Cell Death & Disease
·
2019
·Vol. 10
·期 6
·1-19
·
IF 5.959
Zhou Wenjuan,Ma Liying,Yang Jing,Qiao Hui,Li Lingyu,Guo Qian,Ma Jinlian,Zhao Lijuan,Wang Junwei,Jiang Guozhong,Wan Xiangbin,Adam Goscinski Mariusz,Ding Lina,Zheng Yichao,Li Wencai,Liu Hongmin,Suo Zhenhe,Zhao Wen
Human mutT homolog 1(MTH1), the oxidized dNTP pool sanitizer enzyme, has been reported to be highly expressed in various malignant tumors. However, the oncogenic role of MTH1 in gastric cancer remains to be determined. In the current study, we found that MTH1 was overexpressed in human gastric cancer tissues and cells. Using an in vitro MTH1 inhibitor screening system, the compounds available in our laboratory were screened and the small molecules containing 5-cyano-6-phenylpyrimidine structure were firstly found to show potently and specifically inhibitory effect on MTH1, especially compound MI-743 with IC 50 = 91.44 ± 1.45 nM. Both molecular docking and target engagement experiments proved that MI-743 can directly bind to MTH1. Moreover, MI-743 could not only inhibit cell proliferation in up to 16 cancer cell lines, especially gastric cancer cells HGC-27 and MGC-803, but also significantly induce MTH1-related 8-oxo-dG accumulation and DNA damage. Furthermore, the growth of xenograft tumours derived by injection of MGC-803 cells in nude mice was also significantly inhibited by MI-743 treatment. Importantly, MTH1 knockdown by siRNA in those two gastric cancer cells exhibited the similar findings. Our findings indicate that MTH1 is highly expressed in human gastric cancer tissues and cell lines. Small molecule MI-743 with 5-cyano-6-phenylpyrimidine structure may serve as a novel lead compound targeting the overexpressed MTH1 for gastric cancer treatment.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2022
·
IF 8.101
Jin Li,Zi-Hui Wang,Ya-Min Dang,Dan-Ni Li,Zhen Liu,Da-Peng Dai,Jian-Ping Cai
MTH1 protein can sanitize the damaged (d)NTP pool and MTH1 inhibitors have been developed to impede the growth of rapidly proliferating tumor cells; however, the effect of MTH1 inhibition on breast cancer stemness has not been reported yet. Here, we constructed breast cancer cell lines with the stable depletion of MTH1. MTH1 suppression clearly increased the ratio of CD44 + CD24 −/low subpopulations and promoted the formation of tumorspheres in MCF7 and T47D cells. RNA expression profiling, RT–qPCR and Western blotting showed the upregulation of master stem cell transcription factors Sox2 , Oct4 and Nanog in MTH1 knockdown cells. GSEA suggested and Western blotting verified that MTH1 knockdown increased the expression of phosphorylated STAT3 (Tyr705). Furthermore, we indirectly demonstrated that the increased concentration of 8-oxo-dGTP and 8-oxo-GTP in MTH1 -knockdown cells and exogenous 8-oxoGTP, rather than 8-oxo-dGTP, could significantly increase the phosphorylation of STAT3. In conclusion, this work indicates that MTH1 inhibition increased the proportion of breast cancer stem cells (BCSCs) and promoted stemness properties in MCF7 cells.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2022
·
IF 5.999
Qingcheng Song,Wenbo Yang,Xiangtian Deng,Yiran Zhang,Junyong Li,Xin Xing,Wei Chen,Weijian Liu,Hongzhi Hu,Yingze Zhang
Photodynamic therapy (PDT) is a promising therapeutic strategy for tumor ablation by generating highly toxic reactive oxygen species (ROS) to damage DNA and other biomacromolecules. However, the local hypoxic microenvironment of the tumor and the presence of ROS-defensing system, such as the mobilization of mutt homolog 1 (MTH1) to sanitize ROS-oxidized nucleotide pool, severely limit the efficiency of PDT. Therefore, a novel tumor ablation strategy was developed that not only focused on the enhancement of ROS generation but also weakened the ROS-defensing system by inhibiting MTH1 enzyme activity. In our work, a simple one-step reduction approach was applied to enable platinum nanoparticles (Pt NPs) with catalase activity to grow in situ in the nanochannels of mesoporous silica nanoparticles (MSNs). After physical encapsulation of photosensitizer chlorin e6 (Ce6) and MTH1 inhibitor TH588, the drug loading nanoplatform was modified with an arginine-glycine-aspartic acid (RGD) functionalized liposome shell, resulting in the fabrication of amplified oxidative damage nanoplatform MSN-Pt@Ce6/TH588 @Liposome-RGD (MPCT@Li-R). The prepared MPCT@Li-R NPs could continuously catalyze the decomposition of hydrogen peroxide (H 2 O 2 ) into oxygen (O 2 ) in tumor, thus promoting the generation of singlet oxygen during PDT process for improved oxidative damage of bases. Simultaneously, acid responsive released TH588 hindered MTH1-mediated scavenging of oxidative bases, further aggravating DNA oxidative damage. Consequently, this cascade therapy strategy exhibited excellent tumor suppression efficiency both in vitro and in vivo.
