Telomerase interference in combination with docetaxel therapy for maximal prostate cancer inhibition: In vitro data for a novel therapeutic approach

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14596-e14596
Author(s):  
D. Sahu ◽  
T. Xu ◽  
R. Lau ◽  
L. Xue ◽  
A. Goldkorn
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Vector Control ◽  
Telomere Length ◽  
Statistical Significance ◽  
Telomerase Activity ◽  
Telomerase Rna ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapeutic

e14596 Background: Metastatic castration-resistant prostate cancer (mCRPC) carries a median survival of 18 months with standard docetaxel based therapies. Telomerase interference (TI) is a promising novel therapeutic strategy that exploits the high telomerase activity in cancer cells by introducing a mutated telomerase RNA (MT-Ter) that encodes toxic telomeres and rapidly induces apoptosis. We investigated whether TI can be combined with docetaxel therapy to achieve greater growth inhibition in mCRPC. Methods: PC3 and DU145 mCRPC cell lines were treated with docetaxel in the presence of TI or vector control. TI was accomplished by concurrent lentiviral expression of 2 constructs: telomerase RNA with an altered template region (MT-Ter) and siRNA targeting wild-type telomerase RNA (anti-Ter siRNA). Telomere length and telomerase activity were assessed using RT-PCR and TRAP, respectively. Proliferation, apoptosis, and DNA damage were quantified using MTS, TUNEL, and 53bp1 staining, respectively. Statistical significance was calculated using a 2-sided t-test. Results: Docetaxel (10nM) induced 22% inhibition (p=0.01) of PC3 proliferation in the presence of vector control and 41% inhibition (p=0.001) in the presence of TI (results were similar in DU145 cells). This near-doubling of efficacy was attributable to an independent inhibitory effect (17% inhibition, p=0.04) from TI treatment alone, which occurred without change in bulk telomere length or telomerase activity. TI alone generated increased numbers of DNA damage foci (7/cell vs. 2/cell with vector control) while docetaxel alone did not generate significant increases in DNA damage. Both TI and docetaxel induced a marked increase in the rate of apoptosis. Conclusions: Docetaxel and TI each exerted a pro-apoptotic effect which, when combined, produced an additive inhibition of mCRPC proliferation. TI-mediated apoptosis ensued from DNA damage, consistent with its known telomeric-uncapping effect, while docetaxel-induced apoptosis was not associated with direct DNA damage, also consistent with known docetaxel mechanisms of action. These findings underscore the therapeutic promise of combining standard agents with TI to improve efficacy and reduce toxicity. No significant financial relationships to disclose.

Mouse prostate tumor inhibition via disruption of murine telomerase: In vivo and in vitro data for a new preclinical cancer model

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14631-e14631
Author(s):  
T. Xu ◽  
Y. Xu ◽  
R. Lao ◽  
K. He ◽  
L. Xue ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cancer Cell Line ◽  
Telomerase Activity ◽  
Telomerase Rna ◽  
Prostate Cancer Cells ◽  
Mouse Prostate

e14631 Background: Telomerase-interference (TI), a novel therapeutic strategy, exploits the high telomerase activity in prostate cancer by introducing a mutated telomerase RNA (MT-Ter) that encodes toxic telomeres. Until now, TI has been tested by targeting human telomerase in tumor cells xenografted into immuno-deficient mice, an inadequate model for predicting efficacy and toxicity. We designed and validated 2 new TI gene constructs that specifically target murine telomerase RNA (mTER), enabling the study of TI in preclinical mouse models that are immuno-competent and that develop endogenous prostate tumors. Methods: We designed 2 constructs and cloned them into a lentiviral delivery system: MT-mTER and siRNA against wild type mTer (α-mTer-siRNA). Using a mouse prostate cancer cell line, E4, we tested the 2 constructs for expression (RT-PCR), telomerase activity (TRAP), and biologic activity (53bp1 DNA damage staining, MTS growth assay, TUNEL and caspase apoptosis assays), as well as in vivo efficacy (NOD-SCID allografts). Results: We confirmed MT-mTER expression (∼50-fold) and showed that α-mTer-siRNA specifically depleted WT-mTER (80% reduction) but not MT-mTER when the 2 constructs are co-expressed; thus, the 2 constructs in combination effectively substituted MT-mTer for WT-mTer in the mouse prostate cancer cells. MT-mTER caused mutant telomeric repeats (TTTGGG instead of TTAGGG) to be added to the ends of telomeres, resulting in rapid telomeric uncapping marked by 53bp1 DNA damage foci (an average 7.5 foci/cell vs. 1.4 foci/cell in vector control). This, in turn, led to rapid and significant apoptosis (>90% TUNEL and caspase +) and growth inhibition in vitro (90% reduction by MTS) and in vivo (75% reduction in tumor allograft size). Conclusions: We successfully designed and validated MT-mTer and α-mTer-siRNA, 2 novel gene constructs that specifically target and co-opt murine telomerase activity within mouse prostate cancer cells. These constructs offer a significant advantage, as they can be used to investigate TI in immuno-competent mice that develop prostate cancer, thereby modeling actual human disease and testing TI-based therapies in a much more informative and authentic manner. No significant financial relationships to disclose.

