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Objective:To evaluate the effect of niraparib, the poly (ADP-ribose) polymerase (PARP) inhibitor, on the radiosensitivity of esophageal squamous cell carcinoma (ESCC) and to preliminarily investigate its mechanism.Methods:Human esophageal squamous cell carcinoma cells ECA-109 and KYSE-150 were divided into the control, niraparib, single irradiation, combined (niraparib+irradiation) groups. Cell proliferation was measured by CCK-8 assay. The changes of cell survival rate were detected by colony formation assay. The changes of cell cycle and apoptosis were analyzed by flow cytometry. The number of γH2AX foci was detected by immunofluorescence, and the expression levels of PARP-1, cleaved-PARP, RAD51, mitogen-activated protein kinase (MAPK) [extracellular signal-regulated kinase 1 and 2 (ERK1/2) ] and p-MAPK (ERK1/2) proteins were determined by Western blot. All data were expressed as Mean±SD. Data between two groups conforming to normal distribution through the normality test were subject to independent sample t-test and multiple groups were analyzed using one-way ANOVA. Results:In human ESCC cells ECA-109 and KYSE-150, the proliferation of ESCC cells was significantly inhibited by niraparib combined with irradiation, and the values of average lethal dose (D 0), quasi-threshould dose(D q), survival fraction after 2 Gy irradiation (SF 2) in the combined group were decreased compared with those in the single irradiation group. The effect of irradiation alone on apoptosis of ECA-109 and KYSE-150 cells was limited. Compared to single irradiation group, irradiation combined with niraparib further increased the apoptosis rate in ESCC cells ( P=0.015, P=0.006). In ECA-109 cells, G 2/M phase arrest was significantly increased in combined group compared with irradiation alone group ( P<0.001). In ECA-109 cells, the number of γH2AX foci in combined group was higher than that in the single irradiation group after 2 h, and showed a significantly slower decay of γH2AX foci ( P<0.001). Moreover, niraparib combined with irradiation enhanced the radiation-induced cleavage of PARP-1 and down-regulated the expression of Rad51 and p-MAPK(ERK1/2). Conclusion:Niraparib can increase the radiosensitivity of esophageal cancer cells by inhibiting cell proliferation, promoting cell apoptosis, inhibiting the repair of DNA damage and regulating the MARK-ERK signaling pathway.
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PARP inhibitors are a new class of drugs that target cancer cells with defective DNA repair. Early trials have shown that PARP inhibitors have achieved satisfactory results, but the mechanism of resistance after drug treatment has not been fully revealed. Therefore, it is necessary to find more targeted drugs in combination with PARP inhibitors to kill tumor cells. In this paper, several potential drugs that can synergistically kill ovarian cancer cells with PARP inhibitors were identified based on the combined drug screening of 379 small molecule compound libraries and PARP inhibitor Niraparib through cell proliferation experiments, colony-formation survival experiments and immunofluorescence staining experiments. The results showed that there are eight small molecule compounds with good combination effects, including two small molecule inhibitors STF-118804 and Disulfiram that have been reported to have combined effects with PARP inhibitors. We selected GW441756, an inhibitor of tropomyosin receptor kinase A (TrKA), to verify a variety of tumor cells and explore the preliminary mechanism. The combined therapeutic effects of the Niraparib and the TrKA inhibitor increased the sensitivity of tumor cells to PARP inhibitors (P < 0. 05). Mechanistically, the number of γH2AX foci in the combined treatment group was significantly increased (P<0. 05), indicating that the TrKA inhibitor hindered the DNA damage repair ability. Moreover, combination therapy significantly reduced the formation of RAD51 foci (P<0. 05), a marker of homologous recombination repair (HRR), suggesting that TrKA inhibitors may inhibit DNA damage repair by inhibiting HRR efficiency. Overall, these results suggest that TrKA inhibitor can be used as a potential drug to kill ovarian cancer cells in combination with PARP inhibitors.
ABSTRACT
Poly ADP⁃ribose polymerase 1 (PARP1) is an important modification enzyme in cells. Its most well⁃known function is to recruit multiple DNA damage repair effector proteins through its own PARylation, such as XRCC1, to participate in DNA single and double strand damage repair. In addition, PARP1 can also provide favorable conditions for DNA damage repair and maintain genomic stability by promoting replication fork stall and nucleosome depolymerization. In recent years, in addition to the function of DNA damage repair, PARP1 has also been found to play an important role in cell apoptosis, autophagy and inflammatory pathways, which is closely related to the occurrence and development of neurodegenerative diseases. PARP inhibitor (PARPi) is an antitumor drug that targets PARP1 and works together with a homologous recombination (HR) deficient phenotype to produce a synthetic lethality. The drug can trap PARP1 and inhibit its activity. On the one hand, it directly interferes with the DNA damage repair pathway that PARP1 participates in; and on the other hand, it also inhibits the selection of PARP1⁃mediated DNA damage repair pathway and replication fork stall, making the cell genome instable. However, tumor cells are often found to be insensitive to PARPi in clinical treatment. Drug resistance of tumor cells to PARPi is highly correlated with mutations of their own genes, which respectively act on cell HR repair pathway, PARP1 circulation pathway, replication fork stability and active drug efflux, etc. Identifying specific mutation sites in drug⁃resistant tumor cells will provide help for clinical treatment. The purpose of this review is to give a description about the functions of PARP1, and focus on the mechanism of action of PARPi, the mutated genes related to drug resistance and their drug resistance mechanism, therefore to deepen the understanding of PARP1 mediated DNA damage repair pathway in cells, and provide new ideas for future clinical treatment.