研究领域:
生物医学工程
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2024
·Vol. 17
·期 3
·291
·
IF 4.3
Nannan Kang,Jun Ma,Yuling Hu,Rongrong Di,Lei Wang,Xuanling Zhang,Yisheng Lai,Yu Liu
Background: Breast cancer is a commonly diagnosed cancer worldwide. Human MutT homolog 1 (MTH1) is found to be elevated in breast tumors and cancer cells need MTH1 for survival. Pharmacological inhibition of MTH1 may be potentially beneficial in the treatment of breast cancer. Methods: MA−24 was screened by malachite green colorimetric assay for MTH1 inhibitors and the kinetic characteristics of MA−24 were assessed. The features of MA−24’s binding with MTH1 were ascertained through molecular docking, and the cytotoxic activity of MA−24 was validated in vitro and in vivo. Target engagement assays, comet assay, and Western blot confirmed the intracellular target and mechanism of MA−24. Results: MA−24 shows potent antitumor bioactivity both in vitro and in vivo. MA−24 competitively inhibited the MTH1 and further induced DNA strand breaks, leading to increased apoptosis of cancer cells depending on the upregulation of the cleaved-caspase 3–cleaved-PARP axis. In particular, MA−24 exhibited a powerful efficacy and safety in vivo (tumor growth inhibition rate: 61.8%). Conclusions: MA−24 possesses a broad spectrum of breast cancer cytotoxicity and offered valuable insights for overcoming the challenges of chemotherapy-related toxicity, which holds great potential for the further development MA−24 as an anti-cancer drug.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2023
·Vol. 11
·期 17
·3836-3850
·
IF 7
Qingcheng Song,Yiran Zhang,Xiangtian Deng,Haiyue Zhao,Yueyao Zhang,Junyong Li,Wei Chen,Hongzhi Hu,Yingze Zhang
During chemodynamic therapy (CDT), tumor cells can adapt to hydroxyl radical (˙OH) invasion by activating DNA damage repairing mechanisms such as initiating mutt homologue 1 (MTH1) to mitigate oxidation-induced DNA lesions. Therefore, a novel sequential nano-catalytic platform MCTP-FA was developed in which ultrasmall cerium oxide nanoparticle (CeO2 NP) decorated dendritic mesoporous silica NPs (DMSN NPs) were used as the core, and after encapsulation of MTH1 inhibitor TH588, folic acid-functionalized polydopamine (PDA) was coated on the periphery. Once endocytosed into the tumor, CeO2 with multivalent elements (Ce3+/4+) could transform H2O2 into highly toxic ˙OH through a Fenton-like reaction to attack DNA as well as eliminating GSH through a redox reaction to amplify oxidative damage. Meanwhile, controllable release of TH588 hindered the MTH1-mediated damage repair process, further aggravating the oxidative damage of DNA. Thanks to the excellent photothermal performance of the PDA shell in the near-infrared (NIR) region, photothermal therapy (PTT) further improved the catalytic activity of Ce3+/4+. The therapeutic strategy of combining PTT, CDT, GSH-consumption and TH588-mediated amplification of DNA damage endows MCTP-FA with powerful tumor inhibition efficacy both in vitro and in vivo.
