BIOCHEMICAL PHARMACOLOGY
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2021
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IF 5.858
Cen Zhao,Dawei Yang,Yuchen Ye,Zhenzhong Chen,Tifan Sun,Jiawei Zhao,Kai Zhao,Na Lu
Multiple myeloma (MM) is a malignancy of antibody-producing plasma cells with genomic instability and genetic abnormality as its two hallmarks. Therefore, DNA damage is pervasive in MM cells, which indicates irregular DNA damage response (DDR) pathway. In this study, we demonstrated that LT-171-861, a multiple kinase inhibitor , could inhibit proliferation and induce apoptosis in MM cells. LT-171-861 promoted DDR pathway and triggered DNA damage through impeding the process of homologous recombination in double strand breaks, rather than directly elevating ROS level in MM cells. Mechanism research revealed that Pim2 inhibition was responsible for LT-171-861-indcued DNA damage and cell apoptosis. LT-171-861 mainly suppressed Pim2 kinase activity and reduced the expression of its phosphorylated substrates, such as 4EBP1 and BAD. Moreover, Olaparib , a PARP inhibitor , could enhance the antitumor effect of LT-171-861 in suppressing tumor growth in MM xenografted nude mice . Taken together, our results demonstrated that LT-171-861 showed a promising therapeutic potential for MM and had an additional lethal effect with PARP inhibitors.
研究领域:
癌症生物学
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分子生物学
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药理学
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肿瘤学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 7.3
Yuting Sun,Hui Yang,Jiaqi Yuan,Limin Wang,Shanshan Song,Rongrong Chen,Xubin Bao,Li Jia,Tiantian Yang,Xiaofei Zhang,Qian He,Yong Gan,Zehong Miao,Jinxue He,Chunhao Yang
Poly(ADP-ribose) polymerase inhibitors (PARPi) have significant efficacy in treating BRCA-deficient cancers, although resistance development remains an unsolved challenge. Herein, a series of phthalazin-1(2H)-one derivatives with excellent enzymatic inhibitory activity were designed and synthesized, and the structure–activity relationship was explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity against olaparib- and talazoparib-resistant cells, with IC50 values of 0.89 and 1.13 nM, respectively. Studies of the cellular mechanism revealed that YCH1899 retained sensitivity in drug-resistant cells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 had acceptable pharmacokinetic properties in rats and showed prominent dose-dependent antitumor activity in olaparib- and talazoparib-resistant cell-derived xenograft models. Overall, this study suggests that YCH1899 is a new-generation antiresistant PARPi that could provide a valuable direction for addressing drug resistance to existing PARPi drugs.
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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药物化学
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DOI
PubMed
高影响因子
Acta Biomaterialia
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2021
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IF 8.947
Jiejie Sun,Jingzhou Liu,Chunhong Gao,Jinpeng Zheng,Jinbang Zhang,Yaning Ding,Wei Gong,Meiyan Yang,Zhiping Li,Yuli Wang,Yang Yang,Chunsheng Gao
Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co-modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. Statement of Significance TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane-coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo .
研究领域:
神经科学
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药学
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纳米技术
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生物医学工程
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Yi Tai,Zhihao Chen,Tianqi Luo,Bingling Luo,Chuangzhong Deng,Zhenhai Lu,Shijun Wen,Jin Wang
Soft tissue sarcomas (STS) are highly malignant tumors with limited treatment options owing to their heterogeneity and resistance to conventional therapies. Photodynamic therapy (PDT) and poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown potential for STS treatment, with PDT being effective for sarcomas located on the extremities and body surface and PARPi targeting defects in homologous recombination repair. To address the limitations of PDT and harness the potential of PARPi, herein, a novel therapeutic approach for STS treatment combining nanocapsules bearing integrated metal–organic frameworks (MOFs) and covalent organic frameworks (COFs), i.e., MOF@COF, with PDT and PARPi is proposed. Nanocapsules are designed, referred to as ZTN@COF@poloxamer, which contain a Zr-based MOF and tetrakis (4-carbethoxyphenyl) porphyrin as a photosensitizer, are coated with a COF to improve the sensitizing properties, and are loaded with niraparib to inhibit DNA repair. Experiments demonstrate that this new nanocapsules treatment significantly inhibits STS growth, promotes tumor cell apoptosis, exhibits high antitumor activity with minimal side effects, activates the immune response of the tumor, and inhibits lung metastasis in vivo. Therefore, MOF@COF nanocapsules combined with PARPi offer a promising approach for STS treatment, with the potential to enhance the efficacy of PDT and prevent tumor recurrence.
