Frontiers in Pharmacology
·
2025
·
IF 4.8
Yuxin Shen,Fengsheng Hong,Hualu Wu,Xiaohai Chen,Hailun Xia,Ren-ai Xu,Guanyang Lin,Lu Shi
This study aimed to examine the potential drug-drug interaction (DDI) between vandetanib and luteolin in vivo and in vitro, with the objective of establishing a scientific foundation for their appropriate utilization in clinical settings. Sprague-Dawley (SD) rats were randomly divided into two groups: a control group (vandetanib administered by gavage alone) and an experimental group (vandetanib and luteolin administered together). A series of blood samples were collected at different time intervals. The plasma concentrations of vandetanib and its metabolite N-demethyl vandetanib in rats were determined using an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Incubation systems were set up with rat liver microsomes (RLM) and human liver microsomes (HLM) to measure the Michaelis-Menten constant (Km) and half-maximum inhibitory concentration (IC50) values. Additionally, the inhibitory mechanism of luteolin on vandetanib was also investigated. Ultimately, the molecular mechanism of inhibition was examined through the utilization of molecular docking techniques. In vivo animal experiment results showed that compared with the control group, the AUC(0-t) and Cmax of vandetanib in the experimental group were significantly increased. The findings from the in vitro experiments revealed that luteolin exhibited a moderate inhibitory effect on the metabolism of vandetanib. The IC50 values for RLM and HLM were determined to be 8.56 μM and 15.84 μM, respectively. The identified inhibition mechanism was classified as mixed. This study utilized molecular docking analysis to provide additional evidence supporting the competitive inhibition of luteolin on vandetanib in CYP3A4. The data presented in our study indicated a potential interaction between vandetanib and luteolin, which may necessitate the need for dose adjustment during their co-administration in clinical settings.
研究领域:
药理学
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临床医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2026
·Vol. 22
·期 4
·1752-1774
·
IF 10
Wu Wentong,Du Jiangxia,Li Jinjin,Zhang Shaoyin,Kang Xingchen,Cao Yashi,Chen Jian,Pan Zengyue,Huang Xiangliang,Xu Zhifei,Yang Bo,He Qiaojun,Yang Xiaochun,Yan Hao,Luo Peihua
Vandetanib, a critical therapy for advanced thyroid and RET-driven cancers, is limited by life-threatening hepato-cardiotoxicity. This study identifies lysosomal protease cathepsin B (CTSB) as the central mediator of vandetanib-induced organ damage through STAT3-driven transcriptional activation. CTSB triggers mitochondrial apoptosis by cleaving the lysosomal calcium channel mucolipin TRP cation channel 1 (MCOLN1), disrupting calcium/AMP-activated protein kinase (AMPK) signaling and autophagy flux. Crucially, the natural compound tannic acid directly binds and inhibits CTSB, completely protecting against hepato-cardiotoxicity without compromising vandetanib's antitumor efficacy in preclinical models. Overall, our findings establish CTSB-mediated lysosomal dysfunction and MCOLN1-calcium-AMPK axis disruption as the core mechanism of vandetanib-induced hepato-cardiotoxicity, and identify tannic acid as a readily translatable adjuvant strategy to prevent this toxicity. These findings redefine CTSB as a druggable target for kinase inhibitor toxicities and position tannic acid as a clinically translatable adjuvant to enhance vandetanib's safety profile. By preserving lysosomal function and calcium homeostasis, this strategy addresses a critical unmet need in precision oncology, enabling prolonged, safer use of vandetanib and related tyrosine kinase inhibitors. The discovery of shared lysosomal injury mechanisms across organs also opens avenues for preventing multi-organ toxicities in broader cancer therapies.
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DOI
PubMed
高影响因子
TOXICOLOGY
·
2024
·
IF 4.8
Wenting Wu,Jinglei Sun,Jiali Zhang,Haining Zhao,Suhua Qiu,Congxin Li,Chenxia Shi,Yanfang Xu
The use of tyrosine kinase inhibitors (TKIs) has resulted in significant occurrence of arrhythmias. However, the precise mechanism of the proarrhythmic effect is not fully understood. In this study, we found that nilotinib (NIL), vandetanib (VAN), and mobocertinib (MOB) induced the development of “cellrhythmia” (arrhythmia-like events) in a concentration-dependent manner in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Continuous administration of NIL, VAN, or MOB in animals significantly prolonged the action potential durations (APD) and increased susceptibility to arrhythmias. Using phosphoproteomic analysis, we identified proteins with altered phosphorylation levels after treatment with 3 μM NIL, VAN, and MOB for 1.5 h. Using these identified proteins as substrates, we performed kinase–substrate enrichment analysis to identify the kinases driving the changes in phosphorylation levels of these proteins. MAPK and WNK were both inhibited by NIL, VAN, and MOB. A selective inhibitor of WNK1, WNK-IN-11, induced concentration- and time-dependent cellrhythmias and prolonged field potential duration (FPD) in hiPSC-CMs in vitro; furthermore, administration in guinea pigs confirmed that WNK-IN-11 prolonged ventricular repolarization and increased susceptibility to arrhythmias. Fingding indicated that WNK1 inhibition had an in vivo and in vitro arrhythmogenic phenotype similar to TKIs. Additionally,three of TKIs reduced hERG and KCNQ1 expression at protein level, not at transcription level. Similarly, the knockdown of WNK1 decreased hERG and KCNQ1 protein expression in hiPSC-CMs. Collectively, our data suggest that the proarrhythmic effects of NIL, VAN, and MOB occur through a kinase inhibition mechanism. NIL, VAN, and MOB inhibit WNK1 kinase, leading to a decrease in hERG and KCNQ1 protein expression, thereby prolonging action potential repolarization and consequently cause arrhythmias.
研究领域:
心脏病学
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药理学
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蛋白质组学
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分子生物学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2021
·
IF 6.53
Ying Jin,Xueqin Chen,Zizheng Gao,Xiaofei Shen,Huangxi Fu,Zezheng Pan,Hao Yan,Bo Yang,Qiaojun He,Zhifei Xu,Peihua Luo
High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefits, but the underlying mechanisms and protective strategies are not well studied. Hence, we firstly established an in vivo model by continuously administrating vandetanib at 55 mg/kg/day to C57BL/6 for 21 days and verified that vandetanib could induce skin rash in vivo , which was consistent with the clinical study. We further cultured HaCaT and NHEK cells, the immortalized or primary human keratinocyte line, and investigated vandetanib (0–10 μM, 0–24 h)-caused alteration in cellular survival and death processes. The western blot showed that the expression level of apoptotic-related protein, c-PARP, c-Caspase 3 and Bax were increased, while the anti-apoptotic protein Bcl2 and MCL1 level were decreased. Meanwhile, vandetanib downregulated mitochondrial membrane potential which in turn caused the release of Cytochrome C, excessive production of reactive oxygen species and DNA damage. Furthermore, we found that 5 μM bisdemethoxycurcumin partially rescued vandetanib-induced mitochondria pathway-dependent keratinocyte apoptosis via activation of autophagy in vivo and in vitro , thereby ameliorated cutaneous toxicity. Conclusively, our study revealed the mechanisms of vandetanib-induced apoptosis in keratinocytes during the occurrence of cutaneous toxicity, and suggested bisdemethoxycurcumin as a potential protective drug. This work provided a potentially promising therapeutic strategy for the treatment of vandetanib-induced cutaneous toxicity.
研究领域:
药理学
·
毒理学
·
细胞生物学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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