研究领域:
肿瘤学
·
纳米医学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2024
·
IF 18
Cui Ren,Zhiyong Shi,Xiaowen Zhang,Xueer Yu,Yang Gao,Zhi Qi,Yu Chen,Yong Wang
Chemo-dynamic therapy (CDT) has a great potential in tumor extirpation. It entails producing hypertoxic reactive oxygen species (ROS) that damage the DNA of tumor cells and other biomacromolecules. However, the efficiency of CDT is severely hampered by the massive presence of glutathione (GSH) in tumor cells and the interference of ROS defense systems, such as Mutt homolog 1 (MTH1) protein sanitizes ROS-oxidized nucleotide pools. In this research, DNA-mediated self-assembly nanoparticles (HTCG@TA NPs) were engineered with high-performance amplified oxidative damage and gene therapy effect for synergistic anti-tumor treatment. Cu 2+ was converted into Cu + by redox reactions to deplete GSH while H 2 O 2 was catalyzed to generate hydroxyl radicals (·OH). As a result, the ROS level was evidently improved. Moreover, controllable-released TH588 prevented MTH1-mediated DNA repairing, thus aggravated oxidative damage to tumor cells. Meanwhile, the released functional nucleic acid G3139 downregulated the expression of Bcl-2, and accelerated the apoptosis of tumor cells. In conclusion, the HTCG@TA demonstrated significant effect in oxidative damage amplification and tumor inhibition both in vitro and in vivo , which has provided a new outlook for the clinical application of chemo-dynamic tumor treatment and synergistic gene therapy with self-delivery nanoplatforms.
研究领域:
生物医学工程
·
癌症治疗
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Yutong Shao,Miaomiao Chen,Wenlong Chen,Zehui Wang,Mengzhang Sui,Mingyu Tian,Yingnan Wu,Jitao Song,Debin Ji,Fengling Song
Photodynamic therapy (PDT) uses photosensitizers to convert oxygen (O 2 ) to reactive oxygen species (ROS) under irradiation to induce DNA damage and kill cancer cells. However, the effect of PDT is usually alleviated by apoptosis resistance mechanism of tumor living cells. MTH1 enzyme is known to be such an apoptosis-resistance enzyme which is over expressed as a scavenger to repair the damaged DNA. In this work, a hypoxia-activated nanosystem FTPA, which can be degraded to release the encapsulated PDT photosensitizer 4-DCF-MPYM and an inhibitor TH588 is proposed. The inhibitor TH588 can inhibit the DNA repair process by reducing the activity of MTH1 enzyme, and achieve the purpose of amplifying the therapeutic effect of PDT. This work demonstrates that a precise and augmented tumor PDT is achieved by integration of hypoxia-activation and inhibition resistance of tumor cells to apoptosis.
研究领域:
癌症治疗
·
纳米技术
·
生物化学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Wei Zhang,Yijun Ran,Mi Yang,Yaqin Hu,Zhigang Wang,Yang Cao,Haitao Ran
Amplifying oxidative stress to disrupt intracellular redox homeostasis can accelerate tumor cell death. In this work, an oxidative stress amplifier (PP@T) is prepared for enhanced tumor oxidation therapy to reduce tumor growth and metastases. The nano-amplifier has been successfully constructed by embedding MTH1 inhibitor (TH588) in the PDA-coated porphyrin metal–organic framework PCN-224. The controllable-released TH588 is demonstrated from pores can hinder MTH1-mediated damage-repairing process by preventing the hydrolysis of 8-oxo-dG, thereby amplifying oxidative stress and exacerbating the oxidative DNA damage induced by the sonodynamic therapy of PP@T under ultrasound irradiation. Furthermore, PP@T can effectively induce immunogenic cell death to trigger systemic anti-tumor immune response. When administered in combination with immune checkpoint blockade, PP@T not only impedes the progression of the primary tumor but also achieves obvious antimetastasis in breast cancer murine models, including orthotopic and artificial whole-body metastasis models. Furthermore, the nanoplatform also provides photoacoustic imaging for in vivo treatment guidance. In conclusion, by amplifying oxidative stress and reactive oxygen species sensitized immunotherapy, this image-guided nanosystem shows potential for highly specific, effective combined therapy against tumor cells with negligible side-effects to normal cells which will provide a new insight for precise tumor treatment.
研究领域:
肿瘤学
·
生物医学工程
·
免疫治疗
·
纳米技术
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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