Differential response of prostate cancer cells to ionizing radiation: The RB status.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 106-106
Author(s):  
Robert Benjamin Den ◽  
Steve Ciment ◽  
Ankur Sharma ◽  
Hestia Mellert ◽  
Steven McMahon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Ionizing Radiation ◽  
Cell Survival ◽  
Hormone Sensitive ◽  
Clonogenic Cell ◽  
Castrate Resistant

106 Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation and loss of RB has been observed in 25-30% of prostate cancers. We have previously shown that RB loss results in a castrate resistant phenotype, however the consequences of RB status with regard to radiation response are unknown. We hypothesized that RB loss would downregulate the G1-S cell cycle checkpoint arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to ionizing radiation. Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts. Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in both hormone sensitive and castrate resistant cell lines (p<0.05). Cell death was not mediated through increased apoptosis nor was perturbations in cell cycle noted. However, loss of RB effected DNA repair as measured by gamma H2AX staining as well as cellular senescence. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05). Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. The underlying mechanism appears to be related to DNA damage repair and cellular senescence.

Relationship between the loss of the retinoblastoma tumor suppressor and radiosensitivity.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 34-34 ◽  
Author(s):  
R. B. Den ◽  
S. Ciment ◽  
A. Sharma ◽  
H. Mellert ◽  
S. Mc-Mahon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Ionizing Radiation ◽  
Cell Survival ◽  
Retinoblastoma Tumor Suppressor ◽  
Clonogenic Cell ◽  
Retinoblastoma Tumor

34 Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation. Loss of RB has been observed in 25–30% of prostate cancers and is correlated with increasing tumor stage and grade. The clinical consequences of RB loss are unknown. We have previously shown that RB loss results in a castrate resistant phenotype. We hypothesized that RB loss would downregulate the G1-S cell cycle arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to mitotic catastrophe. Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts. Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in all cell lines (p<0.05). Cell death was not mediated through increased apoptosis, however, there was increased cell cycling despite the presence of DNA damage in the RB knockdown cells. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05). Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. RB status is integral to determining which therapeutic modality should be employed in the management of prostate cancer. No significant financial relationships to disclose.

scholarly journals Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma

Blood ◽  
2015 ◽  
Vol 126 (26) ◽  
pp. 2821-2831 ◽  
Author(s):  
Lu Dai ◽  
Jimena Trillo-Tinoco ◽  
Yueyu Cao ◽  
Karlie Bonstaff ◽  
Lisa Doyle ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Tumor Progression ◽  
Cell Survival ◽  
Cell Cycle Arrest ◽  
Primary Effusion Lymphoma ◽  
Cycle Arrest ◽  
Key Points ◽  
Met Inhibitor

Key Points The HGF/c-MET pathway has a complex network to control KSHV+ PEL cell survival. The c-MET inhibitor induces PEL apoptosis and suppresses tumor progression in vivo.

scholarly journals Phosphorylation-Regulated Transitions in an Oligomeric State Control the Activity of the Sae2 DNA Repair Enzyme

2013 ◽  
Vol 34 (5) ◽  
pp. 778-793 ◽  
Author(s):  
Qiong Fu ◽  
Julia Chow ◽  
Kara A. Bernstein ◽  
Nodar Makharashvili ◽  
Sucheta Arora ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Posttranslational Modifications ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Oligomeric State ◽  
Content Type ◽  
Processing Enzymes

In the DNA damage response, many repair and signaling molecules mobilize rapidly at the sites of DNA double-strand breaks. This network of immediate responses is regulated at the level of posttranslational modifications that control the activation of DNA processing enzymes, protein kinases, and scaffold proteins to coordinate DNA repair and checkpoint signaling. Here we investigated the DNA damage-induced oligomeric transitions of the Sae2 protein, an important enzyme in the initiation of DNA double-strand break repair. Sae2 is a target of multiple phosphorylation events, which we identified and characterizedin vivoin the budding yeastSaccharomyces cerevisiae. Both cell cycle-dependent and DNA damage-dependent phosphorylation sites in Sae2 are important for the survival of DNA damage, and the cell cycle-regulated modifications are required to prime the damage-dependent events. We found that Sae2 exists in the form of inactive oligomers that are transiently released into smaller active units by this series of phosphorylations. DNA damage also triggers removal of Sae2 through autophagy and proteasomal degradation, ensuring that active Sae2 is present only transiently in cells. Overall, this analysis provides evidence for a novel type of protein regulation where the activity of an enzyme is controlled dynamically by posttranslational modifications that regulate its solubility and oligomeric state.

scholarly journals STING enhances cell death through regulation of reactive oxygen species and DNA damage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Thomas J. Hayman ◽  
Marta Baro ◽  
Tyler MacNeil ◽  
Chatchai Phoomak ◽  
Thazin Nwe Aung ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Tumor Cell ◽  
Cell Survival ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Dna Damaging Agents ◽  
Ros Homeostasis

AbstractResistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.

scholarly journals The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ayesha A. Shafi ◽  
Chris M. McNair ◽  
Jennifer J. McCann ◽  
Mohammed Alshalalfa ◽  
Anton Shostak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Ex Vivo ◽  
Functional Studies ◽  
Expression Of Genes ◽  
Mechanistic Investigation ◽  
Transcriptional Coregulator

AbstractMechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.

scholarly journals Combinatorial Effect of PLK1 Inhibition with Temozolomide and Radiation in Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5114
Author(s):  
Arvind Pandey ◽  
Satyendra C. Tripathi ◽  
Junhua Mai ◽  
Samir M. Hanash ◽  
Haifa Shen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Growth ◽  
Apoptotic Cell ◽  
Side Population ◽  
Specific Inhibitor ◽  
M Cell ◽  
Dna Repair Gene

New strategies that improve median survivals of only ~15–20 months for glioblastoma (GBM) with the current standard of care (SOC) which is concurrent temozolomide (TMZ) and radiation (XRT) treatment are urgently needed. Inhibition of polo-like kinase 1 (PLK1), a multifunctional cell cycle regulator, overexpressed in GBM has shown therapeutic promise but has never been tested in the context of SOC. Therefore, we examined the mechanistic and therapeutic impact of PLK1 specific inhibitor (volasertib) alone and in combination with TMZ and/or XRT on GBM cells. We quantified the effects of volasertib alone and in combination with TMZ and/or XRT on GBM cell cytotoxicity/apoptosis, mitochondrial membrane potential (MtMP), reactive oxygen species (ROS), cell cycle, stemness, DNA damage, DNA repair genes, cellular signaling and in-vivo tumor growth. Volasertib alone and in combination with TMZ and/or XRT promoted apoptotic cell death, altered MtMP, increased ROS and G2/M cell cycle arrest. Combined volasertib and TMZ treatment reduced side population (SP) indicating activity against GBM stem-like cells. Volasertib combinatorial treatment also significantly increased DNA damage and reduced cell survival by inhibition of DNA repair gene expression and modulation of ERK/MAPK, AMPK and glucocorticoid receptor signaling. Finally, as observed in-vitro, combined volasertib and TMZ treatment resulted in synergistic inhibition of tumor growth in-vivo. Together these results identify new mechanisms of action for volasertib that provide a strong rationale for further investigation of PLK1 inhibition as an adjunct to current GBM SOC therapy.

Inhibition of Poly ADP Ribose Polymerase (PARP) Activity Exerts Cytotoxic Effects on Chromosomal Instability Syndrome and Leukaemic Cell Lines: Potential for Anti-Leukaemia Therapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2647-2647
Author(s):  
Terry J. Gaymes ◽  
S. Shall ◽  
Farzin Farzaneh ◽  
Ghulam J. Mufti
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Survival ◽  
Cell Lines ◽  
Chromosomal Instability ◽  
Parp Inhibitors ◽  
Dna Breaks ◽  
Leukaemic Cells ◽  
Parp Activity

Abstract Recent reports suggest that BrCA1−/− and BrCA2−/− cells can be selectively targeted for cell death through abrogation of their PARP activity. It is postulated that as a result of PARP inhibition, accumulation of single strand DNA breaks (SSB) leads to the replication fork collapse and conversion of SSB to double strand DNA breaks (DSB). The inability of repair defective cells such as BrCA2−/− to repair the DSB would lead to cell death. Exploitation of DNA repair defects using PARP inhibitors (PI) thus represents a more specific and less toxic form of therapy for a number of haematological malignancies. Chromosomal instability (CI) syndromes that have inherent defects in double strand DNA repair also have a uniformly high incidence of transformation to acute leukaemia or lymphoma. In order to test the efficacy of PI therapy we analysed CI cell lines, myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) cell lines and the potential for combination therapy with inhibitors of DNA methyltransferase (DNMTi) or histone deacetylase inhibitors (HDACi). We report that cells from CI syndromes; Blooms syndrome, Fanconi Anaemia (FancD2 and FancA), Ataxia telancgectasia and Nijmegen break syndrome display abnormal cell cycle profiles and excessive apoptosis in response to the PI’s PJ34 (3μM) and EB47 (45μM). In contrast, normal control cells displayed standard cell cycle profiles and no apoptosis in response to PI at equivalent concentrations. Clonogenic cytotoxicity assays showed that CI syndrome cells exhibit between 30–75% cell survival compared with 100% cell survival in control cells (p<0.05) in response to PI. The homologous recombination (HR) DNA repair component, rad51 forms foci in response to DNA damage. In HR compromised cells, rad51 foci fail to form. In response to PI, immunofluorescent studies show that CI syndrome cells demonstrate severely reduced rad51 foci formation (<5%) compared to control cells (15%). This confirms that PI targets the HR deficiencies in CI syndrome cells. Histone γH2AX, phosphorylated in response to DSB had greatly increased foci formation in CI syndrome cells compared to control cells as a result of unrepaired DNA damage (25.3 vs 9.3%)(p<0.05). CI syndromes have increased transformation potential to the MDS and AML. Addition of 3μM PJ34 to the myelomonocytoid leukaemic/myelodysplastic cell line, P39 exhibited significant apoptosis, with a cell survival fraction of 65% compared to 100% in control cells (p<0.01). Immunofluorescent studies revealed reduced rad51 foci formation (6.3 vs 15%) and increased γH2AX foci formation (17.6 vs 9.3%)(p<0.01). Strikingly, we were also able to reproduce similar PI responses in the Jurkat T-cell leukaemic cell line. We next explored the use of PI in combination with DNMTi or HDACi. Whilst 3μM PJ34 offered only additive effects on decitabine cytotoxicity, a sub-optimal concentration (1μM) of PJ34 behaved synergistically with HDACi potentiating the cytotoxic effect of 200nM MS275 by 55% compared to MS275 alone (p<0.05) in P39 cells. In conclusion, we have shown that in a panel of CI syndrome and leukaemic cells, PI demonstrates significant cytotoxic responses. We also show that PI acts synergistically in combination with HDACi. Parp inhibitors can potentially exploit DSB repair defects in leukaemic cells paving the way for a targeted therapy for MDS and leukaemia.

