ABSTRACT
Aim To investigate the radiosensitizing effect of the PARP inhibitor Olaparib on MCF-7 breast cancer model and to monitor the radiosensitizing effect of Olaparib by F-Fluoroerythronitroimidazole (F-FETNIM) PET/CT. Methods MCF-7 breast cancer model was established and divided into control group, Olaparib group, irradiation group and Olaparib + irradiation group according to random number table method; tumor volume was measured to calculate tumor inhibition rate and survival time of tumor-bearing mice was counted.
ABSTRACT
Colorectal cancer is one of the most common malignant tumors, and its morbidity and mortality increase year by year. In recent years, some patients with colorectal cancer have benefited from precision targeted therapies, but the overall prognosis is still unsatisfactory. Treatment of homologous recombination deficiency represented by BRCA1/2 has become a hot research direction at present. With the wide application and exact curative effect of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, breast cancer, pancreatic cancer and other malignant tumors, PARP inhibitors are also gradually being used in colorectal cancer. This review summarizes the current research progress of PARP inhibitors in treatment of colorectal cancer.
ABSTRACT
@#[Abstract] Objective: To explore the mechanism of TRIM21 regulating the proliferation of ovarian cancer cells and the resistance of PARP inhibitors by activating Wnt/β-catenin signaling pathway. Methods: Eight pairs of ovarian cancer tissues and cervical epithelial tissues that surgically removed at Yan'an People's Hospital from January 2018 to January 2019 were collected for this study. And the tissues were classified into resistant group and non-resistant group (4 case/group) according to whether the patients were resistant to PARP inhibitor (nilapanib). Ovarian cancer cell lines CAOV3, SKOV3, OVCAR3, ES-2, HO8910, A2780 and OV2008 were also collected for this study. qPCR and Western blotting (WB) were used to detect the expression levels of TRIM21 and β-catenin in the above mentioned tissues and cell lines. Cell lines with TRIM21 overexpression and knockdown were constructed. CCK-8 method was used to detect the proliferation activity of ovarian cancer cells in each group, TOP/FOP dual luciferase assay was used to detect the effect of TRIM21 on Wnt signaling pathway activation, qPCR and WB were used to detect the effect of TRIM21 on mRNA and protein levels of β-catenin, which was further verified by Wnt pathway inhibitor XAV-939. Results: The expression level of TRIM21 in ovarian cancer tissues was significantly higher than that in cervical epithelial tissues (P<0.01), and its expression was more higher in the drug-resistant tissues (P<0.01). TRIM21 expression was the highest in ES-2 cells but comparatively low in CAOV3 and A270 cells (all P<0.01). After TRIM21 knockdown, the expression of TRIM21 in ES-2 cells was significantly decreased, and the cell proliferation was significantly reduced (all P<0.01). After overexpressing TRIM21, the proliferative capacity of ovarian cancer CAOV3 cells was significantly increased (P<0.01), and the antitumor effect of nilaparib was inhibited; TRIM21 overexpression could regulate Wnt/β -catenin pathway activation, while β -catenin knockdown or Wnt/β -catenin inhibitor XAV-939 could significantly reverse the effect of TRIM21 in ovarian cancer. Conclusion: TRIM21 can enhance the proliferation of ovarian cancer cells via regulating Wnt/β-catenin pathway, it plays a certain role in the process of drug resistance of PARP inhibitor nilapani.
ABSTRACT
OBJECTIVE：To evaluate the safety of PARP inhibitors in hematological system ，and to provide evidence-based evidence for rational drug use in the clinic. METHODS ：Retrieved from PubMed ，Embase，Cochrane Library ，ScienceDirect， CNKI，CBM，VIP and Wanfang data from May 2014 to June 2019，randomized controlled trials （RCTs）about PARP inhibitors or PARP inhibitors combined with chemical treatment drugs （trial group ）versus chemical treatment drugs alone ，placebo alone or chemical treatment drugs combined with placebo （control group ）were collected. After literature screening ，data extraction and quality evaluation with bias risk assessment tool recommended by Cochrane systematic evaluator manual 5.1.0，and Meta-analysis was performed by using Rev Man 5.3 software，and sensitivity analysis and publication bias analysis. RESULTS ：A total of 10 RCTs were included ，involving 3 129 patients. Meta-analysis showed that the incidence of anemia ≥grade 3 [RR＝7.27，95％CI （2.74，19.27），P＜0.000 1]，neutropenia≥grade 3 [RR＝2.46，95％CI（1.43，4.24），P＝0.001]，and leukopenia ≥grade 3 in trial group [RR ＝1.71，95％CI（1.15，2.54），P＝0.008] in trial group were significantly higher than control group. There was no statistically significant difference in the incidence of thrombocytopenia ≥grade 3 between two groups [RR ＝3.54，95％CI（0.66， 19.05），P＝0.14]. Results of sub-group analysis showed that the incidence of an emia≥grade 3 and neutropenia ≥grade 3 in the patients receiving PARP inhibitors alone ，PARP inhibitors combined with chemical treatment dr ugs as well as the incidence of leukopenia≥grade 3 in the patients receiving PARP inhibitors （No.2018FH001-096） combined with chemical treatment drugs were significantly higher than those receiving placebo alone ，chemical treatment com drugs alone or chemical treatment drugs combined with placebo （P＜0.05）. Sensitivity analysis supported the above results howerer，publication bias was possibility. CONCLUSIONS ：PARP inhibitor in the treatment of cancer can cause hematological system adverse drug reaction ，mainly manifesting as anemia ，neutropenia and leukopenia. These results should be interpreted with caution.
