CHEMICAL RESEARCH IN TOXICOLOGY
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2026
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IF 4.1
QiWei Yang,Lin Yu,Ran Tang,YiShan Peng,Tao Huang,HaoQi Chen,WenFeng Zhu,Qing Yuan,Wei Wang,Xiaojian Jiang,ZhiLi Ma,Lei Yuan,SuMei Wang,XiaoWen Wang,GenShu Wang
Environmental chemical exposure has emerged as an important modulator of cancer progression and therapeutic outcomes. Di-2-ethylhexyl phthalate (DEHP), a ubiquitous environmental plasticizer, has been widely recognized for its endocrine-disrupting effects; however, its impact on intracellular signaling reprogramming and cancer drug responsiveness remains incompletely understood. In this investigation, we aimed to elucidate the toxicological mechanisms by which DEHP alters cellular phenotypes and therapeutic sensitivity in hepatocellular carcinoma (HCC) cells. We demonstrate that DEHP exposure does not primarily promote cancer cell proliferation but instead induces epithelial–mesenchymal transition (EMT), leading to enhanced migratory and invasive capacities and reduced responsiveness to the tyrosine kinase inhibitor lenvatinib. Notably, integrative bioinformatic analyses combined with functional validation identified sperm-associated antigen 4 (SPAG4) as a key DEHP-responsive regulator mediating toxicant-induced cellular reprogramming. Mechanistic studies revealed that DEHP-induced upregulation of SPAG4 activates the MAPK/ERK signaling pathway, thereby driving EMT and attenuating lenvatinib responsiveness. Genetic silencing of SPAG4 or pharmacological inhibition of MAPK/ERK signaling effectively reversed DEHP-induced EMT and drug resistance. In conclusion, we highlight DEHP as a signaling-disrupting environmental toxicant that reprograms cancer cell states and modulates therapeutic responses through a SPAG4-dependent MAPK/ERK pathway. These findings provide mechanistic insight into how environmental chemical exposure can reshape intracellular signaling networks and influence cancer treatment outcomes, underscoring a previously underappreciated aspect of chemical toxicology.
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PubMed
高影响因子
Journal of Pharmaceutical Analysis
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2026
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IF 11.2
Mengyao Dai,Qitai Chen,Jinyuan Song,Xinpeng Ma,Ke Ma,Xiaobao Wei,Yumiao Niu,Tingbo Liang,Qi Zhang,Yangyang Li,Qihan Fu
Lenvatinib, an effective treatment for hepatocellular carcinoma (HCC), faces limitations due to mitochondrial function shift-induced energy metabolism reprogramming. Therefore, interfering with mitochondrial energy metabolism to enhance the curative effect of lenvatinib may represent a promising strategy. In this study, an indocyanine green (ICG)-templated self-assembling nanotherapeutic, lenvatinib-Ga (LGa), containing lenvatinib and gallium (III) ions, was constructed for combination therapy of HCC. LGa significantly enhanced the ability to induce HCC cell death. Subsequent investigations into mitochondrial dysfunction revealed that LGa increased intracellular levels of mitochondrial reactive oxygen species (ROS), leading to the collapse of mitochondrial membrane potential, impairments in adenosine triphosphate (ATP) synthesis and cellular respiration, as well as downregulation of Bcl-2 and activation of cleaved-caspase 3. Additionally, LGa upregulated endoplasmic reticulum (ER) stress-related protein expression (activating transcription factor 4 (ATF4), eukaryotic initiation factor 2 alpha (EIF2α), and C/EBP homologous protein (CHOP)), boosting calcium ion (Ca 2+ ) overload. These effects promoted HCC cell apoptosis and suppressed tumor growth in vivo . Moreover, LGa was further able to induce immunogenic cell death (ICD), promoting dendritic cell (DC) maturation. Simultaneously, LGa promoted the release of mitochondrial DNA (mtDNA), activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and subsequently triggering a DC-mediated immune response. Combined with anti-PD-1 antibody immunotherapy, LGa achieved synergistic anti-tumor effects. Our findings suggest LGa could be a promising therapeutic approach for HCC.