Poly ADP Ribose Polymerase (PARP) Inhibitors Induce Apoptosis Alone or Synergistically with Histone Deacetylase Inhibitors in Primary Acute Myeloid Leukemic Patient Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2974-2974 ◽  
Author(s):  
Terry J Gaymes ◽  
Sydney Shall ◽  
Farzin Farzaneh ◽  
Ghulam J Mufti
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Survival ◽  
Histone Deacetylase ◽  
Normal Control ◽  
Histone Deacetylase Inhibitors ◽  
Parp Inhibitors ◽  
Leukemic Cells ◽  
Acute Myeloid

Abstract It has been previously reported that cells defective for double strand break (dsb) DNA repair can be selectively targeted for apoptosis through abrogation of their PARP activity. It has also been reported that leukemic cells have inherent defects in dsb DNA repair. Exploitation of DNA repair defects using PARP inhibitors (PI) thus represents a specific and less toxic form of therapy for a number of hematological malignancies. In order to test the efficacy of PI therapy we analysed primary cells from acute myeloid leukemia (AML) patients and the potential for combination therapy with inhibitors of DNA methyltransferase (DNMTi) or histone deacetylase inhibitors (HDACi). We report that from a panel of 12 AML patients, 2 AML patient cells demonstrated abnormal cell cycle profiles and apoptosis in response to the PI, KU-0058948 (1μM). In contrast, normal control cells displayed standard cell cycle profiles and no apoptosis in response to PI. Clonogenic cytotoxicity assays also showed that these PI sensitive AML patient cells exhibited between 45–55% cell survival compared with 100% cell survival in control cells (p&lt;0.05) in response to PI. The homologous recombination (HR) DNA repair component, rad51 forms foci in response to DNA damage. In HR compromised cells, rad51 foci fail to form. In response to PI, immunofluorescent studies show that the 2 PI sensitive AML patients cells demonstrated severely reduced rad51 foci formation (&lt;1%) compared to PI insensitive and normal control cells (15%). This confirmed that PI targets the HR deficiencies in PI sensitive cells. Histone H2AX, phosphorylated in response to DSB had greatly increased foci formation in PI sensitive cells compared to PI insensitive control cells as a result of unrepaired DNA damage (32.3 vs 19.3%)(p&lt;0.05). We next explored the use of PI in combination with DNMTi or HDACi. Whilst KU-0058948 offered only additive effects on DNMTi cytotoxicity, a non-cytotoxic concentration of KU-0058948 (10nM) behaved synergistically with HDACi potentiating the cytotoxic effect of MS275 by 45% compared to MS275 alone (p&lt;0.05). Furthermore, non-cytotoxic doses of MS275 (50nM) potentiated the cytotoxic effects of KU-0058948 in PI sensitive cells (25–30%) compared to KU-0058948 alone (P&lt;0.05). In conclusion, we have shown that primary AML cells are sensitive to the cytotoxic actions of PI. We have also showed that PI acts synergistically in combination with HDACi. PARP inhibitors can potentially exploit dsb repair defects in leukemic cells paving the way for a targeted therapy for leukemia.

Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 240-240
Author(s):  
Ying Zhang Mazzu ◽  
Travis A. Gerke ◽  
Goutam Chakraborty ◽  
Joshua Armenia ◽  
Mohammad Omar Atiq ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Growth ◽  
Protein Expression ◽  
Ribonucleotide Reductase ◽  
Rna Seq ◽  
Oncogenic Signaling ◽  
Downstream Targets

240 Background: DNA-repair defects are common in advanced prostate cancer (PC) and high-risk localized tumors. Besides deficiency of DNA repair, overexpression of DNA repair genes could also contribute to poorer outcomes for PC patients. The nucleotide metabolism enzyme ribonucleotide reductase (RNR) plays the key role in DNA synthesis and repair. RRM2, the rate-limiting RNR subunit, is frequently up-regulated in cancer, and its overexpression leads to chemoresistance. Although targeting RRM2 by siRNA and small molecules has been applied in clinical trials in multiple cancers, limited knowledge of RRM2 function in PC delays potential clinical application of RRM2 inhibition. Methods: We leveraged publically available PC clinical cohorts to examine RRM2 levels and clinical outcomes. siRNAs was applied to knockdown of RRM2 in multiple PC cell lines. Cell growth, cell cycle and apoptosis were analyzed to determine siRRM2 or RRM2 inhibitor (COH29)-induced phenotypes. RNA-seq and protein array were performed to identify downstream targets of RRM2. Immunohistochemistry staining was applied to determine prevalence of RRM2 protein expression in PC tissues microarrays (TMAs). Results: In PC cohorts, increased RRM2 expression was associated with a higher likelihood of metastasis, poorer disease-free survival, and increased risk of development of lethal disease (N = 1200, PHS/HPFS cohorts). In PC cells, Inhibition of RRM2 induced remarkable cell growth inhibition, cell cycle arrest (at S phase) and apoptosis. DNA damage was observed in siRRM2/COH29-treated PC cells with increased activation of DNA damage markers. GSEA analysis of the RNA-seq dataset revealed multiple biological processes were affected by inhibition of RRM2, such as cell cycle, apoptosis, and DNA damage response. Intriguingly, MYC oncogenic signaling is the major downstream targets of RRM2. Furthermore, inhibition of RRM2 can block multiple oncogenic signaling including mTOR/AKT, SFK, and STAT signaling by repressing the key phospho-kinases in PC cells. Among 121 cases on the PC TMAs, 20% showed strong RRM2 protein expression. Conclusions: RRM2 may serve as a prognostic biomarker and novel therapeutic target in PC.

scholarly journals All-Purpose Nanostrategy Based on Dose Deposition Enhancement, Cell Cycle Arrest, DNA Damage and ROS Production as Prostate Cancer Radiosensitizer for Potential Clinical Translation

2021 ◽  
Author(s):  
Xiao-xiao Guo ◽  
Zhen-hu Guo ◽  
Meng Wu ◽  
Jing-song Lu ◽  
Wen-sheng Xie ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Clinical Translation ◽  
Ros Production ◽  
Cycle Arrest ◽  
Dose Deposition

Abstract Background Radiotherapy (RT) is one of the main treatments for men with prostate cancer (PCa). Yet, to date, with numerous sophisticated nano-formulations as radiosensitizers have been synthesized with inspiring therapeutic effect both in vitro and in vivo, there still lacks the successful clinical translation of such nanosystems. Meanwhile, almost all the attention has been paid on the enhanced dose deposition effect by secondary electrons of nanomaterials with high atomic numbers (Z), despite that cell-cycle arrest, DNA damage and also reactive oxygen species (ROS) production are critical working mechanisms accounting for radiosensitization. Methods Herein, an ‘all-purpose’ nanostrategy based on dose deposition enhancement, cell cycle arrest and ROS production as prostate cancer radiosensitizer for potential clinical translation was proposed. The rather simple structure of docetaxel loaded Au nanoparticles (NPs) with prostate specific membrane antigen (PSMA) ligand conjugation have been successfully synthesized by a rather facile protocol. Results Enhanced cellular uptake achieved via selective internalization of the NPs by PCa cells with positive PSMA expression could guarantee the enhanced dose deposition. Moreover, the as-synthesized nanosystem could arrest cell cycle at G2/M phases, which would reduce the ability of DNA damage repair for more irradiation sensitive of the PCa cells. Meanwhile, G2/M phases arrest would further promote cascade retention and enrichment of the NPs within the cells. Furthermore, ROS generation and double strand breaks greatly promoted by the NPs under irradiation (IR) could also provide an underlying basis for effective radiosensitizers. Conclusions Investigations from in vitro and in vivo confirmed the as-synthesized NPs as an effective nano-radiosensitizer with ideal safety. More importantly, all the moieties within the present nanosystem have been approved by FDA for the purpose of PCa treatment, thus making the it highly attractive for clinical translation.

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