scholarly journals PARP Inhibitor Olaparib Enhances the Efficacy of Radiotherapy on Xrcc2-deficient Colorectal Cancer Cells

2021 ◽  
Author(s):  
changjiang Qin ◽  
Zhi-Yu Ji ◽  
Er-Tao Zhai ◽  
Kai-Wu Xu ◽  
Quan-Ying Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Clonogenic Survival ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Abstract Background: Loss of XRCC2 compromises DNA damage repairs, and induced DNA damage burdens may increase the reliance on PARP-dependent DNA repairs of cancer cells to render cell susceptibility to PARP inhibitor therapy. Here, we study if XRCC2 loss sensitizes colorectal cancer(CRC) to PARP inhibitor in combination with radiotherapy (RT).Methods: The relationships between the expression of XRCC2 and PARP with patient outcome were investigated in 167 patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy (neoCRT). The in vitro radiosensitizing effects of olaparib were tested in XRCC2-deficient CRC using a clonogenic survival assay, determination of γH2AX foci, and measurement of β-galactosidase activity. An in vivo mouse xenograft model was used to determine the effect of olaparib on sensitization of tumors to ionizing radiation (IR).Results: High levels of XRCC2 or PARP1 were significantly associated with poor overall survival (OS) in patients with LARC who received neoCRT, co-expression analyses found low PARP1 and low XRCC2 expression have better OS. Our in vitro experiments indicated that olaparib+IR reduced clonogenic survival, increased persistent DNA damage, and prolonged cell cycle arrest and senescence in XRCC2-deficient cells relative to wild-type cells. Furthermore, our mouse xenograft experiments indicated that RT+olaparib had greater anti-tumor effects and led to long-term remission in mice with XRCC2-deficient tumors.Conclusions: XRCC2-deficient CRC acquire high sensitivity to PARP inhibition after IR treatment. Our preclinical findings provide a rationale for the use of Olaparib as a radiosensitizer for treatment of XRCC2-deficient CRC.

scholarly journals Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zizhen Si ◽  
Lei Yu ◽  
Haoyu Jing ◽  
Lun Wu ◽  
Xidi Wang
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Cancer Proliferation ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Abstract Background Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. Methods ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. Results We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. Conclusion In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.

scholarly journals Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 386 ◽  
Author(s):  
Hiroshi Sugano ◽  
Yoshihiro Shirai ◽  
Takashi Horiuchi ◽  
Nobuhiro Saito ◽  
Yohta Shimada ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Cytotoxic Agents ◽  
Migration And Invasion ◽  
Nafamostat Mesilate ◽  
Tumor Invasiveness ◽  
Radiation Induced ◽  
Induced Apoptosis

Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC.

In Vitro and In Vivo Enhancement of Chemoradiation Using the Oral PARP Inhibitor ABT-888 in Colorectal Cancer Cells

2013 ◽  
Vol 86 (3) ◽  
pp. 469-476 ◽  
Author(s):  
Joseph W. Shelton ◽  
Timothy V. Waxweiler ◽  
Jerome Landry ◽  
Huiying Gao ◽  
Yanbo Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Colorectal Cancer Cells

scholarly journals Senescent peritoneal mesothelium induces a pro-angiogenic phenotype in ovarian cancer cells in vitro and in a mouse xenograft model in vivo

2015 ◽  
Vol 33 (1) ◽  
pp. 15-27 ◽  
Author(s):  
Justyna Mikuła-Pietrasik ◽  
Patrycja Sosińska ◽  
Eryk Naumowicz ◽  
Konstantin Maksin ◽  
Hanna Piotrowska ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Ovarian Cancer Cells ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model ◽  
Peritoneal Mesothelium

scholarly journals Cytotoxic, genotoxic and apoptotic effects of Viburnum opulus on colon cancer cells: an in vitro study

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Kubra Bozali ◽  
Eray Metin Guler ◽  
Ahmet Sadik Gulgec ◽  
Abdurrahim Kocyigit
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Methanolic Extract ◽  
Cancer Cell Line ◽  
Dependent Manner ◽  
Apoptotic Effects

AbstractObjectiveIntake of various fruits is quite significant for maintaining the human body, due to their supply of useful constituents. V. opulus has been found to have outstanding antioxidant activity while showing a pro-oxidant effect at high doses. Due to this feature, V. opulus would be anticipated to have a healing impact on cancer treatment. In this study, it has been proposed to examine the cytotoxic, genotoxic, and apoptotic effects of V. opulus on human colorectal cancer cell.MethodDifferent concentrations of V. opulus methanolic extract (5–2000 μg/mL) were incubated for 24 h with colorectal cancer cell line (Lovo). The cell viability, intracellular reactive oxygen species (iROS), DNA damage, and apoptosis were measured after incubation.ResultsThe obtained results of this research demonstrate decreased cell viability and increased DNA damage, iROS, and apoptosis levels of V. opulus in Lovo cells in a concentration-dependent manner in the range of 14.88–52.06%. There were strong positive relationships between apoptosis, genotoxicity, and cytotoxicity in V. opulus methanolic extract treated cancer cell line.DiscussionThis in vitro research clearly demonstrated that V. opulus methanolic extract induces DNA damage, apoptosis, and cytotoxicity in a dose-dependent manner in cancer cells due to its pro-oxidant activity.ConclusionAlthough in vitro results are favorable, in vivo and further studies are needed.

