageous to finding those bioactive principles efficiently within active extracts. This correlative association can be employed in further studies focused on the targeted isolation of anti-proliferative compounds from Genista plants and accessions.

show abstract

“…Chromene derivatives have demonstrated antifungal activity in vitro against several kind of pathogenic fungi, such as Cryptococcus neoformans, Torulopsis glabrata, Trichosporon cutaneum, Candida albicans, C. parapsilosis and C. tropicalis [18]. Moreover, there are descriptions in the literature of 4H-chromenes as specific inhibitors of enzymes involved in tumor growth, including topoisomerases I and II [19,20], tubulin [21], caspase [22], COT kinase [23], 17β-dehydrogenase-4 (HSD17B4) [24], telomerase [25], and tyrosinase [26]. However, few reports exist on topoisomerase IB, and no molecular docking studies have yet been carried out, to our knowledge, for 2-amino-3-cyano-4H-chromenes at the active site of this enzyme.…”

Section: Introductionmentioning

confidence: 99%

Three-Component Synthesis of 2-Amino-3-cyano-4H-chromenes, In Silico Analysis of Their Pharmacological Profile, and In Vitro Anticancer and Antifungal Testing

et al. 2021

View full text Add to dashboard Cite

Chromenes are compounds that may be useful for inhibiting topoisomerase and cytochrome, enzymes involved in the growth of cancer and fungal cells, respectively. The aim of this study was to synthesize a series of some novel 2-amino-3-cyano-4-aryl-6,7-methylendioxy-4H-chromenes 4a–o and 2-amino-3-cyano-5,7-dimethoxy-4-aryl-4H-chromenes 6a–h by a three-component reaction, and test these derivatives for anticancer and antifungal activity. Compounds 4a and 4b were more active than cisplatin (9) and topotecan (7) in SK-LU-1 cells, and more active than 9 in PC-3 cells. An evaluation was also made of the series of compounds 4 and 6 as potential antifungal agents against six Candida strains, finding their MIC50 to be less than or equal to that of fluconazole (8). Molecular docking studies are herein reported, for the interaction of 4 and 6 with topoisomerase IB and the active site of CYP51 of Candida spp. Compounds 4a–o and 6a–h interacted in a similar way as 7 with key amino acids of the active site of topoisomerase IB and showed better binding energy than 8 at the active site of CYP51. Hence, 4a–o and 6a–h are good candidates for further research, having demonstrated their dual inhibition of enzymes that participate in the growth of cancer and fungal cells.

show abstract

Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)

Cited by 24 publications

References 25 publications

HSD17B4, ACAA1, and PXMP4 in Peroxisome Pathway Are Down-Regulated and Have Clinical Significance in Non-small Cell Lung Cancer

HSD17B4, ACAA1, and PXMP4 in Peroxisome Pathway Are Down-Regulated and Have Clinical Significance in Non-small Cell Lung Cancer

Identification of Anti-Proliferative Compounds from Genista monspessulana Seeds through Covariate-Based Integration of Chemical Fingerprints and Bioactivity Datasets

Three-Component Synthesis of 2-Amino-3-cyano-4H-chromenes, In Silico Analysis of Their Pharmacological Profile, and In Vitro Anticancer and Antifungal Testing

Contact Info

Product

Resources

About