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OBJECTIVE To systematically evaluate the efficacy and safety of olaparib in adjuvant therapy of breast cancer susceptibility gene （BRCA） 1/2 mutated human epidermal growth factor receptor 2 （HER2）-negative breast cancer， and to provide evidence-based reference for clinical treatment. METHODS Retrieved from CNKI， VIP， Wanfang data， PubMed， ScienceDirect， the Cochrane Library and Embase databases， randomized controlled trials about adjuvant therapy of olaparib （trial group） versus adjuvant therapy of other drugs （control group） were collected. After literature screening and data extraction， meta-analysis， publication bias analysis and sensitivity analysis were performed by using RevMan5.4 software. RESULTS A total of 5 randomized controlled trials were included， with a total of 2 633 patients， including 1 495 cases in trial group and 1 174 cases in control group. Meta-analysis showed that in terms of efficacy， compared with control group， overall survival [HR＝1.02， 95%CI （1.01，1.03）， P＝0.000 8] and progression-free survival [HR＝1.78， 95%CI（1.46，2.17）， P＜0.000 01] were longer significantly in the trial group. In terms of safety， compared with the control group， the incidence of adverse drug reactions at any level in the trial group was higher [RR＝1.41， 95%CI （1.12， 1.78）， P＝0.004]， while there was no statistically significant difference in the incidence of adverse drug reactions above level 3 between the two groups [RR＝1.75， 95%CI （0.82， 3.74）， P＝0.15]. The results of publication bias indicated that the possibility of publication bias in this study was relatively low. The results of sensitivity analysis showed that the results obtained in this study were robust. CONCLUSIONS Compared with patients without adjuvant therapy of olaparib， adjuvant therapy of olaparib can prolong overall survival and progression-free survival of patients with BRCA1/2 mutated HER2-negative breast cancer，but the risk of adverse drug reactions is relatively high.
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Human epidermal growth factor receptor 2 (HER2)?negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)?positive and HR?negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR?positive HER2?negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin?dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP?ribose) polymerase inhibitors (PARPi) have emerged for HER2?negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA?mutated (gBRCAm) HER2?negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2?negative breast cancer.
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Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP?ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA?associated cancers, especially high?grade OC and breast cancers. They lead to synthetic lethality in BRCA?mutated cells by stalling the replication forks in homologous recombination?deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA?associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance
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Solid dispersion, a dispersion system in which drug molecules are highly dispersed in carrier materials, has been commonly used to improve the solubility and dissolution rate of poorly soluble drugs. The miscibility between drug and carrier is crucial to improve the dissolution performance and stability of solid dispersion. Therefore, the selection of carrier types and the optimization of drug loading are very important. In the current study, the solubility parameter method and Flory-Huggins theory were used to predict the miscibility between olaparib (OLP) and different carriers (VA64, Soluplus, Plasdone S630 and Kollidon K29/32). Besides, the carrier material with good miscibility was experimentally screened by differential scanning calorimetry (DSC). The optimum of drug-carrier ratio was further performed based on the miscibility phase diagram of drug and carrier. Theoretical calculation and experimental evaluation showed that the miscibility of OLP and VA64 was the best, and the drug loading of 30% could meet the requirements of large drug loading and physical stability. Polarizing light microscope, X-ray powder diffraction, DSC and laser confocal Raman spectroscopy exhibited that OLP was amorphous form in the solid dispersion system. Powder dissolution test demonstrated that the solid dispersion showed significantly enhanced dissolution rate in comparison to crystalline OLP. In this study, theoretical calculation and experimental evaluation were used to screen the types of carriers and optimize the drug loading, which provides an efficient strategy for the selection of carrier and the amount used in solid dispersion.
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Metastatic castrate-resistant prostate cancer (mCRPC) is the last stage of prostate cancer. Although new hormonal agents and taxane-based chemotherapies occurred for mCRPC treatment, the overall survival of mCRPC patients is limited. Olaparib is an inhibitor of poly ADP-ribose polymerase (PARP), which has a key role in DNA damage response. It has been approved for ovarian cancer and breast cancer treatment. PROfound, a phase III clinical trial of olaparib in mCRPC treatment, has been reported in 2019 ESMO and 2020 ASCO-GU. In this paper, we will bring the results and updates of PROfound.