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高影响因子
Journal of Materials Chemistry B
·
2021
·Vol. 9
·期 48
·9908-9922
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IF 6.331
Qi Xu,Qiuting Li,Zhe Yang,Piao Huang,Han Hu,Zhimin Mo,Zizhen Qin,Zushun Xu,Tianyou Chen,Shengli Yang
Lenvatinib (LT) is gradually replacing sorafenib as an alternative targeted drug against advanced hepatocellular carcinoma (HCC). However, the anticancer effects of LT are still limited because of its low cytotoxicity, multidrug resistance (MDR), and tumor relapse. Herein, we constructed a smart biophotonic nanoplatform to overcome the barriers preventing high performance. LT and copper sulfide nanocrystals (Cu2−xS NCs) with excellent photothermal properties in the near-infrared-II (NIR-II) zone were co-encapsulated in poly(D,L-lactide-co-glycolide) (PLGA) through nanoprecipitation. Both in vitro and in vivo evaluations demonstrated that Cu2−xS NCs enhanced the anticancer efficacy of LT, without recurrence. In addition, the presence of copper ions could allow glutathione (GHS) to be consumed and oxygen to be produced, likely suppressing the expression of P-glycoprotein (P-gp) and overcoming the issue of MDR relating to LT. More importantly, synergistic chemo-photothermal therapy with LT and Cu2−xS NCs was more effective than any single therapy or theoretical combination. This nanoplatform is promising for advancing future LT-based treatment strategies for HCC therapy.
研究领域:
肿瘤学
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纳米医学
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药物递送系统
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生物材料
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高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2025
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IF 2.2
Yanyan Zhou,Shengnan Luo,Zhe Jiang,Xiang Luo,Zhangsen Yu,Zhixin Wang,Kewu Zhu
Objective Lenvatinib (LEN), a first-line treatment for advanced hepatocellular carcinoma (HCC), faces limitations due to adverse effects and drug resistance. This study aimed to develop LEN-loaded solid lipid nanoparticles (SLNs) modified with Twenty-polyglycerol vitamin E succinate (PG20-VES@LEN-SLNs) to enhance therapeutic efficacy and compare them with Tween80-modified SLNs (Tween80@LEN-SLNs).Methods The formulation of LEN-SLNs was optimized based on particle size and polydispersity index (PDI) by screening lipid matrices (GMS, GMP, SA, CP, GB, GMD), surfactant types (Tween80, PG20-VES, TPGS1000, F68), and GMS:SPC ratios. Physicochemical properties were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FTIR). Encapsulation efficiency (EE), drug loading (DL), and in vitro drug release profiles were evaluated. Cytotoxicity against HepG2, Huh-7, and L02 cells was assessed via MTT assay, while cellular uptake in HepG2 was visualized using Nile Red-labeled SLNs.Results Optimized PG20-VES@LEN-SLNs exhibited a smaller particle size (294.6 ± 10.4 nm vs. 308.6 ± 29.5 nm for Tween80@LEN-SLNs) and higher EE (80.7 ± 5.1% vs. 72.7 ± 4.0%). Both formulations showed sustained drug release over 48 h, significantly slower than free LEN (97.4% released in 24 h). PG20-VES@LEN-SLNs demonstrated superior cytotoxicity against HepG2 cells (IC50 = 36.47 μM) compared to Tween80@LEN-SLNs (IC50 = 42.49 μM) and free LEN (IC50 = 116.8 μM), with enhanced cellular uptake observed via confocal microscopy. In Huh-7 cells, PG20-VES@LEN-SLNs and Tween80@LEN-SLNs reduced the IC50 of lenvatinib from 189.21 μM (free LEN) to 18.04 μM and 18.41 μM, respectively.Conclusion PG20-VES@LEN-SLNs effectively improved LEN’s therapeutic index through sustained release, enhanced tumor cell targeting, and synergistic cytotoxicity. This study highlights PG20-VES as a multifunctional surfactant for advanced HCC nanotherapy, offering a promising strategy to overcome clinical limitations of LEN.
研究领域:
药剂学
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纳米技术
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肿瘤学
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药物递送系统
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生物医学工程
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PubMed
高影响因子
Thoracic Cancer
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2023
·Vol. 14
·期 33
·3331-3341
·
IF 2.9
Mengming Xia,Xueyi Song,Zebei Lu,Yu Wang,Quan Zhou,Peiwu Geng,Shuanghu Wang,Yunfang Zhou,Qingjun Wu,Aixia Han
Background Lenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when orally administered to rats. Methods A total of 30 Sprague–Dawley rats were randomly allocated into five groups and administered 20 mg/kg of ketoconazole, voriconazole, isavuconazole and 30 mg/kg of posaconazole and 0.5% CMC-Na, through gavage for a duration of 7 days prior to the commencement of the experiment. On the final day, the rats were given 10 mg/kg of lenvatinib. The blood concentration of lenvatinib was determined using UPLC-MS–MS. In vitro lenvatinib were incubated with azoles and rat liver microsomes (RLMs) or human liver microsomes (HLMs). Molecular docking was lastly used to examine the binding strength of the enzymes and ligands with Autodock Vina. Results AUC and C max of lenvatinib significantly increased with each of the azoles ( p < 0.05), whereas CLz/F decreased 0.83-flod, 0.41-fold ( p < 0.05) and 0.72-fold ( p < 0.01) in voriconazole, isavuconazole and ketoconazole in rats. The IC50 of lenvatinib with the azoles were 0.237, 1.300, 0.355 and 2.403 μM in RLMs and 0.160, 1.933, 3.622 and 1.831 μM in HLMs. Molecular docking analysis suggested that azoles exhibited a strong binding ability towards the target enzymes. Conclusion It is imperative to acknowledge the potential drug–drug interactions mediated by CYP3A4 between azoles and lenvatinib, as these interactions hold significant implications for their clinical utilization.
