The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation

Guo, Yangyang; Xiao, Yanyi; Guo, Hangcheng; Zhu, Hengyue; Chen, Dong; Wang, Jilong; Deng, Junjie; Lan, Junjie; Liu, Xiaodong; Zhang, Qiyu; Bai, Yongheng

doi:10.18632/aging.203301

Cited by 21 publications

(15 citation statements)

References 48 publications

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“…Fraxetin is a simple coumarin that is extracted from Cortex Fraxini [11]. The ongoing reports throw light on the detrimental effects of fraxetin on tissue inflammation and edema induced by cytotoxic agents [12]. Moreover, fraxetin was proven to affect the complexes of the electron transport chain and modulate the generation of ATP at the mitochondrial level [13].…”

Section: Introductionmentioning

confidence: 99%

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Kabel

Salama

Adwas³

et al. 2021

Pharmaceuticals

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Doxorubicin belongs to the class of anthracycline antibiotics that is widely used in the treatment protocols of a wide range of malignancies. The major deleterious effect of doxorubicin use is the possible occurrence of cardiotoxicity. This study aimed to delineate the possible effects of targeting oxidative stress, NLRP3 inflammasome, and autophagy by fraxetin on doxorubicin-induced cardiac dysfunction in rats. In a model of doxorubicin-induced cardiotoxicity, the effects of different doses of fraxetin were assessed by determination of biochemical, histopathological, immunohistochemical, and electron microscopic changes. Fraxetin, in a dose-dependent manner, was found to have the ability to mitigate the harmful effects of oxidative stress and inflammation on myocardial muscles with significant decrease in NLRP3 inflammasome, augmentation of autophagy, and amelioration of the apoptotic signaling pathways. In addition, fraxetin, in a dose-dependent manner, had the ability to combat the echocardiographic, histopathological, immunohistochemical, and electron microscopic changes induced by doxorubicin in cardiomyocytes. As a result, fraxetin may be put into consideration as a new adjuvant line of therapy on the way to mitigate doxorubicin-induced cardiotoxicity.

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Section: Introductionmentioning

confidence: 99%

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Kabel

Salama

Adwas³

et al. 2021

Pharmaceuticals

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“…For instance, fraxetin isolated from the bark of Fraxinus bungeana A.DC. , piperlongumine isolated from the fruit of the pepper Piper longum , and curcumin extracted from Curcuma longa were found to significantly enhance the anti- pancreatic cancer activity of gemcitabine ( 70 – 72 ). Therefore, the combination of TMPs and chemotherapy as therapeutic regimens has potential clinical value in APC treatment.…”

Section: Discussionmentioning

confidence: 99%

“…They can suppress pancreatic cancer cell proliferation or induce apoptotic and autophagic by modulating various oncogenic pathways including Wnt, phosphoinositide 3-kinase/protein kinase B/ mammalian target of rapamycin, mitogen-activated protein kinases and Nuclear factor-kappa B pathways (69). For instance, fraxetin isolated from the bark of Fraxinus bungeana A.DC., piperlongumine isolated from the fruit of the pepper Piper longum, and curcumin extracted from Curcuma longa were found to significantly enhance the anti-pancreatic cancer activity of gemcitabine (70)(71)(72). Therefore, the combination of TMPs and chemotherapy as therapeutic regimens has potential clinical value in APC treatment.…”

Section: ⊕⊕⊕ο Moderatementioning

confidence: 99%

Clinical Efficacy and Safety of Traditional Medicine Preparations Combined With Chemotherapy for Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

Jiang

et al. 2022

Front. Oncol.

