BIOORGANIC CHEMISTRY
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2021
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IF 5.275
Lanmei Chen,Jie Wang,Xianhong Cai,Suxiang Chen,Jingjing Zhang,Baojun Li,Weigang Chen,Xinhua Guo,Hui Luo,Jincan Chen
Both ruthenium (Ru) and isoquinoline (IQ) compounds are regarded as potential anticancer drug candidates. Here, we report the synthesis and characterization of three novel cyclometalated Ru(II)-isoquinoline complexes: RuIQ-3 , RuIQ-4 , and RuIQ-5, and evaluation of their in vitro cytotoxicities against a panel of cell lines including A549/DDP, a cisplatin-resistant human lung cancer cell line. A549/DDP 3D multicellular tumor spheroids (MCTSs) were also used to detect the drug resistance reversal effect of Ru(II)-IQ complexes. Our results indicated that the cytotoxic activities against cancer cells of Ru(II)-IQ complexes, especially RuIQ-5 , were superior compared with cisplatin. In addition, RuIQ-5 exhibited low toxicity towards both normal HBE cells in vitro and zebrafish embryos in vivo . Further investigation on cellular mechanism of action indicated that after absorption by A549/DDP cells, RuIQ-5 was mainly distributed in the nucleus, which is different from cisplatin. Besides, RuIQ-5 could induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, ROS-mediated DNA damage, and cycle arrest at both S and G2/M phases. Moreover, RuIQ-5 could inhibit the overexpression of Nrf2 through regulation of Akt/GSK-3β/Fyn signaling pathway and hindering the nuclear translocation of Nrf2. Based on these findings, we firmly believe that the studied Ru(II)-IQ complexes hold great promise as anticancer therapeutics with high effectiveness and low toxicity.
研究领域:
药理学
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肿瘤学
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细胞生物学
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化疗
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DOI
PubMed
高影响因子
Cancer Management and Research
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2023
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IF 3.3
Ping Huang,Shi-Xia Du
Objective The effect of PUE on enhancing the anti-cancerous efficacy of DDP on drug-resistant A549/DDP cancer and the underlying mechanisms were thoroughly investigated.Materials and Methods The cytotoxicity of PUE, DDP, and PUE + DDP to A549 cells and A549/DDP cells, respectively, is determined by cell apoptosis experiments. Anti-proliferation effect of PUE, DDP, and PUE + DDP on A549 cells and A549/DDP cells is evaluated by the cell cloning assay. Qualitative and quantitative analysis of the levels of PUE, DDP, and PUE + DDP of cell proliferation-related genes and proteins expressions in A549/DDP cells are determined by Western blot assay. The levels of VEGF in A549/DDP cells after different treatment strategies are determined by ELISA assay. Qualitative and quantitative determination of VEGF expression in tumor tissues are done by immunohistochemical staining.Results In vitro cellular experiments revealed that co-incubation of A549/DDP cells with PUE and DDP led to a dramatically decreased cell viability and cell survival rate compared with the cells only treated by DDP. Such a stimulating effect of PUE on DDP was further confirmed in vivo with results shown that the A549/DDP cancer-bearing mice treaded by combination therapy achieved the lowest tumor growth rate and longest survival time.Conclusion Taking these results together, we can draw the conclusion that the PUE enhances the anti-tumor effect of DDP on the drug-resistant A549 cancer in vivo and in vitro through activation of the Wnt signaling pathway.
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
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2023
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IF 4.5
Wenhui Ye,Huaiyou Lv,Qinxiu Zhang,Jianxiong Zhao,Xin Zhao,Guozhi Zhao,Chongzheng Yan,Fengqin Sun,Zhongxi Zhao,Xiumei Jia
Non-small cell lung cancer (NSCLC) accounting for about 80-85% of all lung cancer cases is one of the fastest-growing malignancies in terms of incidence and mortality worldwide and is commonly treated with cisplatin (DDP). Although treatment may initially be effective, the DDP therapy often leads to the development of chemoresistance and treatment failure. Disulfiram (DSF), an old alcohol-aversion drug, has been revealed to help reverse drug resistance in several cancers. In addition, several studies have shown a close relationship between drug resistance and cancer cell stemness. In this study, DDP and DSF were embedded in hydroxypropyl-β-cyclodextrin (CD) to prepare a co-loaded inclusion complex of DDP and DSF (DDP-DSF/CD) with enhanced solubility and therapeutic effects. The effects and mechanism of DSF on the DDP resistance from the perspective of cancer cell stemness were determined. Our data show that DDP-DSF/CD increased cytotoxicity and apoptosis of DDP-resistant A549 (A549/DDP) cells, inhibited stem cell transcriptional regulatory genes and drug resistance-associated proteins and reversed the DDP resistance in vitro and in vivo. Overall, DDP-DSF/CD could be a promising formulation for the reversal of DDP resistance in NSCLC by inhibiting cancer cell stemness.