scholarly journals Anti-Tumor Effects of Wee1 Kinase Inhibitor with Radiotherapy in Human Cervical Cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yoo-Young Lee ◽  
Young-Jae Cho ◽  
Sung-won Shin ◽  
Changhoon Choi ◽  
Ji-Yoon Ryu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Chemotherapeutic Agent ◽  
Locally Advanced ◽  
Clonogenic Survival ◽  
Recurrent Cervical Cancer ◽  
Cervical Cancer Cells ◽  
Human Cervical Cancer

Abstract Although the concurrent use of a chemotherapeutic agent and radiotherapy improves survival in patients with locally advanced or recurrent cervical cancer, severe side effects related to chemotherapy are frequent and may result in a low quality of life for the patients. In this study, we investigated the effects of a combination of Wee1 inhibitor (AZD1775) and irradiation in cervical cancer. In vitro effects of AZD1775 with irradiation in human cervical cancer cells were assessed by clonogenic survival and apoptosis assays. The effects on DNA damage response signaling and the cell cycle were also explored. Tumor growth delay was evaluated to investigate the in vivo effects of AZD1775 with irradiation in cervical cancer mouse models, including xenografts and patient-derived xenografts (PDXs). The co-treatment of AZD1775 and irradiation significantly decreased clonogenic survival and increased apoptosis in cervical cancer cells. These effects were associated with G2 checkpoint abrogation which resulted in persistent DNA damage. Both in the xenografts and the PDXs, the co-treatment significantly decreased tumor growth compared tothe irradiation alone (p < 0.05). These results demonstrate that the Wee1 inhibitor (AZD1775) can be considered as a potential alternative as a radiosensitizer in cervical cancer instead of a chemotherapeutic agent such as cisplatin.

scholarly journals Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models

2021 ◽  
Vol 22 (18) ◽  
pp. 9766
Author(s):  
Chin-Chuan Chen ◽  
Chi-Yuan Chen ◽  
Shu-Fang Cheng ◽  
Tzong-Ming Shieh ◽  
Yann-Lii Leu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Mouse Xenograft ◽  
Liver Cancer Cells ◽  
Mouse Xenograft Model ◽  
Damage Response ◽  
Chemotherapy Adjuvant

Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

scholarly journals O11: MYOFERLIN: A NOVEL BIOMARKER OF RADIOSENSITIVITY IN LOCALLY ADVANCED RECTAL CANCER

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
H Fowler ◽  
P Sutton ◽  
D Bowden ◽  
J Parsons ◽  
D Vimalachandran
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Cancer Cells ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Radiation Doses ◽  
Clonogenic Assays ◽  
Colorectal Cancer Cells

Abstract Introduction Our proteomic data has validated that high levels of the protein myoferlin confers poorer response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Myoferlin plays a role in membrane repair and VEGF signal transduction, and is associated with worse prognosis in numerous other epithelial cancers. We aim to assess the impact of myoferlin on the radiosensitivity of rectal cancer. Method Clonogenic assays were performed using immortalised colorectal cancer cells (HCT116,HT29,LIM,MDST8) to assess survival at escalating radiation doses following knockdown with myoferlin siRNA or a small molecular inhibitor(WJ460). 3D models (spheroids) were used to examine the effect of WJ460 on tumour growth. Result Quantification of myoferlin using immunoblotting demonstrated that MDST8 and LIM were higher expressors than HCT116 and HT29. Higher levels correlated with increasing radio-resistance as calculated by colony formation efficiency (CFE). Using clonogenic assays, cells treated with myoferlin siRNA or WJ460 demonstrated increased radiosensitivity compared to controls across all radiation doses, most significantly at 4Gy. Treatment of spheroids with WJ460 significantly reduced growth compared to controls at all radiation doses (p&lt;0.05), with WJ460 limiting growth considerably more than treatment with the current gold standard 5-FU. HCT116 spheroid volume day 15; WJ460 4.96um3,5-FU 6.74um3,DMSO 24.9um3. Conclusion Inhibition of myoferlin is associated with increased radiosensitivity of colorectal cancer cells, and treatment with a small molecular inhibitor significantly reduces growth in spheroid models. Further work is required further validate its potential use as a biomarker in locally advanced rectal cancer. Take-home message We have found that myoferlin is a protein associated with poor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Manipulation of this protein sensitises the cancer cells to radiotherapy.

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