TOXICOLOGY IN VITRO
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2023
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IF 3.2
Weiyi Ye,Zhen Wang,Xin Lv,Hang Yin,Lili Jiang,Zhe Wang,Yong Liu
Ponatinib is an efficient oral tyrosine kinase inhibitor (TKI) for T315I-positive Ph + ALL and T315I-positive chronic myeloid leukemia (CML) or BCR-ABL when no other TKIs can be prescribed. In this research, we evaluated the inhibitory effects of ponatinib on human recombinant UDP-glucuronosyltransferases (UGTs) and predicted the magnitude of potential drug-drug interaction (DDI) risk of co-treatment with ponatinib and UGTs substrates by using in vitro-in vivo extrapolation (IVIVE) method. Our study presented that ponatinib showed a broad-spectrum inhibition against UGTs. Particularly, ponatinib exhibited potent inhibitory effects towards UGT1A7, UGT1A1, and UGT1A9 with IC 50 values of 0.37, 0.41, and 0.89 μM, respectively, which might lead to clinically significant DDI.
研究领域:
药理学
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临床医学
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生物化学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 23
·期 19
·11711
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IF 6.208
Huan-Chau Lin,Ferry Saputra,Gilbert Audira,Yu-Heng Lai,Marri Jmelou M. Roldan,Honeymae C. Alos,Charlaine A. Aventurado,Ross D. Vasquez,Guan-Jhe Tsai,Ken-Hong Lim,Chung-Der Hsiao
BCR-ABL, a fusion protein kinase, is a druggable target exclusively expressed in patients with chronic myeloid leukemia (CML). Several anti-leukemia medicines targeting this protein have been developed in recent years. However, therapeutic options are limited for CML patients bearing multiple BCR-ABL1 mutations. Ponatinib (PON), a potent tyrosinase inhibitor, was one of the approved drugs for managing BCR-ABL1 T315I mutant disease. However, treatment of patients with PON reported severe side effects related to cardiovascular events. Asciminib (ASC) was the first allosteric inhibitor approved to target the myristoyl pocket of BCR-ABL protein to inhibit protein activity. The different mechanism of inhibition opens the possibility of co-exposure with both medicines. Reports on cardiovascular side effects due to the combination use of PON + ASC in pre-clinical and clinical studies are minimal. Thus, this study aimed to observe the potential cardiovascular-related side effect after co-exposure to ASC and PON using zebrafish as an animal model. In this study, zebrafish were acutely exposed to both compounds. The cardiovascular physiology parameters and gene expression related to cardiovascular development were evaluated. We demonstrate that combining ASC with PON at no observed effect concentration (NOEC) did not cause any significant change in the cardiac performance parameter in zebrafish. However, a significant increase innkx2.5expression level and a substantial decrease in blood flow velocity were recorded, suggesting that combining these compounds at NOEC can cause mild cardiovascular-related side effects.Keywords:zebrafish;anti-cancer drug;asciminib;ponatinib;cardiovascular toxicity;molecular docking
研究领域:
药理学
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毒理学
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发育生物学
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Hualu Wu,Haoxin Fu,Fangyuan Xia,Jun Wu,Peiqi Wang,Lu Cao,Ren-ai Xu,Lu Shi
Cariprazine is an antipsychotic medication that has been approved for the treatment of schizophrenia and manic or mixed episodes. Patients with tumors frequently develop psychiatric disorders, necessitating the combination of antitumor and antipsychotic drugs. The objective of the present study was to examine the inhibitory impacts of three antitumor drugs (olmutinib, napabucasin and ponatinib) on the metabolism of cariprazine, and the molecular docking of cariprazine and ponatinib in relation to CYP3A4 was also evaluated. As the results, the half-maximal inhibitory concentration (IC 50 ) values of ponatinib and olmutinib in vitro were < 10 μM, whereas napabucasin was >20 μM. Among these, ponatinib exhibited the smallest IC 50 value. The metabolic stability of cariprazine was observed in the presence or absence of ponatinib in rat liver microsomes (RLM). The IC 50 shift experiments demonstrated that the inhibition of cariprazine by ponatinib was non-time-dependent. In addition, ponatinib was shown to inhibit cariprazine in a mixed manner (RLM) and a competitive manner (HLM), respectively. In the in vivo study, the co-administration of ponatinib resulted in a significant 0.35-fold increase in both AUC (0-t) and AUC (0-∞) for cariprazine, accompanied by a significant 0.25-fold decrease in the CL z/F . Furthermore, the metabolites desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR) exhibited disparate increases in both AUC (0-t) and AUC (0-∞) . Molecular docking studies had demonstrated that both cariprazine and ponatinib could engage in hydrophobic interactions with residue PHE-304 on CYP3A4. Consequently, when ponatinib is employed in conjunction with cariprazine in a clinical setting, it is imperative to assess the efficacy and adverse effects, and adjust the dosage to attain the optimal efficacy.