研究领域:
肿瘤学
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纳米技术
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药学
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免疫治疗
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Ming Jiang,Xueyu Man,Moya Yang,Qiwei Yan,Haijuan Wu,Feng Yang,Youhuan Wei
DNA serves as the primary target for numerous metal complexes in suppression tumor cell proliferation, and Poly ADP ribose polymerase-1 (PARP-1) is critical for DNA repair. In this study, benzothiazole hydrazone was used as a framework to design and synthesize a series of Cu(II) complexes (Cu1-Cu3), which functions as novel PARP-1 inhibitors. These Cu(II) complexes not only effectively inhibited the proliferation of a panel of tumor cells (IC 50 range: 0.51–5.37 μM) but also exhibited potent PARP-1 inhibitory activity (IC 50 range: 0.45–1.52 μM). Notably, complex Cu3 had the most potent activities, exhibiting strong cytotoxicity against T98G cells (IC 50 = 0.51 μM) and significant PARP-1 inhibition (IC 50 = 0.45 μM). Additionally, Cu3 effectively inhibited the migration of T98G cells. Mechanistic studies revealed that Cu3 generated excessive reactive oxygen species (ROS), induced DNA damage, exacerbated DNA double-strand breaks by inhibiting PARP-1 activity, and promoted apoptosis in tumor cells via the mitochondrial pathway.
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高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Jialu Zhang,Xiaoxuan Wang,Lu Guo,Shan Xiao,Dong Meng,Mengmeng Shang,Xiao Sun,Dandan Shi,Yading Zhao,Rui Liu,Shuting Huang,Xinyu Zeng,Jie Li
PARP inhibitor (PARPi)-based synthetic lethal therapies have displayed limited benefits in BRCA-proficient ovarian cancer. To potentiate the application of PARPi, an ultrasound contrast agent OLA-NDs for delivery of the PARPi olaparib (OLA) was established for enhancing DNA damage by blocking DNA repair. OLA-NDs were endowed with endogenous pH- and exogenous ultrasound (US)-responsiveness to target tumors, as well as contrast-enhanced US imaging for diagnostic and therapeutic integration. OLA-NDs could upregulate NOX4 to induce oxidative stress and sensitize BRCA wild-type A2780 cells to DNA oxidative damage through the utilization of ultrasound-targeted microbubble destruction (UTMD). In addition, the strategy further increased ROS production by interfering with mitochondrial function, thereby exacerbating DNA double-strand breaks (DSBs) and inducing mitochondria-mediated apoptosis. As a consequence, the combined application of UTMD and OLA-NDs demonstrated significant antitumor effects in vitro and in vivo . This combined strategy of amplifying oxidative damage improved lethality by promoting DNA DSBs and apoptosis with reduced adverse side effects, which would provide new insight for the clinical application of PARPi in BRCA-proficient ovarian cancer.
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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PubMed
高影响因子
TURKISH JOURNAL OF CHEMISTRY
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2022
·Vol. 43
·期 5
·1290-1305
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IF 1.151
TOK FATİH,KAYMAKÇIOĞLU BEDİA,İLHAN RECEP,YILMAZ SİNEM,KIRMIZIBAYRAK PETEK BALLAR,TOK TUĞBA TAŞKIN
Poly (ADP-ribose) polymerase (PARP) enzyme catalyzes the transfer of ADP-ribose into target proteins. Therefore, PARP is responsible for DNA repair, cell proliferation, and cell death. In this study, potential PARP enzyme inhibitors were designed and synthesized. The synthesized compounds were elucidated by Fourier-transform infrared spectroscopy, $^{1}$H NMR, $^{13}$C NMR, heteronuclear single-quantum correlation, and mass spectrometry, and their purity was checked via thin-layer chromatography, high-performance liquid chromatography, and elemental analysis. A total of 63 newly synthesized compounds were screened in terms of PARP inhibition by cellular PARylation assay in the HeLa cell line. It was found that 19 compounds significantly inhibited the H$_{2}$O$_{2}$-induced cellular PARylation. The chemosensitizer effect of these compounds in cancer cells treated with doxorubicin (doxo) was investigated. It was found that the combination of potent PARP inhibitors with doxo potentiated a cytotoxic effect, similar to that of olaparib. The results of the molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis revealed that compound 60 might be classified as a potential PARP inhibitor candidate. Taken together, all of the results suggested that carbohydrazide derivatives could be a promising lead for the treatment for cancer disorders.