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Prostate cancer is one of the most common malignancies in older men. Prostate cancer patients with distant metastasis often have a poor prognosis, and more than half of Chinese prostate cancer patients have developed distant metastasis at the time of initial diagnosis. In recent years, with the disclosure of the results of a number of global multi-center clinical trials, combination therapy and precision therapy have become two major themes in the treatment of metastatic prostate cancer (mPCa). The American Society of Clinical Oncology Genitourinary (ASCO-GU) Cancers Symposium is a grand meeting of the urologic oncology community. Several research advances reported at the meeting will help to update the treatment strategy of mPCa. This article interprets and comments on a number of milestone studies on mPCa treatment at the ASCO-GU 2022 annual meeting, with a view to providing help for the clinical treatment decisions of mPCa patients.
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DNA damage repair (DDR) defects occurred in 8%-16% of metastatic castration resistant prostate cancer (mCRPC). DDR gene mutation was related to poorer prognosis. Patients with DDR gene mutation, especially BRCA1/2 mutation, showed high sensitivity to poly ADP-ribose polymerase inhibitor (PARPi) and platinum.
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Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break (DSB) signaling. P53-binding protein 1 (53BP1) plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining (NHEJ)-mediated DSB repair pathway that rejoins DSB ends. New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination (HR) signaling. This review focuses on the up- and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair, which in turn promotes the sensitivity of poly(ADP-ribose) polymerase inhibitor (PARPi) in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.
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Applying poly(ADP-ribose) polymerase inhibitors (PARPi) to the treatment of cancers with homologous recombination deficiency (HRDness) has been a great advance in the field of molecular therapeutics. However, in the clinic patients lacking the specific mutations or developing reverse mutations in the process of PARPi treatment may not benefit from PARPi monotherapy. Therefore, targeting homologous recombination (HR) repair with molecularly targeted agents is becoming an attractive research focus and is raising the concept of "chemical HRDness". HR repair is an evolutionarily conserved and extensively regulated process that employs sister chromatids as the template to repair DNA double-strand breaks with high fidelity. In addition to directly targeting HR components, modulation of regulatory pathways controlling HR repair is effective in achieving the "HRDness" phenotype; this includes modulation of the cell cycle checkpoint regulatory pathway, the phosphatidylinositol 3-kinase (PI3K) signaling pathway, the chromatin remodeling pathway, etc. Targeting HR repair can not only result in "synthetic lethality" when combined with PARPi, but also sensitizes cancers to traditional radio/chemotherapy and novel immunotherapy. In this review we describe the HR repair pathway and its regulatory pathways, summarize the preclinical and clinical outcomes of targeting HR repair, discuss the remaining problems in this field and provide a prospective on its application in tumor therapy.
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Objective To investigate the protective effects of poly-ADP-ribose polymerase inhibitor 3-aminobenzamide (3-AB) on lung injury in rats with severe acute pancreatitis (SAP) and to explore the mechanisms.Methods Thirty-six Wistar rats were randomly (random number) divided into three groups (n =12 for each group),namely sham operation (SO) group,SAP group and 3-AB-treated group.The model of SAP-associated lung injury was established by retrograde injection of 5％ sodium taurocholate (STC) into the biliopancreatic duct.In the treated group,3-AB in dose of 10 mg/kg was administered twice by intravenous injection 30 min before and 30 min after STC infusion.The survival rats were sacrificed 12hours after SAP modeling,and the serum amylase,lung wet/dry ratio and myeloperoxidase (MPO) activity were determined,and pathological scores of pancreas and lung tissue were evaluated under light microscope.Expressions of interleukin (IL) -1 β and IL-6 mRNA,tumor necrosis factor α (TNF-α) and inter-cellular adhesion molecule-1 (ICAM-1) protein were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot,respectively. Results The serum amylase level,lung wet/dry ratio and MPO activity,IL-1β and IL-6 mRNA expressions,TNF-α and ICAM-1 protein levels were dramatically increased in SAP group ( P ＜ 0.05 ).Treatment with 3-AB significantly reduced these biomarkers in 3-AB group than in SAP group (P ＜ 0.05 ).Conclusions Poly-ADP-ribose polymerase inhibitor 3-AB exerts the protective and therapeutic effects on lung injury associated with severe acute pancreatitis through inhibiting intrapulmonary MPO activity and down-regulating the expressions of IL-1 β and IL-6 mRNA as well as the levels of TNF-α,and ICAM-1.