研究领域:
药理学
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临床医学
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生物化学
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PubMed
高影响因子
JOURNAL OF HYPERTENSION
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2025
·Vol. 43
·期 5
·827
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IF 4.1
Tang Liang-Liang,Xu Xin-Yu,Zhang Mei,Qin Qi,Xue Rong,Jiang Shuai,Yang Xu,Liang Chen,Wang Qiu-Shi,Yu Chang-Jiang,Zhang Zhi-Ren
Background and purpose: Ponatinib, a tyrosine kinase inhibitor (TKI) leads to hypertension; however, the mechanisms remain elusive. We aimed to investigate whether lysine acetyltransferase 7 (KAT7), a key regulator of cellular senescence that is closely associated with cardiovascular diseases, involves in ponatinib-induced hypertension. Methods and results: After administering ponatinib to Sprague–Dawley (SD) rats for 8 days, we measured blood pressure, vasodilation, and endothelial function using tail-cuff plethysmography, isometric myography, and the Total NO Assay kit, respectively. The results indicated that ponatinib increased blood pressure, impaired endothelium-dependent relaxation (EDR), and caused injury to endothelial cells in SD rats. Furthermore, PCR and Western blot experiments demonstrated an upregulation of KAT7 expression in rat mesenteric artery endothelial cells (MAECs) following ponatinib treatment. To further study the role of KAT7 in ponatinib-induced hypertension, we divided the SD rats into four groups: control, ponatinib, WM-3835 (a KAT7 inhibitor), and ponatinib plus WM-3835. Notably, WM-3835 administration significantly improved ponatinib-induced hypertension and EDR dysfunction in SD rats. Mechanistically, over-expression of KAT7 (OE-KAT7) in MAECs led to cellular senescence and inflammation, phenomena that were also observed in the mesenteric arteries of ponatinib-treated rats and in MAECs exposed to ponatinib. However, WM-3835 mitigated these detrimental effects in both in vivo and in vitro experiments. Additionally, both OE-KAT7 and ponatinib treatment induced H3K14 acetylation (H3K14ac), with OE-KAT7 also elevating the recruitment of the H3K14ac to the p21 promoter. Moreover, BAY 11-7085, a nuclear factor (NF)-κB inhibitor, potently alleviated the accumulation of IL-6 and IL-8, as well as endothelial cell senescence induced by ponatinib and KAT7 overexpression. Conclusion: Our data indicate that ponatinib-induced elevation of KAT7 led to endothelial cells senescence and inflammatory responses through H3K14 acetylation and NF-κB signaling pathway, subsequently caused vasotoxicity and hypertension.