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OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) is an important molecule in the early stress response of DNA damage, which is involved in DNA damage repair and cellular senescence. Olaparib, as PARP inhibitor, has an anti-tumor effect on high grade serous ovarian cancer, but its effects on cellular senescence have not been reported. This study intends to explore the role of olaparib in the regulation of senescence in ovarian cancer cells. METHODS: The effects of olaparib on the senescence of ovarian cancer cells were detected by using the senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated heterochromatin aggregation (SAHF). Quantitative real-time polymerase chain reaction was used to analyze the senescence-associated secretory phenotype (SASP). Cell cycle and apoptosis were detected by flow cytometry. The effect of olaparib on tumor growth was analyzed in a nude mouse xenograft transplantation model. RESULTS: Long-term (6 days) treatment with olaparib (5 μM) significantly inhibited the growth of ovarian cancer cells, leading to arrest the cell cycle at G0/G1 phase, significant increase the number of positive SA-β-Gal stained cells and positive SAHF cells. The expression of P16 and retinoblastoma protein (p-RB) were significantly enhanced in SKOV3 cells under olaparib treated, meanwhile, the expression of P53 and p-RB were upregulated in A2780 cells. In OVCAR-3 cells, the expression of P53 was downregulated and p-RB was upregulated. Mice with SKOV3 xenograft transplantation was given olaparib (10 mg/kg/day) via abdominal cavity administration, the tumor volume was reduced (p < 0.01). CONCLUSION: Continuous low dosage administration of olaparib induced senescence under P16 or P53 dependent manner in ovarian cancer.
Subject(s)
Animals , Mice , Abdominal Cavity , Aging , Apoptosis , Cellular Senescence , Cell Cycle , DNA Damage , Flow Cytometry , Heterochromatin , Mice, Nude , Ovarian Neoplasms , Phenotype , Real-Time Polymerase Chain Reaction , Retinoblastoma Protein , Transplantation, Heterologous , Tumor BurdenABSTRACT
OBJECTIVE: To analyze the involvement of PI3K/AKT/mTOR signaling pathway on the inhibiting the proliferation of ovarian cancer SKOV3 cell line by olaparib. METHODS: The SKOV3 cells were randomly divided into five groups: control group, olaparib low dose group (10 mg•L-1), olaparib medium dose group (30 mg•L-1), olaparib high dose group (90 mg•L-1), and PI3K protein inhibitor LY294002 group (10 mg•L-1). In addition to the control group, the rest of the cells were incubated with the corresponding doses of the compounds. DAPI and Western blotting were used to analyze the expression of apoptotic protein. qPCR, Western blotting and immunocytochemistry were adopted to detect the expression of PI3K/AKT/mTOR signaling pathway related proteins. RESULTS: After olaparib treatment, the proliferation of ovarian cancer SKOV3 cells was significantly inhibited (P<0.05). Apoptotic bodies in SKOV3 cells increased gradually, and the expression of caspase 3 and caspase 9 increased gradually (P<0.05), PI3K, AKT and mTOR expression gradually decreased (P<0.05) after olaparib medication. With the increase of olaparib level, the above effects were more obvious (P<0.05). CONCLUSION: Olaparib has an inhibitory effect on ovarian cancer SKOV3 cells, and it may play a role by inhibiting the PI3K/AKT/mTOR signaling pathway.