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BackgroundTraditional medicine preparations (TMPs) combined with chemotherapy is widely used for patients with advanced pancreatic cancer (APC); however, its efficacy and safety are still unclear. The purpose of this meta-analysis was to evaluate the clinical efficacy and safety of TMPs combined with chemotherapy for the treatment of APC.MethodsA systematic search of eight electronic databases for randomized controlled trials (RCTs) was conducted from inception to October 15, 2021. Tumor response was identified as primary outcome, whereas quality of life (QoL), cancer biomarkers, and adverse drug reactions (ADRs) were identified as secondary outcomes. Quality of the evidence for each outcome was evaluated by GRADE profiler.ResultsIn total, 31 RCTs involving 1,989 individuals were included. This meta-analysis showed that TMPs combined with chemotherapy significantly improved the objective response rate (ORR) (RR=1.64, 95% CI [1.43 to 1.88], p <0.00001), disease control rate (DCR) (RR=1.29, 95% CI [1.21 to 1.38], p <0.00001), and QoL (continuous data: SMD=0.81, 95% CI [0.44 to 1.18], p <0.0001, dichotomous data: RR=1.44, 95% CI [1.22 to 1.70], p<0.0001), compared to those with chemotherapy alone. In addition, the combined treatment group also had lower levels of CA19-9 (SMD=-0.46, 95% CI [-0.90 to -0.02], p=0.04) and CEA (SMD=-0.55, 95% CI [-0.93 to -0.17], p=0.004). Moreover, TMPs reduced the ADRs during chemotherapy.ConclusionThis systematic review suggests that TMPs combined with chemotherapy might be a potential option to enhance therapeutic effects and reduce ADRs during the treatment of APC. However, more high-quality randomized controlled trials with more participants are needed.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=209825, identifier PROSPERO Number: CRD42021264938.

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“…Shuo Ren et al reported that FXT inhibited the growth of colon adenocarcinoma cells by regulating the JAK2/STAT3 signaling pathway (Ren et al, 2020). Yangyang Guo et al reported that FXT inhibited the development of pancreatic cancer by antagonizing STAT3 activation (Guo et al, 2021). Of note, Liangchen Qu et al found that FXT inhibits the proliferation and metastasis of glioma cells by inhibiting the JAK2/STAT3 signaling pathway (Qu et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Fraxetin exerts anticancer effect in glioma by suppressing MiR‐21‐3p

Yao

Pan

et al. 2021

Drug Development Research

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Fraxetin (FXT) exerts anticancer function in multiple cancers, but its function on glioma was ill‐defined. This article expounded the mechanism by which FXT exerts an anticancer effect in glioma. The effect of gradient concentration of FXT on the viability of glioma cell lines was determined by cell counting kit 8. Effects of FXT on proliferation, apoptosis, and cell cycle in glioma cell lines were determined by colony formation assay, flow cytometry, and Hoechst 33342 staining. Expressions of apoptosis‐related gene, cycle‐related gene, and glioma‐related miRNAs after FXT (25 and 50 μmol/L) treatment were determined by quantitative reverse transcription polymerase chain reaction and western blot as needed. After miR‐21‐3p overexpression, cell viability and apoptosis of glioma cell lines treated with FXT (50 μmol/L) were tested again. Although 1 μmol/L FXT had no significant effect on cell viability, 5, 10, 25, and 50 μmol/L FXT suppressed cell viability in a concentration‐dependent manner. FXT inhibited proliferation, promoted apoptosis, and induced cell cycle arrest in G0/G1 phase in glioma cell lines. These effects may be achieved by elevated expressions of Bax and cleaved caspase‐3 and diminished expressions of Bcl‐2, Bcl‐XL, cyclin E1, cyclin D1, and cyclin‐dependent kinase‐6. FXT attenuated the contents of miR‐21‐3p and miR‐455‐3p, and escalated the contents of miR‐124‐3p and miR‐7‐5p. The regulation of FXT on cell viability, proliferation and apoptosis was reversed by miR‐21‐3p overexpression. FXT suppressed the development of glioma cells by downregulating miR‐21‐3p.

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The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation

Cited by 21 publications

References 48 publications

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Clinical Efficacy and Safety of Traditional Medicine Preparations Combined With Chemotherapy for Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

Fraxetin exerts anticancer effect in glioma by suppressing MiR‐21‐3p

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