研究领域:
心血管药理学
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分子生物学
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病理生理学
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PubMed
高影响因子
Journal of Ginseng Research
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2026
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IF 7.5
Lei Quan,Yue Gao,Chen Zhang,Yue Ding,Sijuan Sun,Xinran Tai,Qingqing Yu,Dong Wang,Yumei Wang
Background Breast cancer ranks among the most prevalent malignant tumors in women worldwide, with lung metastasis accounting for over 90% of fatalities. Despite this high mortality, effective targeted therapies remain insufficient. Although ponatinib (PNT) shows potential for treating breast cancer lung metastasis (BCLM), its delivery requires optimization. This study aims to construct a biomimetic nanomedicine for targeted delivery of PNT, thereby efficiently treating BCLM. Methods Ginsenoside Rg3 (Rg3) can serve as a substitute for cholesterol as a membrane support material while also acting as an adjuvant in cancer treatment. We replaced cholesterol with Rg3 to prepare PNT-Rg3-Lipo liposomes, extracted the cell membrane of M1 macrophages to coat it on the surface of PNT-Rg3-Lipo, and obtained biomimetic nano MM/PNT-Rg3-Lipo. The characterization of biomimetic nanomedicines was conducted, and the functionality of biomimetic nanomedicines was evaluated at both animal and cellular levels. Results The macrophage membrane-modified MM/PNT-Rg3-Lipo retains most proteins found on M1-type macrophages, including the characteristic proteins integrin α4 and β1. This macrophage membrane-modified MM/PNT-Rg3-Lipo reduces macrophage phagocytosis, while enhancing uptake by metastatic breast cancer cells. In vitro , macrophage membrane-modified MM/PNT-Rg3-Lipo exhibits a stronger cytotoxic effect on breast cancer cells compared to free PNT. In vivo , MM/PNT-Rg3-Lipo shows a lower hemolysis rate, demonstrating its safety. Macrophage membrane modification guides liposomes to lung metastatic sites, leading to localized drug release and consequential inhibition of breast cancer lung metastases. Conclusion The biomimetic macrophage membrane-coated liposomes, MM/PNT-Rg3-Lipo, which we have innovatively prepared, exhibit promising therapeutic effects against breast cancer lung metastases.
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Yali Wu,Yunnan Ma,Wanling Zhong,Huijuan Shen,Jinhong Ye,Shouying Du,Pengyue Li
Ethnopharmacological relevance Thrombus generation is one of the leading causes of death in human, and vascular endothelial dysfunction is a major contributor to thrombosis. Pheretima guillemi (Michaelsen), a traditional medicinal animal known as “Dilong”, has been utilized to cure thrombotic disorders for many years. DPf3, a group of functional proteins extracted from P. guillemi , has been characterized and identified to possess antithrombotic bioactivity via in vitro and ex vivo experiments. Aim of the study This study is aimed to investigate the vascular-protection activity and related mechanism of antithrombotic protein DPf3 purified from Pheretima guillelmi systematically. Materials and methods The antithrombotic activity and vascular endothelium protection effect of DPf3 was explored in vivo using ponatinib-induced vascular endothelial injury zebrafish thrombus model. Then, (hi) ox-LDL-induced HUVECs was applied to investigate the protection mechanism of DPf3 against the injury of vascular endothelium. In addition, TMT-based proteomics analysis was used to study the biomarkers, biological processes and signal pathways involved in the antithrombotic and vascular protective effects of DPf3 holistically. Results DPf3 exerted robust in vivo antithrombosis and vascular endothelial protection ability. DPf3 was identified to prevent HUVECs from damage by reducing ROS production, and to reduce monocyte adhesion by decreasing the protein content of adhesion factor VCAM 1. DPf3 was also observed to weaken the migration ability of injured cells and inhibit abnormal angiogenesis. The mechanism of DPf3's antithrombotic and vascular protective activity was mainly related to the regulation of lipid metabolism, energy metabolism, complement and coagulation system, ECM receptor interaction, MAPK signal pathway, etc. Conclusions This study demonstrates that DPf3 has strong antithrombotic and endothelial protective effects. The endothelial protective ability and related mechanisms of DPf3 provide a scientific reference for the traditional use of earthworms in the treatment of thrombosis.
研究领域:
民族药理学
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药理学
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分子生物学
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蛋白质组学
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心血管疾病
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DOI
PubMed
高影响因子
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