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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PubMed
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Yufeng Deng,Qi hu,Zhiying Song,Mengyuan Nie,Zhiguo Wu,Yongrong Lei,Meng Liu,Dujuan Zhan,Baogang Xie
Objective Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality. Targeted therapies like lenvatinib face limitations due to resistance and immunosuppression. d -Glucaro-1,4-lactone (1,4-GL), a bioactive natural compound with anti-HCC activity, holds unexplored synergistic potential with lenvatinib. This study investigates the combinatorial efficacy of 1,4-GL and lenvatinib against HCC and elucidates the underlying mechanisms. Methods Efficacy was evaluated in H22 tumor-bearing mice treated with lenvatinib (20 mg/kg/day) ± 1,4-GL (25, 50, 100 mg/kg/day). Tumor inhibition, serum cytokines (TNF-α, IFN-γ, AFP), oxidative stress markers (MDA, SOD), liver enzymes (ALT, AST), and splenic T-cell subsets (flow cytometry) were assessed. Histopathology was analyzed via H&E staining. Lenvatinib pharmacokinetics (serum, liver, tumor) with/without 1,4-GL was determined in mice and SD rats using UPLC-MS/MS. In vitro, combinatorial effects on proliferation (CCK-8), migration (scratch assay), and clonogenicity (colony formation) were tested in Huh7 and HepG2 cells. STAT3 phosphorylation and PD-L1 expression (protein: Western blot; mRNA: RT-qPCR) were analyzed. PD-L1 induction was achieved using IFN-γ (20 ng/ml). Results The medium-dose combination (LMGL) achieved 89.97% tumor inhibition in H22 mice, significantly reducing tumor mass by 75% vs. lenvatinib alone (0.21±0.18 g vs. 0.84±0.79 g, p < 0.01). H&E staining revealed extensive necrosis in combination groups. Serum TNF-α and IFN-γ levels significantly increased ( p < 0.001), while AFP approached baseline. Flow cytometry showed an elevated CD4⁺/CD8⁺ T-cell ratio. Oxidative stress was modulated (reduced MDA and elevated SOD, p < 0.01). Pharmacokinetic studies revealed no significant differences in lenvatinib exposure or steady-state concentrations ( p > 0.05) with 1,4-GL co-administration. In vitro, 1,4-GL significantly reduced lenvatinib's IC 50 (Huh7: 18.54 μmol/l; HepG2: 30.34 μmol/l). Combinatorial treatment markedly downregulated PD-L1 protein/mRNA and inhibited STAT3 phosphorylation ( p < 0.05). Scratch and colony formation assays indicated synergy stemmed from immunomodulation and signaling inhibition, not enhanced anti-migration/proliferation. Conclusion 1,4-GL potently synergizes with lenvatinib against HCC by enhancing oxidative stress, reconstituting antitumor immunity, and suppressing the STAT3/PD-L1 signaling axis, without perturbing lenvatinib pharmacokinetics. This defines a novel phytochemical-based combinatorial strategy with significant clinical translation potential for HCC therapy.