ABSTRACT
Small cell lung cancer (SCLC), characterized by early metastasis, relapse, relapse and resistance and poor prognosis, still faces difficulties in treatment. Recently, Immunotherapy is a novel treatment for SCLC, researchers are also eager to achieve a breakthrough in targeted treatment of SCLC. Genomic instability of SCLC and sensitivity to cytotoxic chemotherapy, therefore, poly ADP-ribose polymerase (PARP) inhibitors targeting DNA repair related pathways have become a hotspot in the research of SCLC targeted therapy. Studies on PARP inhibitors in SCLC have been conducted in combination with other therapeutic strategies, including the treatment of recurrent SCLC and first-line treatment,as well as maintenance treatment after induction. These studies also explored the predictive markers of PARP inhibitors in SCLC. Although the current results of PARP inhibitors in SCLC are limited, and the predictive markers are also inconsistent, we also see that PARP inhibitors could be a breakthroughfor precision medicine of SCLC. .
ABSTRACT
Small cell lung cancer (SCLC), characterized by early metastasis, relapse, relapse and resistance and poor prognosis, still faces difficulties in treatment. Recently, Immunotherapy is a novel treatment for SCLC, researchers are also eager to achieve a breakthrough in targeted treatment of SCLC. Genomic instability of SCLC and sensitivity to cytotoxic chemotherapy, therefore, poly ADP-ribose polymerase (PARP) inhibitors targeting DNA repair related pathways have become a hotspot in the research of SCLC targeted therapy. Studies on PARP inhibitors in SCLC have been conducted in combination with other therapeutic strategies, including the treatment of recurrent SCLC and first-line treatment,as well as maintenance treatment after induction. These studies also explored the predictive markers of PARP inhibitors in SCLC. Although the current results of PARP inhibitors in SCLC are limited, and the predictive markers are also inconsistent, we also see that PARP inhibitors could be a breakthroughfor precision medicine of SCLC. .
ABSTRACT
Poly ADP-ribose polymerase (PARP) inhibitors can block the repair of DNA single-strand breaks, and BRCA mutation can cause the loss of repair function of DNA double-strand damage in breast cancer cells. Therefore, PARP inhibitors are used to treat BRCA-mutant breast cancer by simultaneously blocking the repair of DNA single-strand breaks and DNA double-strand damage, which leads to the failure of DNA repair, resulting in the death of cancer cells. At present, a variety of PARP inhibitors have been developed that primarily inhibit PARP1 and PARP2 subtypes with high sensitivity and specificity. This review summarizes the mechanism of PARP inhibitors in the treatment of breast cancer with BRCA mutation, and states the progress of several reported PARP inhibitors used alone or in combination with commonly used chemotherapeutic agents for the treatment of advanced breast cancer.
ABSTRACT
Objective The inhibitory effect of the PARP inhibitor olaparib on human acute myeloid leukemia HL-60 cells was studied. Methods The HL-60 cells in logarithmic growth phase were treated with different concentrations(1. 25,2. 5,5 and 10 μmol/L) of olaparib for different time. The CCK-8 assay was used to detect the inhibitory effect of olaparib on HL-60 cells. The apoptotic level of HL-60 cells was detected by Annexin-V/PI double staining method,and the expression of related signal proteins ( PARP-1 and caspase-3)in HL-60 cells was detected by Western blot. Results HL-60 cells were inhibited by olaparib at dif-ferent concentrations(1. 25,2. 5,5 and 10 μmol/L) for 48 h,and the inhibition rate gradually increased with the prolongation of the action time;at the same time,the apoptotic rate was increased in HL-60 cells after olaparib treatment for 48 h,showing a dose-de-pendent manner;the PARP activity was inhibited and caspase-3 was activated in HL-60 cells treated with olaparib. Conclusion The PARP inhibitor olaparib not only inhibits proliferation of HL-60 cells,but it also promotes apoptosis of HL-60 cells by inhibi-ting PARP activity and activating caspase-3.
