JOURNAL OF DRUG TARGETING
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2018
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IF 3.408
Xuefei Zhou,Zimo Liu,Huifang Wang,Xin Liu,Zhuxian Zhou,Jianbin Tang,Xiangrui Liu,Min Zheng,Youqing Shen
Non-viral gene delivery is an attractive approach for the treatment of many diseases including cancer, benefiting from its safety and large-scale production concerns. However, the relatively low transfection efficacy compared with viral vectors restricts the clinical applications of non-viral gene vectors. Reactive oxygen species (ROS) triggered charge reversal polymers (named B-PDEAEA) presented improved transfection efficacy, because of fast release of plasmid DNA responding to enhanced oxidative stress in cancer cells. But inadequate dissociation can still occur owing to the insufficient intracellular ROS generation. Here, we report SAHA (vorinostat), which is a clinical histone deacetylase inhibitor and anticancer drug, induces the ROS accumulation in cancer cells, and facilitates the charge reversal process of B-PDEAEA and the cellular dissociation of the delivered gene from the vectors. As a result, SAHA remarkably increases the gene transfection efficacy in an ROS-dependent manner. Importantly, SAHA synergizes with B-PDEAEA mediated therapeutic gene TNF-related apoptosis-inducing ligand (TRAIL) delivery in inducing apoptosis of cancer cells. These findings support the first concept of improving the gene delivery efficacy of stimuli-responsive vectors through upregulating the cellular ROS via an FDA approved anticancer agent. Additionally, combination of SAHA and TRAIL gene therapy could be a potential strategy for cancer treatment.
研究领域:
癌症研究
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基因治疗
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药理学
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DOI
PubMed
高影响因子
RSC Advances
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2016
·Vol. 6
·期 103
·100765-100771
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IF 3.289
Chang Shu,Eboka Majolene B. Sabi-mouka,Wen Yang,Zhongyang Li,Li Ding
In this work, we designed a self-assembly peptide hydrogel encapsulated paclitaxel (PTX) and suberoylanilide hydroxamic acid (SAHA) for cancer co-delivery (Nap–PTX–SAHA). The hydrogels exhibited uniform nanofibers that entangle to form stable networks and pore microstructures (about 140–180 nm) resulting in absorption and storage of hydrophobic drugs. The circular dichroism (CD) spectra of hydrogels exhibit β-turn-like features. Nap–PTX–SAHA hydrogels achieved control over different types of drugs loading and released by diffusion and relaxation processes. Hydrogels exhibited better therapeutic effect and greater synergetic effect compared to the free drugs in vitro and in vivo. Injection of the hydrogels appears to achieve long-term drug release with higher efficacy and better biocompatibility than free drugs. As for the drug biodistribution studies in tumor-bearing mice, the PTX and SAHA from Nap–PTX–SAHA gels uptake in liver, lung and tumor were more than that of free PTX and SAHA. In comparison with free PTX or SAHA, the Nap–PTX–SAHA gels lower the uptake of released drug significantly in the heart, spleen, and kidney to reduce the cardiotoxicity and renaltoxicity. In conclusion, the Nap–PTX–SAHA gels certainly reduce the side effects of PTX and SAHA, enhance synergistic anticancer effects and suppress the drug resistance of PTX. This strategy can be a basis for designing appropriate clinical trials and will hold promise in nanomedicine for different drug combinations.
研究领域:
药学
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癌症研究
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纳米技术
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药物递送系统
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生物医学工程
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DOI
高影响因子
Phytochemistry Letters
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2026
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IF 1.7
Zhenzhen Zhang,Longfei Zhang,Mengting Yang,Zhenhui Wang,Xueqian He
One undescribed aniline-containing phthalide was induced by SAHA. • Azoxy compound 2 was generated via the biotransformation of SAHA. • Talarophthalide D showed antibacterial activity against Proteus mirabilis . A previously undescribed aniline-containing phthalide derivative, talarophthalide D ( 1 ), and an azoxy compound, azoxybenzene ( 2 ), were obtained from the Yellow River wetland-derived Talaromyces funiculosus HPU-Y01 treated with the histone deacetylase inhibitor SAHA (suberanilohydroxamic acid). The structures of 1–2 were elucidated by comprehensive analysis of NMR spectroscopy and HRESIMS data. Talarophthalide D ( 1 ) is characterized as a hybrid incorporating an aniline-phthalide moiety and a long-chain unsaturated fatty acid. Azoxybenzene ( 2 ) was produced via a rare fungal-catalyzed biotransformation of aniline, a degradation product of SAHA. Talarophthalide D showed antimicrobial activity against Proteus mirabilis with MIC value of 6.25 μ M. Download: Download high-res image (104KB) Download: Download full-size image
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DOI
高影响因子
Advanced Healthcare Materials
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2024
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IF 10
Xuemeng Guo,Xiang Li,Sijie Wang,Yingying Shi,Jiaxin Huang,Xu Liu,Yichao Lu,Junlei Zhang,Lihua Luo,Jian You
Adoptive cell therapy (ACT) emerged as a promising approach for cancer treatment, yet its application in solid tumors faced challenges such as inadequate tumor infiltration and cellular dysfunction. Histone acetylation is reported to play a crucial role in restoring T-cell function within tumor tissues. Building upon previous research, a novel strategy involving the co-loading of two drugs, G3C12 and vorinostat (SAHA), into PLGA microspheres to form G3C12+SAHA@PLGA is developed for intratumoral injection. The G3C12 peptide enhances adoptive T-cell recruitment to the tumor site by modulating the binding state of IFN-γ. While SAHA, a histone deacetylase inhibitor, promotes memory phenotypes of infiltrating T-cells and prevents their transition to an exhausted state. This synergistic approach effectively augmentes the efficacy of ACT in the “cold” tumor model (4T1) or the “hot” tumor model (CT26). These findings highlight the potential of combining epigenetic regulation with recruitment signaling as a means to enhance the therapeutic impact of ACT in treating solid tumors.
