Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential

Fermaintt, Charles S.; Peramuna, Thilini; Cai, Shengxin; Takahashi‐Ruiz, Leila; Essif, Jacob Nathaniel; Grant, Corena V.; O'Keefe, Barry R; Mooberry, Susan L.; Cichewicz, Robert H.; Risinger, April L.

doi:10.3390/cancers13112834

Cited by 11 publications

(17 citation statements)

References 44 publications

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“…BL1 anchorages a deficiency in HR (homologous recombination) repair, which is mainly driven by mutations or epigenetic changes in the BRCA1/2. The BL2 subgroup, on the other hand, is exclusively improved in development issue signaling pathways such as EGF, NGF, and MET pathways [12][13][14][15][16]. Consequently, directing DNA repair deficit by DNA damage mediators looks to be a gifted action for BL-TNBC.…”

Section: Platinum-based Chemotherapymentioning

confidence: 99%

“…Consequently, directing DNA repair deficit by DNA damage mediators looks to be a gifted action for BL-TNBC. Satisfactory response rates to platinum-based chemotherapy have been related to low BRCA1 mRNA levels and high BRCA1 methylation [12][13][14][15][16]. Platinum-based chemotherapy has been reported to increase the pathological complete response (pCR) rate in TNBC patients [15].…”

Section: Platinum-based Chemotherapymentioning

confidence: 99%

“…Secondary endpoints included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity [14,16]. Platinum salts have been increasingly tested for TNBC in combination with various other chemotherapy drugs (e.g., gemcitabine, which masquerades as cytidine and inhibits DNA synthesis) [12]. Moreover, identifying predictive biomarkers is imperative for the selection of appropriate patients for platinum-based regimens in the adjuvant setting.…”

Section: Platinum-based Chemotherapymentioning

confidence: 99%

“…PARP inhibitors are actively involved in HR-repair deficiency and responding to ss-DNA damage and continue genomic integrity by using BER (Base Excision Repair Mechanism) [12,13,17]. Ds-DNA damage is typically repaired via HR, which requires normal functions of the tumor suppressor proteins BRCA1/2 [17].…”

Section: Poly (Adp Ribose) Polymerase Inhibitorsmentioning

confidence: 99%

“…Preclinical model systems showed increased radiosensitivity due to HR restoration via 53BP1 pathway inactivation. HR is a complex process, requiring a myriad of proteins [12]. The MRN-complex, composed of MRE11, Rad50, and Nbs1, plays several roles in the DNA damage response.…”

Section: Poly (Adp Ribose) Polymerase Inhibitorsmentioning

confidence: 99%

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TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy

Singh

Yadav

2021

Biomedicines

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Triple-negative breast cancer (TNBC) is a heterogeneous, recurring cancer associated with a high rate of metastasis, poor prognosis, and lack of therapeutic targets. Although target-based therapeutic options are approved for other cancers, only limited therapeutic options are available for TNBC. Cell signaling and receptor-specific targets are reportedly effective in patients with TNBC under specific clinical conditions. However, most of these cancers are unresponsive, and there is a requirement for more effective treatment modalities. Further, there is a lack of effective biomarkers that can distinguish TNBC from other BC subtypes. ER, PR, and HER2 help identify TNBC and are widely used to identify patients who are most likely to respond to diverse therapeutic strategies. In this review, we discuss the possible treatment options for TNBC based on its inherent subtype receptors and pathways, such as p53 signaling, AKT signaling, cell cycle regulation, DNA damage, and programmed cell death, which play essential roles at multiple stages of TNBC development. We focus on poly-ADP ribose polymerase 1, androgen receptor, vascular endothelial growth factor receptor, and epidermal growth factor receptor as well as the application of nanomedicine and immunotherapy in TNBC and discuss their potential applications in drug development for TNBC.