ABSTRACT
Genomic instability is one of the most pervasive characteristics of cancer cells,and DNA damage response (DDR) pathway plays a crucial role in genomic stability.The DDR pathway is a complex signaling network,which involves cell DNA repair,apoptosis and cell cycle regulation.Deficiencies in these repair pathways can result in several different genetic disorders,including cancer.Targeted therapy based on inhibiting the DDR pathway in cancers offers a novel therapy strategy for patients with tumors lacking specific DDR functions.Many small-mole-cule compounds targeting DDR pathway are typically developed for solid cancer therapy.The poly (ADP-ribose) polymerase (PARP) inhibitor is a kind of DDR inhibitors which exploits the principle of synthetic lethality to selectively kill cancer cells.This review highlights the molecular mechanisms of PARP inhibitor action,the progress of PARP inhibitors in cancer therapy,drug resistance and the challenge of PARP inhibitor in the future.
ABSTRACT
Purpose To investigate the effect of subcellular location of tumor BRCA1 on the sensitivity to ionizing radiation (IR) and PARP inhibitor.Methods siRNA of BRCA1 were first used to inhibit endougenous BRCA1 expression in MCF7 cells.Then,plasmids of pCMV-3xFlag-WT-BRCA1,pCMV-3xFlag-NES-BRCA1 and pCMV-3xFlag-NLS-BRCA1 were transfected in MCF7 cells.Immunofluorescence staining was used to detect BRCA1 subcellular location as well as the formation of Rad51 and γ-H2AX foci.Apoptotic cells were analyzed by flow cytometry,and colony formation assay was performed to evaluate the survival of cells.Results There were 47％ cells with nuclear BRCA1,23％ cells with cytoplasmic BRCA1 and 30％ cell with mixed nuclear and cytoplasmic BRCA1 expression in WT-BRCA1 transfected cell.There were 87％ cells with nuclear BRCA1 in NES-BRCA1 transfected cell,and 82％ cells with cytoplasmic BRCA1 in NLS-BRCA1 transfected cell.There were 87％,84％ and 13％ Rad51 foci positive cells at 2 hours after 4 Gy radiation treatment and 22％,25％ and 59％ γ-H2AX foci positive cells at 24 hours after 4Gy radiation treatment in WT-BRCA1,NES-BRCA1 mutant and NLS-BRCA1 mutant transfected cell respectively.ABT-888 and radiation treatment induced more apoptosis and fewer colonies in NLS-BRCA1 transfected cell than WT-BRCA1,NES-BRCA1 mutant transfected cell.Conclusion Subcellular location of BRCA1 might affect homologous recombination repair of DNA double strand breaks and can be used to predict sensitivity to IR and PARP inhibitor.
ABSTRACT
Ten topics were chosen among major clinical research achievements in gynecologic oncology in 2012. For ovarian cancer, comprehensive review of the history of bevacizumab studies was followed by poly adenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitors and other molecular targeted agents such as epidermal growth factor receptor tyrosine kinase inhibitor and AMG 386. For the development of genomic study in gynecologic cancers, BRCA and DICER1 mutations were covered in epithelial and nonepithelial ovarian cancer, respectively. For endometrial cancer, targeted agents including mammalian target of rapamycin (mTOR) inhibitors and bevacizumab were discussed. Radiation therapy "sandwiched" between combination chemotherapy schedules for the treatment of uterine papillary serous carcinoma was also reviewed. Preoperative prediction of lymph node metastasis, definition of low-risk group, and recurrence and survival outcomes of laparoscopic approaches were addressed. For cervical cancer, we reviewed long-term benefit of human papillomavirus test and efficacy of paclitaxel/carboplatin versus paclitaxel/cisplatin in stage IVB, persistent or recurrent disease. In addition, the effect of three dimensional image-based high-dose rate brachytherapy was also reviewed. For vulvar cancer, the diagnostic value of sentinel lymph node biopsy was discussed. For breast cancer, positive results of three outstanding phase III randomized clinical trials, CLEOPATRA, EMILIA, and BOLERO-2 were introduced. Lastly, updates of major practice guidelines were summarized.