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DOI
高影响因子
Frontiers in Bioscience-Landmark
·
2026
·Vol. 31
·期 7
·
IF 4.1
Wenlong Li,Xinyue Pei,Yongpei Li,Yanji Lu,Xian Hong,Ming Sui,Qiang Li,Xueying Sun,Jingqiu Wang,Enming Zhang,Yihan Liu,Tao Wang,Jing Xu,Zhihui Deng
Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown limited efficacy in gastric cancer, primarily due to the rarity of inherent homologous recombination (HR) deficiency. The nuclear Arp2/3 complex was recently implicated in DNA double-strand break repair via HR. Here, we investigate whether pharmacological inhibition of Arp2/3 can induce a functional HR-deficient state to synergize with PARPi in gastric cancer cells. Methods: HR repair efficiency was assessed using a direct repeat green fluorescent protein (DR-GFP) reporter assay in HEK-293T cells following Arp2/3 inhibition with CK666, siRNA-mediated knockdown, or CRISPR/Cas9-mediated knockout of ACTR2/ACTR3. HGC-27 and AGS gastric cancer cells were treated with CK666 alone and in combination with olaparib or niraparib. Cell viability and synergy were evaluated by Cell Counting Kit-8 (CCK-8) and clonogenic assays (n = 3 independent experiments). DNA damage and apoptosis were assessed by immunofluorescence for gamma H2A histone family member X (γH2AX) foci (≥100 cells per condition) and Western blot analysis for cleaved PARP. Results: Arp2/3 inhibition with CK666 significantly impaired HR repair efficiency in the DR-GFP assay (p < 0.01). This effect was recapitulated by genetic knockdown or knockout of ACTR2/ACTR3. CK666 alone exerted minimal cytotoxicity, but synergized with both olaparib and niraparib to suppress proliferation (Combination Index <1), reducing the half-maximal inhibitory concentration (IC50) of PARPi by approximately threefold. Combination treatment markedly enhanced γH2AX foci formation (p < 0.0001) and increased the level of cleaved PARP compared with either monotherapy. Conclusions: Inhibition of Arp2/3 compromises HR repair capacity, thereby creating a synthetic lethal interaction with PARP inhibition in gastric cancer cells. This combination strategy represents a promising therapeutic approach to broaden the clinical utility of PARPi in HR-proficient tumors and may also enable dose reduction to mitigate associated toxicities.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Yaqi Pu,Tianxin Li,Zihe Zhao,Qian Xu,Yi Jin,Huan Dou,Zhao Liu
Background Abdominal aortic aneurysm (AAA) is a prevalent and potentially fatal cardiovascular disease, yet the precise therapeutic mechanism of the bioactive compound Senkyunolide I (SEI) against AAA is not fully understood. Methods Utilizing an elastase/BAPN-induced AAA mouse model, this study employed integrated network pharmacology, proteomics (LiP-MS), and biophysical validation (molecular docking, MST) to identify and confirm PARP-1 as a direct target of SEI. The therapeutic effect of SEI was evaluated in vivo by monitoring aortic dilation and histopathology, and its inhibitory effect on TNF-α-induced macrophage migration was assessed in vitro . The functional role of the SEI-PARP-1 axis was further verified using PARP-1 inhibitors and macrophage-targeted PARP-1 overexpression. Results In the elastase/BAPN-induced AAA model, which mimics human AAA progression and rupture risk, SEI treatment attenuated disease progression by reducing aortic dilation, collagen deposition, and elastin degradation. SEI directly bound to and downregulated PARP-1 expression in both AAA tissues and large peritoneal macrophages (LPMs). It dose-dependently suppressed TNF-α-induced LPMs migration in vitro and restored the AAA-induced reduction in peritoneal LPMs proportion in vivo , an effect also seen with pharmacological PARP-1 inhibition. In contrast, macrophage-specific PARP-1 overexpression abolished SEI's protection and promoted LPMs migration into aortic lesions. Conclusion This study demonstrates that SEI attenuates AAA progression by targeting PARP-1 and inhibiting the migration of LPMs from the peritoneal cavity to the aortic lesion. These findings elucidate a novel pharmacological mechanism of SEI and underscore PARP-1 as a promising therapeutic target for AAA.