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OBJECTIVE To investigate the protective effect of olaparib on the inflammatory damage to alveolar epithelial cells induced by lipopolysaccharide (LPS). METHODS The alveolar epithelial cells (A549) were cultured in vitro and incubated with LPS 10 mg-L-1 and olaparib 10 and 25 μmol-L-1 for 24 h. The levels of cytokines interleukin 6 (IL-6), IL-8, and IL-10 were detected by enzyme linked immunosorbent assay (ELISA), the mRNA expression levels of TNF-α, IL-1β, IL-6, IL-8, and ICAM-1 were analyzed by real-time PCR, the level of ROS was analyzed by flow cytometry, and the expression of poly (ADP-ribose) polymerase-1 (PARP-1) and phosphorylation of proteins involved in NF-ΚB signaling pathway in cells were detected by Western blotting. RESULTS Compared with LPS 10 mg-L-1 injury group, olaparib 10 and 25 μmol·L-1 could significantly reduce the release of IL-6, IL-8 and ROS levels in A549 cells induced by LPS (P<0.01), and increase the release of IL-10 (P<0.01). Olaparib 10 and 25 μmol·L-1 could also inhibit the mRNA expressions of TNF-α, IL-1β, IL-6, IL-8, and ICAM-1 (P<0.01), and inhibit the expression of PARP-1 and phosphorylation proteins involved in NF-ΚB signaling pathway induced by LPS (P<0.01). CONCLUSION Olaparib has some protective effect on inflammatory damage and oxidative stress in alveolar epithelial cells induced by LPS, and the mechanism may be that it inhibits the expression and release of cytokines by down-regulating the expression of PARP-1 and subsequently affecting the activation of the NF-ΚB pathway.
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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.
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Objective To investigate the effects of Olaparib on cell proliferation and radiosensitization of human non-small cell lung cancer cells.Methods Non-small cell lung H460 and H1299 cell lines were cultured in vitro and the cells in logarithmic growth phase were selected for experiments.MTT and colony formation assays were used to determine cell proliferation and radiosensitization,respectively.Single cell gel electrophoresis assay (comet assay) was used to detect irradiation-induced DNA damage.Results The results of MTT assay showed that Olaparib inhibited the proliferation of H460 and H1299 cells in a dose-dependent pattern (all P＜0.05).H1299 cell line was more sensitive to Olaparib than H460 cells.The results of colony formation assay showed that Olaparib enhanced the radiosensitizition of H460 and H1299 cells (all P＜0.05).The results of comet assay showed that Olaparib increased γ ray-induced DNA damage.Conclusions Olapani can enhance the radiosensitization of human non-small cell lung cancer cells,and the radiosensitization effect of Olaparib may be associated with the inhibition of cell proliferation and induction of irradiation-induced DNA damage.
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Ovarian cancer is one of the highest mortality rate of gynecologic malignant tumors. Chemotherapy can improve the survival rate of the traditional ovary. In recent years, PARP [poly(ADP-ribose)polymerase]inhibitors in breast cancer susceptibility gene (breast cancer susceptibility gene, BRCA) mutations in patients with ovarian cancer can significantly improve the disease-free survival, may change the prognosis of patients with ovarian cancer. This part of PARP [poly(ADP-ribose)polymerase] inhibitors, inhibiting the repairment of DNA damage in tumor cell, causing DNA damage accumulation, eventually killing tumor cells.In breast cancer susceptibility gene 1 (breast cancer susceptibility gene1, BRCA1)/BRCA2 mutation patients with ovarian cancer, PARP inhibitors and BRCA mutation of the synthetic lethal effect provides a new direction for the development of anti-cancer drugs. Now, many highly selective and sensitive PARP inhibitors have been developed and applied in clinical trials.Although PARP inhibitor monotherapy can produce a therapeutic effect in BRCA mutation in patients with ovarian cancer, but the clinical application is still used in combination with other chemotherapy or radiotherapy. This review is focused on the recent progress in clinical trials of PARP inhibitors in combination with common chemotherapeutic agents.
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Poly (ADP-ribose) polymerase 1/2(PARP1/2) can catalyze the poly (ADP ribose) (PAR) substrate protein modification and play an important role in the regulation of DNA damage repair, cell death and transcriptional activity. The PARP inhibitor olaparib (AZD2281) can be used as a sensitizer of radiotherapy and chemotherapy in the cancer treatment. Through establishment of biological fluorescent labeled 4T1 ectopic breast tumor model, we found that olaparib exhibited a poor effect on 4T1 breast cancer alone. However, in the combination with Taxol, olaparib significantly increased the anti-tumor effect of Taxol, and reduced the PAR levels of the tumor tissues. Importantly, olaparib did not amplify the toxicity of chemotherapy drugs. This study suggests that olaparib is a representative of the PARP inhibitor that can enhance Taxol 's antitumor effect in the 4T1 ectopic breast tumor model, which sets the foundation for future study of the mechanism of olaparib action.