Subject(s)
Female , Humans , Achievement , Adenosine Diphosphate , Antibodies, Monoclonal, Humanized , Appointments and Schedules , Bevacizumab , Brachytherapy , Breast Neoplasms , Drug Therapy, Combination , Endometrial Neoplasms , Lymph Nodes , Neoplasm Metastasis , Nitriles , Ovarian Neoplasms , Protein-Tyrosine Kinases , Pyrethrins , ErbB Receptors , Recombinant Fusion Proteins , Recurrence , Sentinel Lymph Node Biopsy , Sirolimus , Uterine Cervical Neoplasms , Vulvar NeoplasmsABSTRACT
BACKGROUND: The pathological hallmark of Parkinson's disease (PD) is dopaminergic cell death in the substantia nigra (SN), but the cause of cell death is unknown. 6-Hydroxydopamine (6-OHDA) is one of the neurotoxins used in experimental models of PD, and its use has led to greater understanding of the pathogenesis of PD. The present study examined the role of poly(ADP-ribose) polymerase (PARP) in 6-OHDA toxicity. METHODS: An in-vitro study was performed using PC12 cells. After treatment with 6-OHDA, the poly(ADP-ribosyl) ation was monitored using a monoclonal antibody to poly(ADP-ribose) (PAR) to examine the PARP activity. To evaluate the effect of the PARP inhibition in 6-OHDA-induced cell death, 3-aminobenzamide or nicotinamide was administered 30 minutes before 6-OHDA treatment. An in-vivo study was performed using a Parkinson rat model. 6-OHDA was stereotactically injected into the unilateral SN of rats. PAR immunolabeling was used to examine the time-dependent activation of PARP. The dopaminergic cell death in the SN was quantified using apomorphine-induced rotations and tyrosine hydroxylase- immunoreactive cell numbers in the SN 2 weeks after lesioning. RESULTS: Poly(ADP-ribosyl)ation of nuclear proteins was maximal at 6 hr, and was still present 24 hr after 6-OHDA treatment. Pretreatment of 3-aminobenzamide or nicotinamide significantly attenuated the 6-OHDA-induced PC12 cell death. In 6-OHDA injected rats, PAR formation was seen 6 hr after 6-OHDA injection, peaked at 12 hr, and was still detectable at 24 hr. The dopaminergic cell death in the SN was significantly decreased by intraperitoneal injection of nicotinamide in 6-OHDA injected rats. CONCLUSIONS: These results provide evidence suggesting an involvement of the PARP in 6-OHDA-induced dopaminergic cell death, and inhibitors of PARP may have a protective benefit in PD.
Subject(s)
Animals , Rats , Cell Count , Cell Death , Dopaminergic Neurons , Injections, Intraperitoneal , Models, Animal , Models, Theoretical , Neurotoxins , Niacinamide , Nuclear Proteins , Oxidopamine , Parkinson Disease , PC12 Cells , Poly Adenosine Diphosphate Ribose , Poly(ADP-ribose) Polymerases , Substantia Nigra , TyrosineABSTRACT
BACKGROUND: Nuclear enzyme poly (ADP-ribose) polymerase (PARP) activated by DNA damage participates in DNA repair. However, overactivation of PARP could be an important pathogenic mechanism of ischemic cell death. We investigated the protective effect of an inhibitor of PARP, 3-aminobenzamide (3-AB), against ischemia/reperfusion injury in ischemic stroke model. METHODS: Occlusion of left middle cerebral artery (MCA) was done by intraluminal filament technique in 24 rats weighing from 315 g to 358 g, and reperfusion was done at 2 hours after occlusion. To evaluate the effect of PARP inhibitor in ischemic stroke, 3-AB was administered to 12 rats (3-AB group) 10 minutes before artificial occlusion of left MCA. Infarct area was confirmed by using 2, 3, 5-triphenyltetrazolium chloride stain. The immunoreactivities of poly (ADP-ribose) reflecting activity of enzyme PARP and activated caspase-3 were compared in infarct, peri-infarct and normal zones in 3-AB group and 12 controls. RESULTS: The volume of infarction was decreased about 34% in 3-AB group compared with controls. In 3-AB group, immunoreactivities of PAR were significantly reduced in ischemic regions, especially peri-infarct zone, but those of activated caspase-3 were significantly increased in same region. CONCLUSIONS: These results suggest that treatment of PARP inhibitor can reduce the infarct volume by converting necrotic cell death into apoptosis. PARP inhibition can be another potential neuroprotective strategy in ischemic stroke.