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PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2024
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IF 9.1
Yilan Huang,Siwei Wang,Xiaojun Zhang,Chen Yang,Sikai Wang,Hongxia Cheng,Aiwu Ke,Chao Gao,Kun Guo
Lenvatinib is a frontline tyrosine kinase inhibitor for patients with advanced hepatocellular carcinoma (HCC). However, just 25% of patients benefit from the treatment, and acquired resistance always develops. To date, there are neither effective medications to combat lenvatinib resistance nor accurate markers that might predict how well a patient would respond to the lenvatinib treatment. Thus, novel strategies to recognize and deal with lenvatinib resistance are desperately needed. In the current study, a robust Lenvatinib Resistance index (LRi) model to predict lenvatinib response status in HCC was first established. Subsequently, five candidate drugs (Mercaptopurine, AACOCF3, NU1025, Fasudil, and Exisulind) that were capable of reversing lenvatinib resistance signature were initially selected by performing the connectivity map (CMap) analysis, and fasudil finally stood out by conducting a series of cellular functional assays in vitro and xenograft mouse model. Transcriptomics revealed that the co-administration of lenvatinib and fasudil overcame lenvatinib resistance by remodeling the hedgehog signaling pathway. Mechanistically, the feedback activation of EGFR by lenvatinib led to the activation of the GLI2-ABCC1 pathway, which supported the HCC cell's survival and proliferation. Notably, co-administration of lenvatinib and fasudil significantly inhibited IHH, the upstream switch of the hedgehog pathway, to counteract GLI2 activation and finally enhance the effectiveness of lenvatinib. These findings elucidated a novel EGFR-mediated mechanism of lenvatinib resistance and provided a practical approach to overcoming drug resistance in HCC through meaningful drug repurposing strategies.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症生物学
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PubMed
高影响因子
International Journal of Biological Sciences
·
2023
·Vol. 19
·期 12
·3678-3693
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IF 9.2
Cao Mingbo,Ren Yupeng,Li Yuxuan,Deng Junfeng,Su Xiaorui,Tang Yongchang,Yuan Feng,Deng Haixia,Yang Gaoyuan,He Zhiwei,Liu Bo,Yao Zhicheng,Deng Meihai
Long non-coding RNAs have been reported to play a crucial role in tumor progression in hepatocellular carcinoma (HCC). Lnc-ZEB2-19 has been validated to be deficiently expressed in HCC. However, the capabilities and underlying mechanisms of lnc-ZEB2-19 remain uncertain. In this study, we verified that the downregulation of lnc-ZEB2-19 was prevalent in HCC and significantly correlated with the unfavorable prognosis. Further in vitro and in vivo verified that lnc-ZEB2-19 notably inhibited the proliferation, metastasis, stemness, and lenvatinib resistance (LR) of HCC cells. Mechanistically, lnc-ZEB2-19 inhibited HCC progression and LR by specifically binding to transformer 2α (TRA2A) and promoting its degradation, which resulted in the instability of RSPH14 mRNA, leading to the downregulation of Rela(p65) and p-Rela(p-p65). Furthermore, rescue assays showed that silencing RSPH14 partially restrained the effect of knockdown expression of lnc-ZEB2-19 on HCC cell metastatic ability and stemness. The findings describe a novel regulatory axis, lnc-ZEB2-19/TRA2A/RSPH14, downregulating the nuclear factor kappa B to inhibit HCC progression and LR.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
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IF 16.744
Yan Du,Chunlei Shan,Yuchan You,Minjiang Chen,Luwen Zhu,Gaofeng Shu,Gang Han,Liming Wu,Jiansong Ji,Hong Yu,Yongzhong Du
Lenvatinib (LEN) combined with immune checkpoint PD-1 blockade is among the most effective treatment strategies for advanced hepatocellular carcinoma (HCC) and has been deemed a breakthrough therapy by the Food and Drug Administration. However, this combined strategy is associated with disadvantages such as non-tumor targeted aggregation and low oral bioavailability after long-term administration of LEN, and some patients show poor responses to immunotherapy as well. To overcome these drawbacks, SP94 peptide-modified thermal-sensitive micelles (SP94-poly(ethylene glycol)-poly(acrylamide- co -acrylonitrile, SP94-PEG-p(AAm- co -AN)) with an upper critical solution temperature (UCST) of 43 °C were designed. The micelles were further co-loaded with LEN and IR-1061-Acridine (IR-1061-AcD) to simultaneously achieve small molecule targeted drug, photothermal and photodynamic therapy for HCC under the guidance of near-infrared second-region (NIR-II) fluorescence imaging. After intravenous injection, the co-loaded micelles (SP94-PEG-p(AAm- co -AN)/LEN/IR-1061-AcD, SPLI) showed greater accumulation at tumor sites because SP94 has a high affinity for glucoregulatory protein 78 (GRP78), which is overexpressed on HCC cells. Given these HCC-targeted effects, SPLI appeared useful for NIR-II fluorescence imaging, enabling real-time tumor monitoring and surgical resection. In addition, SPLI could extensively induce immunogenic cell death in tumors, resulting in beneficial systemic immune responses. When further combined with anti-PD-1 immunotherapy, SPLI displayed a superior potential in suppressing tumor growth and metastasis while avoiding immune inhibition. Taken together, our study suggests that the aforementioned combinational strategy could serve as a desired multifunctional approach for HCC management.
研究领域:
肿瘤学
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药学
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生物医学工程
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免疫学
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材料科学
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高影响因子
危险品化学品经营许可证（带存储）