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Section: Platinum-based Chemotherapymentioning

confidence: 99%

Section: Platinum-based Chemotherapymentioning

confidence: 99%

Section: Platinum-based Chemotherapymentioning

confidence: 99%

Section: Poly (Adp Ribose) Polymerase Inhibitorsmentioning

confidence: 99%

Section: Poly (Adp Ribose) Polymerase Inhibitorsmentioning

confidence: 99%

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TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy

Singh

Yadav

2021

Biomedicines

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Metabolism, pharmacokinetics, and bioavailability of yuanhuacine in rat using LC–MS

Dang

et al. 2022

Biomedical Chromatography

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Yuanhuacine is a Daphne‐type diterpene ortho‐ester and is one of the main active ingredients of genkwa flos. Anticancer activity of yuanhuacine has been well investigated in various tumor cells and animal models, but information on metabolism and pharmacokinetics is limited. The aims of the present study were to investigate the metabolic and pharmacokinetic profiles of yuanhuacine in rat. The metabolic profile of yuanhuacine was obtained from rat plasma, urine, and feces using ultra‐high‐performance liquid chromatography‐quadrupole‐time‐of‐flight mass spectrometry. A total of seven metabolites were detected, and the proposed metabolic pathways involved oxidation and glucuronidation. A simple and sensitive ultra‐high‐performance liquid chromatography‐tandem mass spectrometry method was developed for the determination of yuanhuacine in rat plasma. The linear range of yuanhuacine was 1–1000 ng/ml (R2 = 0.998). The intra‐ and inter‐precision (coefficient of variation %) of the assay was 3.86–6.18% and 2.65–5.75%, respectively, and the intra‐ and inter‐accuracy (relative error %) was −3.83–4.77% and −3.03–5.11%, respectively. The extraction recovery, matrix effect, stability, and incurred sample reanalysis of yuanhuacine were within acceptable levels. The established method was validated and successfully applied to the preclinical pharmacokinetic study of yuanhuacine. The absolute oral bioavailability of yuanhuacine was calculated as 1.14%, and it reached the maximum plasma concentration of 28.21 ± 2.79 ng/ml in rat plasma at 2 h in the oral dosing group. The apparent volume of distribution of intravenous and intragastric administrations was 26.07 ± 6.45 and 21.83 ± 3.54 L/kg, respectively. The half‐life of elimination of yuanhuacine was 9.64 ± 1.53 h in the intravenous dosing group.

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Blockage of MDM2‐mediated p53 ubiquitination by yuanhuacine restrains the carcinogenesis of prostate carcinoma cells by suppressing LncRNA LINC00665

Yan

et al. 2022

J Biochem & Molecular Tox

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Prostate cancer (PCa) is known as a challenging issue for the global men health due to its uncontrolled proliferation and high metastatic potential. Increasing evidence has supported plant extracts and plantderived natural derivatives as a promising anti-tumor therapeutics as their less toxic side effects.Yuanhuacine is an active component isolated from Daphne genkwa and can effectively suppress tumorigenesis of several cancers. However, its role in PCa is still unclear. In this study, yuanhuacine dosedependently inhibited PCa cell proliferation and induced cell apoptosis. Moreover, yuanhuacine treatment also restrained PCa cell invasion and migration. Mechanically, yuanhuacine decreased p53 protein ubiquitination, degradation and ultimately increased p53 levels, which was regulated by inhibiting phosphorylation and total protein levels of Mouse Double Minute 2 (MDM2). Moreover, elevation of MDM2 reversed the suppressive e cacy of yuanhuacine in PCa cell viability, invasion and migration. The network pharmacology and bioinformatics analysis con rmed that MDM2 might be a common target of Daphne genkwa and LINC00665. Furthermore, yuanhuacine reduced LINC00665 expression. Upregulation of LINC00665 inversed yuanhuacine-mediated inhibition in MDM2 protein expression and suppressed p53 levels by enhancing its ubiquitination in yuanhuacine-treated cells. Importantly, the inhibitory effects of yuanhuacine on cell viability and metastatic potential were offset after LINC00665 elevation. Together, the current nding highlight that yuanhuacine may possess its tumor-suppressive e cacy by inhibiting LINC00665-mediated MDM2/p53 ubiquitination signaling. Therefore, this data indicate that yuanhuacine may be a promising candidate for the treatment of PCa.

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Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential

Cited by 11 publications

References 44 publications

TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy

TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy

Metabolism, pharmacokinetics, and bioavailability of yuanhuacine in rat using LC–MS

Blockage of MDM2‐mediated p53 ubiquitination by yuanhuacine restrains the carcinogenesis of prostate carcinoma cells by suppressing LncRNA LINC00665

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