Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1‐mediated carcinogenic estradiol metabolite formation

An, Dongchen; Song, Zijing; Yi, Yingyue; Zhang, Qing; Liu, Jinfeng; Zhang, Yongjie; Zhou, Jing; Zhao, Guang‐Hui; Cong, Danhua; Li, Ning; Lu, Yang; Chen, Xijing; Zhao, Di

doi:10.1002/ptr.6297

Cited by 13 publications

(6 citation statements)

References 29 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, it has been reported that 4-hydroxyestradiol (4-OHE2), a metabolite of estradiol, plays a critical role in the occurrence and progression of hormone-related cancers [ 19 ]. 4-OHE2 is highly carcinogenic in a variety of malignant tumors, including endometrial cancer [ 20 ] and breast cancer [ 21 , 22 ]. 4-OHE2 induces anchorage-independent growth of human mammary epithelial cells [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation

Lin

Cao

et al. 2022

Cell Commun Signal

View full text Add to dashboard Cite

Background Resistance to androgen deprivation therapy remains a major challenge for the clinical treatment of patients with castration-resistant prostate cancer (CRPC). CYP1B1, a critical enzyme that catalyzes the conversion of estradiol to 4-Hydroxy-17β-estradiol (4-OHE2), has been reported to promote the development and progression of hormone-related cancer, but its role in CRPC is unclear. Methods To explore the underlying mechanism which CYP1B1 promotes the prostate cancer stem cells (PCSCs) characteristics, bioinformatics analyses of human clinical prostate cancer (PCa) datasets were performed. CYP1B1, IL6, and estrogen receptor-α (ERα) expression levels were evaluated in PCa and CRPC tissues via immunohistochemistry. The high-performance liquid chromatography-mass spectrometry assay was carried out to examine intracellular 4-OHE2 levels. Serum-free suspension culture and flow cytometry assays were performed to evaluate PCSCs. Chromatin immunoprecipitation was used to validate that 4-OHE2 recruited ERα to the IL6 promoter. Results CYP1B1 expression was significantly increased in CRPC tissues and androgen-independent PCa cell lines. CYP1B1+ PCa cells were significantly enriched in bicalutamide-treated LNCaP cells, and CYP1B1 knockdown reduced the cell viability under bicalutamide treatment. In addition, CYP1B1 knockdown decreased the intracellular 4-OHE2 concentration, accompanied by reduced PCSC characteristics. In PCa cells, 4-OHE2 stimulated ERα transcriptional activity and upregulated the expression of IL6 and downstream genes of the IL6-STAT3 signaling. 4-OHE2 increased cell viability under bicalutamide treatment and promoted PCSC characteristics, while IL6 neutralizing antibody reversed these effects. Mechanistically, siERα and the ER antagonist ICI182780 significantly attenuated 4-OHE2-induced IL6 expression, and 4-OHE2 promoted the binding of ERα to the estrogen response element of the IL6 promoter. Conclusions Our findings indicate that CYP1B1-catalyzed 4-OHE2 enhanced PCSC characteristics and attenuated bicalutamide sensitivity by ERα-mediated the IL6-STAT3 pathway activation. Our study further emphasizes the role of CYP1B1 in castration resistance and illustrates a novel mechanism of CRPC development. Graphical Abstract

show abstract

Section: Introductionmentioning

confidence: 99%

CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation

Lin

Cao

et al. 2022

Cell Commun Signal

View full text Add to dashboard Cite

show abstract

“…13 2,4-Bis(3,5-dimethoxyphenyl)pyrimidine (11). A flask was charged with 0.2 g of 2,4-dibromopyrimidine (0.84 mmol, 1 equiv), 0.337 g of 3,5-Bis (3,5-dimethoxyphenyl)pyridine (12). A flask was charged with 0.21 g of 3,5-dibromopyridine (0.89 mmol, 1 equiv), 0.338 g of 3,5-dimethoxyphenylboronic acid (1.85 mmol, 2.1 equiv), 0.01 g of Pd(OAc) 2 (0.042 mmol, 0.05 equiv), and 0.03 g of CataCXium A (0.084 mmol, 0.01 equiv) under a flow of N 2 , and the general procedure B mentioned above was carried out.…”