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高影响因子
Theranostics
·
2026
·Vol. 16
·期 4
·1720
·
IF 13.3
Bingchun Zeng,Kai Ling,Qingpeng Yuan,Zeyang Chen,Guangrong Zhang,Wenyue Kang,Xuanjun Zheng,Chuanghong Liao,Youqing Mai,Zhongjie Huang,Ruibin Huang,Tiantian Zhai,Hongyan Jiang
Rationale: The efficacy of radiotherapy in triple-negative breast cancer (TNBC) is often limited by an immunosuppressive tumor microenvironment (TME), requiring high radiation doses that cause systemic toxicity. There is a critical need for theranostic strategies capable of guiding therapy and amplifying the efficacy of low-dose radiation. Methods: We developed a multifunctional organolutetium nanosensitizer (LSPA) for image-guided, low-dose radioimmunotherapy. Lutetium (Lu) serves as both a contrast agent for CT imaging and a radiosensitizer through the generation of reactive oxygen species (ROS). The LSPA nanoparticles were engineered to selectively accumulate in tumors and release their therapeutic payload in response to the acidic TME. Results: At a low 6 Gy X-ray dose, LSPA synergized with the PARP inhibitor Olaparib to induce extensive DNA damage. This activated the cGAS-STING pathway and remodeled the TME. The treatment promoted immunogenic cell death, dendritic cell maturation, and M1 macrophage repolarization. It also decreased regulatory T cells, leading to increased CD4 + and CD8 + T cell infiltration in both primary and metastatic tumors. Conclusion: This theranostic strategy suppressed primary and distant (abscopal) tumors, prevented recurrence, and established durable immune memory with low-dose irradiation. Our findings present a clinically translatable approach that combines a nanosensitizer with PARP inhibition to turn immunologically “cold” tumors into “hot” ones, thereby enhancing the efficacy of low-dose radioimmunotherapy while limiting systemic toxicity.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 12.6
Song Wanli,Zhao Chuanyi,Mai Youqing,Zhang Guangrong,Kang Wenyue,Zheng Xuanjun,Yuan Qingpeng,Chen Zeyang,Zhong Chengxun,Tang Junbao,Fu Duoyi,Zhai Tiantian,Ling Kai,Jiang Hongyan
Low-dose X-ray-activated radiodynamic therapy (RDT) is a promising strategy for precision oncology. However, its therapeutic efficacy is limited by tumor radioresistance and insufficient generation of reactive oxygen species (ROS). Here, we describe a biomimetic lutetium-coordinated black phosphorus nanosheet platform (BPNS@Lu 3+ /Lap-CMV) capable of initiating a tripartite synthetic lethality cascade upon low-dose irradiation. Through a single coordination strategy utilizing high atomic number (high-Z) Lu 3+ ions, the nanoplatform simultaneously stabilizes the black phosphorus scaffold, functions as an efficient X-ray antenna, and integrates a pH-responsive gate for the controlled release of β-lapachone (Lap). Additionally, surface camouflage using cancer cell membrane vesicles (CMV) enables homologous tumor targeting and reduces clearance by the reticuloendothelial system. A multi-pathway therapeutic cascade is initiated upon exposure to low-dose X-ray. First, Lu 3+ -amplified RDT generates a burst of ROS. Second, tumor-overexpressed NAD(P)H: quinone oxidoreductase 1 (NQO1) bioactivates Lap, intensifying redox stress (GSH depletion and H 2 O 2 overproduction) and promoting ferroptosis. Third, co-administration of the PARP inhibitor olaparib (Ola) functionally impairs PARP-mediated DNA repair, thereby converting RDT-induced DNA lesions into lethal damage and promoting apoptosis. Guided by its intrinsic computed tomography-mediated visibility, which revealed peak tumor accumulation at 12 h post-administration, the triple‑combination regimen achieved 85.5% tumor suppression in an orthotopic triple-negative breast cancer model without evident toxicity. This study presents a strategic framework for an intelligent nanoplatform capable of converting low-dose physical energy into biological cascades, thereby systematically disrupting parallel tumor defense mechanisms and broadening the therapeutic scope of radiotherapy. Graphical abstract
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高影响因子
iScience
·
2024
·
IF 4.6
Lele Xu,Yuting Chen,Tao Wu,Jiaqi Fan,Yuying Hu,Xuefeng Gao,Yuliang Wang,Tao Chen,Xueting Zhao,Min Zeng,Fei Wang,Qingyou Zheng,Xiaojuan Pei,Dinglan Wu
Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) represent a promising novel treatment for castration-resistant prostate cancer (CRPC) with encouraging results. However, the combination targets in CRPC remain largely unexplored. N6-methyladenosine (m 6 A) has been shown to play a crucial role in cancer progression and DNA damage response. Here, we observed a higher overall level of m 6 A and a downregulation of Fat mass and obesity-associated protein (FTO), which correlated with unfavorable clinicopathological parameters in prostate cancer (PCa). Functionally, reduced FTO promotes PCa growth, while overexpression of FTO has the opposite effect. Mechanistically, FOXO3a was identified as the downstream target of FTO in PCa. FTO downregulates the expression of FOXO3a in an m 6 A-dependent manner, leading to the degradation of its mRNA. Importantly, DNA damage can degrade FTO through the ubiquitination pathway. Finally, we found that overexpression of FTO can enhance the effect of PARPi on PCa. Therefore, our findings may provide insight into novel therapeutic approaches for CRPC.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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PubMed
高影响因子
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