研究领域:
肿瘤学
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药学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2023
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IF 9.9
Xucan Yang,Lulu Cheng,Yile Zhao,Haoran Ma,Haitao Song,Xuanmin Yang,Kang-Nan Wang,Yanrong Zhang
The efficacy of imaging-guided photodynamic therapy (PDT) is compromised by the attenuation of fluorescence and decline in reactive oxygen species (ROS) generation efficiency in the physiological environment of conventional photosensitizers , limited near-infrared (NIR) absorption, and high systemic cytotoxicity. This paper presents the synthesis of two cyclometalated Ir (III) complexes (Ir-thpy and Ir-ppy) by using a triphenylamine derivative (DPTPA) as the primary ligand and their encapsulation into an amphiphilic phospholipid to form nanoparticles (NPs). These complexes exhibit aggregation-induced emission features and remarkably enhanced ROS generation compared to Chlorin e6 (Ce6). Moreover, Ir-thpy NPs possess the unique ability to selectively target mitochondria , leading to depolarization of the mitochondrial membrane potential and ultimately triggering apoptosis. Notably, Ir-thpy NPs exhibit exceptional photocytotoxicity even towards cisplatin-resistant A549/DDP tumor cells. In vivo two-photon imaging verified the robust tumor-targeting efficacy of Ir-thpy NPs. The in vivo results unequivocally demonstrate that Ir-thpy NPs exhibit excellent tumor ablation along with remarkable biocompatibility. This study presents a promising approach for the development of multifunctional Ir-NPs for two-photon imaging-guided PDT and provides novel insights for potential clinical applications in oncology.
研究领域:
材料科学
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纳米技术
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癌症研究
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生物医学工程
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药学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Xi Wang,Guiquan Liu,Xueyu Pu,Tangjun Ren,Fan Zhang,MengJie Shen,Yan Zhu,Alexander Kros,Jian Yang
Drug resistance to chemotherapy in treating cancers becomes an increasingly serious challenge, which leads to treatment failure and poor patient survival. Drug-resistant cancer cells normally reduce intracellular accumulation of drugs by controlling drug uptake and promoting drug efflux, which severely limits the efficacy of chemotherapy. To overcome this problem, a membrane fused drug delivery system (MF-DDS) was constructed to treat cisplatin (DDP)-resistant lung cancer (A549-DDP) by delivering DDP via membrane fusion using a complementary coiled-coil forming peptides (CP 8 K 4 /CP 8 E 4 ). The lipopeptide CP 8 K 4 was pre-incubated firstly and decorated on the surface of A549-DDP cells, and then the cells interacted with the lipopeptide CP 8 E 4 modified on the lipid bilayer (LB) coated PLGA nanoparticles loading DDP (PLGA-DDP@LB-CP 8 E 4 ), leaded to the direct cytosolic DDP delivery and cancer cell death. Compared with free DDP, this MF-DDS achieved a 13.42-folds reduced IC 50 value of A549-DDP cells in vitro , and tumor size was down-regulated, showing only 1/5.26 of the original weight in vivo . Meanwhile, the anti-drug resistant mechanism was explored, where the MF-DDS inhibited the expression of efflux protein genes, including MRP1, MRP2, and ABCG2, leading to increased intracellular drug accumulations. Altogether, this MF-DDS effectively delivered DDP into DDP-resistant cancer cells, making it a promising and improved pharmacological therapeutic approach for drug-resistant tumor treatment.
研究领域:
肿瘤学
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药理学
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
SYNTHETIC COMMUNICATIONS
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2023
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IF 2.1
Jun Yang,Guang-Ping Liang,Xiong-Li Liu
To investigate the effects and mechanisms of 4-(1H-indol-1-yl)-4-oxobutanoic acid spliced podophyllotoxin derivatives (3a–3l) on tumor cells. The MTT method was adopted to evaluate (3a–3l) antitumor activity in vitro against A549 cells, A549/DDP cells, MCF-7 cells. The results showed that compound 3l had the most prominent inhibitory effect and high selectivity with IC50 18.53 ± 1.51 µM against A549/DDP cells. Meanwhile, the effects of compound 3l on the nuclear state, cell cycle and apoptosis of A549/DDP cells showed that compound 3l induced apoptosis by delaying the G2/M phase of A549/DDP cell cycle. In addition, molecular docking of compound 3l also showed that it could form a good hydrogen bond with ARG-158 (d = 2.6, 2.7 Å) and HIS-406 (d = 2.5 Å) at the colchicine site of tubulin. Compound 3l could provide lead compound for the development of new multi-drug resistant anti-tumor drugs.
研究领域:
药理学
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肿瘤学
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化学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
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