Section: 3″55″-tetramethoxy-11′:2′1″-terphenyl (2)mentioning

confidence: 99%

“…In recent years, CYP1B1 has emerged as a promising therapeutic target. In addition to its well-studied role as an activator of procarcinogens, CYP1B1 is overexpressed in cancer tissues, − is associated with cellular resistance to taxanes, cisplatin, and gemcitabine − and is responsible for the oxidation of endogenous 17β-estradiol into the DNA-damaging agent 4-hydroxyestradiol. , Expression of CYP1B1 is also known to be induced by estrogen, resulting in a dangerous feedback loop for tissues exposed to high levels of this hormone. In addition, CYP1B1 expression is associated with poor survival in associated cancers. , Thus, highly selective inhibitors for CYP1B1 may serve multiple purposes in treating and preventing drug-resistant cancers.…”

Section: Introductionmentioning

confidence: 99%

“…5 μM) and pHLMs (3.9 μM). With an array of scaffolds in hand, we elected to eliminate those scaffolds with 1A1/1B1 selectivity indices <50, and those with high cytotoxicity(12). This strategy afforded two candidate scaffolds with low toxicity and good inhibitory activity, 2,4substituted pyrimidine (11) and 2,4-substituted thiazole (7), to pursue further optimization.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Design of Cytochrome P450 1B1 Inhibitors via a Scaffold-Hopping Approach

et al. 2022

View full text Add to dashboard Cite

Cytochrome P450 1B1 (CYP1B1) is a potential drug target in cancer research that is overexpressed in several solid tumors but is present only at low levels in healthy tissues. Its expression is associated with resistance to common chemotherapeutics, while inhibitors restore efficacy to these drugs in model systems. The majority of CYP1B1 inhibitors are derived from a limited number of scaffolds, and few have achieved outstanding selectivity against other human CYPs, which could impede clinical development. This study explores a new chemical space for CYP1B1 inhibitors using a scaffold-hopping approach and establishes 2,4-diarylthiazoles as a promising framework for further development. From a small library, compound 15 emerged as the lead, with picomolar CYP1B1 inhibition, and over 19,000-fold selectivity against its relative, CYP1A1. To investigate the activity of 15, molecular dynamics, optical spectroscopy, point mutations, and traditional structure–activity relationships were employed and revealed key interactions important for the development of CYP1B1 inhibitors.

show abstract

“…(48) Oroxylin A Formed as a metabolite of baicalein, oroxylin A is yet another fl avonoid of high phytotherapic relevance. (49) There are published associations of the substance with the suppression of cancer via apoptosis, (50) and the study by Zou, et al (51) was the only one found that also addresses autophagy.…”

Section: Sotetsu Flavonementioning

confidence: 99%

Therapeutic Properties of Flavonoids in Treatment of Cancer through Autophagic Modulation: A Systematic Review

Silva

Lopes

Viali

et al. 2022

Chin. J. Integr. Med.

View full text Add to dashboard Cite

cancer is the second leading cause of death in the world, and it was estimated to occupy the first place in the coming decades, especially in poor and developing countries. This pathology is characterized, among other factors, by the disordered growth of cells, through cell cycle alterations. (1) It is a disease of multiple origins, which can be caused by lifestyle, environmental factors, genetic infl uence, and the aging process of the organism. (2) Because it is a disease related to the cell cycle, processes that can damage cellular structures are factors favorable to neoplastic development. In this sense, fl avonoids-phytocomposites that have varied actions in plants, such as protection against ultra violet rays, protection against pathogenic organisms and antioxidant action-have been studied. Due to these properties, flavonoids have been evaluated for their therapeutic potential in the treatment of cancer, for having an antioxidant function, acting in the control of cell proliferation and in blocking neoplastic formation by mechanisms that regulate enzymes of the carcinogenic metabolic pathway. In addition, some of these compounds can inhibit the cyclooxygenase (COX) and lipoxygenase pathways, and important infl ammatory markers, showing an antiinfl ammatory property, (3) demonstrating their potential for maintaining cellular homeostasis, thus decreasing the chances of cell damage and the consequent neoplastic development. Studies demonstrate the therapeutic use of flavonoids to improve the prognosis, as well as prophylactic action regarding the development of breast cancer and thyroid cancer. (4,5)

show abstract

Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1‐mediated carcinogenic estradiol metabolite formation

Cited by 13 publications

References 29 publications

CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation

CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation

Design of Cytochrome P450 1B1 Inhibitors via a Scaffold-Hopping Approach

Therapeutic Properties of Flavonoids in Treatment of Cancer through Autophagic Modulation: A Systematic Review

Contact Info

Product

Resources

About