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Objective To investigate the radiobiological effects of radiation with different dose rates on human nasopharyngeal carcinoma cell line CNE-2 treated with or without a poly ADP-ribose polymerase (PARP) inhibitor,olaparib.Methods The concentration of olaparib used to treat cells equaled to the inhibition concentration IC10 of olaparib to CNE-2 cells.The CNE-2 cells were divided into acute radiotherapy (RT) group,fractionated radiotherapy (FRT) group,olaparib + RT group,and olaparib + FRT group.All groups were exposed to radiation of 0,1,2,3,5,7,and 10 Gy at a dose rate of 3 Gy/min.The delivery time for each dose point was 4 min in RT and 30 min in FRT.The colony forming assay was used to evaluate the survival of CNE-2 cells at each dose point.The multi-target,single-hit model was used to fit the cell survival curves and the parameters,D0,Dq,and SF2,were calculated.At dose points of 0.1,and 2 Gy,western blot was used to determine the expression of PARP-1 in the RT group and the FRT group and γH2AX in each group.Immunofluorescence was used to evaluate the γH2AX focus formation.A single factor analysis of variance was used to compare the 4 groups,and two two compared with SNK-q test.Results The IC10 value of olaparib to CNE-2 cells was 4.0 μmoL/L.At dose points of 1 and 2 Gy,the PARP-1 expression was significantly higher in the FRT group than in the RT group (P=0.029,0.022),while the γH2AX focus number was significantly smaller in the FRT group than in the other three groups (all P＜0.05);compared with the RT group,the D0,Dq,and SF2 values in the FRT group were increased by 11.67％,15.78％,and 23.61％,respectively;compared with the FRT group,the D0,Dq,and SF2 values in the Olaparib+ FRT group decreased by 11.19％,6.44％,and 13.26％,respectively;there were no significant differences in above indices between the RT group,the Olaparib+RT group,and the Olaparib+FRT group.Conclusions For the same radiation dose,fractionation reduces the relative dose rate and weakens the radiobiological effects.lowdose olaparib can compromise the single strand break repair induced by the decline of the relative dose rate in a fractionated irradiation mode,which promotes the formation of double-strand break and improves the radiobiological effects.
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Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes ,and was developed by AstraZen-eca Pharmaceuticals LP .Olaparib has therapeutic potential for treating cancers associated with impaired DNA repair capabili-ties ,particularly those with deficiencies in the homologous recombination repair (HRR) pathway .Olaparib is an available ther-apy option for ovarian cancer patients with deficiencies in the BRCA 1 and BRCA2 genes .Olaparib can selectively kill cancer cells without compromising normal cells .Compared to traditional chemotherapy means ,adverse reactions are much smaller .
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PURPOSE: Trabectedin induces synthetic lethality in tumor cells carrying defects in homologous recombinant DNA repair. We evaluated the effect of concomitant inhibition of nucleotide-excision repair and poly (ADP-ribose) polymerase (PARP) activity with trabectedin and PARP inhibitors, respectively, and whether the synthetic lethality effect had the potential for a synergistic effect in breast cancer cell lines. Additionally, we investigated if this approach remained effective in BRCA1-positive breast tumor cells. METHODS: We have evaluated the in vitro synergistic effect of combinations of trabectedin and three different PARP inhibitors (veliparib, olaparib, and iniparib) in four breast cancer cell lines, each presenting a different BRCA1 genetic background. Antiproliferative activity, DNA damage, cell cycle perturbations and poly(ADP-ribosyl)ation were assessed by MTT assay, comet assay, flow cytometry and western blot, respectively. RESULTS: The combination of trabectedin and olaparib was synergistic in all the breast cancer cell lines tested. Our data indicated that the synergy persisted regardless of the BRCA1 status of the tumor cells. Combination treatment was associated with a strong accumulation of double-stranded DNA breaks, G2/M arrest, and apoptotic cell death. Synergistic effects were not observed when trabectedin was combined with veliparib or iniparib. CONCLUSION: Collectively, our results indicate that the combination of trabectedin and olaparib induces an artificial synthetic lethality effect that can be used to kill breast cancer cells, independent of BRCA1 status.