研究领域:
肿瘤免疫学
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表观遗传学
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癌症治疗
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DOI
PubMed
高影响因子
Scientific Reports
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2024
·Vol. 14
·期 1
·1-15
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IF 3.8
Chen Linli,Guo Xiaojing,Lin Wen,Huang Yingying,Zhuang Suling,Li Qianfeng,Xu Jianhua,Ye Shengnan
Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies.
研究领域:
肿瘤学
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病毒学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
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2020
·Vol. 8
·期 17
·4739-4749
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IF 6.183
Zhicheng Zhang,Li Wang,Yawen Ding,Jinhui Wu,Yiqiao Hu,Ahu Yuan
Radiotherapy (RT) is one of the most extensive and effective approaches available for clinical tumor treatment. However, tumor microenvironments including hypoxia and histone deacetylase (HDAC) overexpression could induce radiation resistance, leading to tumor recurrence. Herein, nanoparticles (CAT-SAHA@PLGA) encapsulating catalase and HDAC inhibitor SAHA exhibited protected catalytic activity of catalase and prolonged the pharmacokinetic exposure of the HDAC inhibitor. Overall, the established CAT-SAHA@PLGA nanoparticles could overcome radiation resistance by synergistically increasing tumor oxygenation and inhibiting HDAC activity.
研究领域:
肿瘤学
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放射生物学
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纳米技术
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药理学
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产品关联
DOI
PubMed
高影响因子
Cancer Nanotechnology
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2020
·Vol. 11
·期 1
·1-17
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IF 4.7
Pisano S.,Wang X.,Garcia-Parra J.,Gazze A.,Edwards K.,Feltracco V.,Hu Y.,He L.,Gonzalez D.,Francis L. W.,Conlan R. S.,Li C.
Background Amphiphilic block copolymers used as nanomicelle drug carriers can effectively overcome poor drug solubility and specificity issues. Hence, these platforms have a broad applicability in cancer treatment. In this study, Pluronic F127 was used to fabricate nanomicelles containing the histone deacetylase inhibitor SAHA, which has an epigenetic-driven anti-cancer effect in several tumor types. SAHA-loaded nanomicelles were prepared using a thin-film drying method and characterized for size, surface charge, drug content, and drug release properties. Loaded particles were tested for in vitro activity and their effect on cell cycle and markers of cancer progression.Results Following detailed particle characterization, cell proliferation experiments demonstrated that SAHA-loaded nanomicelles more effectively inhibited the growth of HeLa and MCF-7 cell lines compared with free drug formulations. The 30 nm SAHA containing nanoparticles were able to release up to 100% of the encapsulated drug over a 72 h time window. Moreover, gene and protein expression analyses suggested that their cytoreductive effect was achieved through the regulation of p21 and p53 expression. SAHA was also shown to up-regulate E-cadherin expression, potentially influencing tumor migration.Conclusion sThis study highlights the opportunity to exploit pluronic-based nanomicelles for the delivery of compounds that regulate epigenetic processes, thus inhibiting cancer development and progression.
研究领域:
药学
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癌症生物学
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纳米技术
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药物递送系统
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产品关联
DOI
高影响因子
Advanced Science
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2022
·Vol. 9
·期 23
·2201271
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IF 17.521
Yihang Gong,Wenjie Chen,Xiuxing Chen,Yizhan He,Hua Jiang,Xijian Zhang,Lijie Pan,Beibei Ni,Fan Yang,Yan Xu,Qi Zhang,Lei Zhou,Yusheng Cheng
Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.
研究领域:
肿瘤学
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免疫治疗
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药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2021
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IF 5.811
Miao Jiefei,Meng Chi,Wu Hongmei,Shan Wenpei,Wang Haoran,Ling Changchun,Zhang Jinlin,Yang Tao
A novel hybrid CHC was designed and synthesized by conjugating β-carboline with an important active fragment N-hydroxyacrylamide of histone deacetylase (HDAC) inhibitor by an amide linkage to enhance antitumor efficacy/potency or even block drug resistance. CHC displayed high antiproliferative effects against drug-sensitive SUMM-7721, Bel7402, Huh7, and HCT116 cells and drug-resistant Bel7402/5FU cells with IC50 values ranging from 1.84 to 3.27 μM, which were two-to four-fold lower than those of FDA-approved HDAC inhibitor SAHA. However, CHC had relatively weak effect on non-tumor hepatic LO2 cells. Furthermore, CHC exhibited selective HDAC1/6 inhibitory effects and simultaneously augmented the acetylated histone H3/H4 and α-tubulin, which may make a great contribution to their antiproliferative effects. In addition, CHC also electrostatically interacted with CT-DNA, exerted remarkable cellular apoptosis by regulating the expression of apoptosis-related proteins and DNA damage proteins in Bel7402/5FU cells, and significantly accumulated cancer cells at the G2/M phase of the cell cycle by suppressing CDK1 and cyclin B protein with greater potency than SAHA-treated groups. Finally, CHC displayed strong inhibitory potency to drug-resistant hepatic tumors in mice. Our designed and synthetic hybrid CHC could be further developed as a significant and selective anticancer agent to potentially treat drug-resistant hepatocellular carcinoma.
研究领域:
药理学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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