scholarly journals hsa_circ_0001275 Is One of a Number of circRNAs Dysregulated in Enzalutamide Resistant Prostate Cancer and Confers Enzalutamide Resistance In Vitro

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6383
Author(s):  
Marvin C. J. Lim ◽  
Anne-Marie Baird ◽  
John Greene ◽  
Ciara McNevin ◽  
Karine Ronan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Quantitative Polymerase Chain Reaction ◽  
Statistical Significance ◽  
Control Cell ◽  
Plasma Samples ◽  
Castration Resistant Prostate Cancer ◽  
Liquid Biopsies ◽  
Control Cell Line

Background: Enzalutamide is part of the treatment regimen for metastatic castration-resistant prostate cancer (MCRPC). However, both intrinsic and acquired resistance to the drug remain substantial clinical quandaries. circRNAs, a novel type of non-coding RNA, have been identified in a number of cancers including prostate cancer and have been associated with cancer development and progression. circRNAs have shown great potential as clinically useful blood-based ‘liquid biopsies’ and as therapeutic targets in prostate cancer. The aim of this study was to examine the role of circRNA transcripts in enzalutamide-resistant prostate cancer cells and assess their utility as biomarkers. Methods: An isogenic cell line model of enzalutamide resistance was subjected to circRNA microarray profiling. Several differentially expressed circRNAs, along with their putative parental genes were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). circRNAs of interest were stably overexpressed in the control cell line and drug sensitivity was assessed using an ELISA-based proliferation assay. The candidate circRNA, hsa_circ_0001275, was measured in patient plasma samples using RT-droplet digital PCR (RT-ddPCR). Results: hsa_circ_0001275 and its parental gene, PLCL2, were significantly up-regulated in strongly resistant clones vs. control (p < 0.05). Overexpression of hsa_circ_0001275 in the control cell line resulted in increased resistance to enzalutamide (p < 0.05). While RT-ddPCR analysis of hsa_circ_0001275 expression in plasma samples of 44 clinical trial participants showed a trend that mirrored the stages of disease activity (as defined by PSA level), the association did not reach statistical significance. Conclusions: Our data suggest that increased levels of hsa_circ_0001275 contribute to enzalutamide resistance. hsa_circ_0001275 plasma expression showed a trend that mirrors the PSA level at specific disease time points, indicating that circRNAs mirror disease recurrence and burden and may be associated with enzalutamide resistance.

Synergistic effects of the PARP inhibitor olaparib and pharmacological ascorbate in castration-resistant prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 326-326
Author(s):  
Nicolas Gordon ◽  
Matthew Joseph Schiewer ◽  
Peter Gallagher ◽  
Amy C Mandigo ◽  
Emanuela Dylgjeri ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Lethal Dose ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
In Vivo Models ◽  
Tumor Doubling Time ◽  
Castration Resistant

326 Background: The administration of ascorbate has proved lethal to and highly selective for a variety of cancer cell types; however, despite an increasingly impressive body of evidence, there has not been a robust effort to translate the observed in vitro and in vivo outcomes to the clinic. This is partially due to the fact that the mechanism by which ascorbate exerts its anti-cancer effect is still under investigation. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), by inhibiting DNA damage repair, would augment the toxicity of ascorbate. Methods: In vitro and in vivo models systems queried for anti-tumor effects of PARP inhibitors and ascorbate. Results: Two distinct castration-resistant prostate cancer (CRPC) models were sensitive to ascorbate at physiologically attainable concentrations. These in vitro models were then subjected to treatment with three different PARP inhibitors (olaparib, niraparib, and talazoparib) alone and in combination with ascorbate. The addition of a sub-lethal dose of ascorbate significantly increased cell death across a range of doses for all three PARP inhibitors. A combination index was generated for olaparib and ascorbate in both CRPC models; the results suggest a strongly synergistic relationship between olaparib and ascorbate. Use of a CRPC in vivo model demonstrated that the combination of olaparib and ascorbate significantly increased tumor doubling time compared to vehicle controls and monotherapy. This in vivo efficacy was even more profound in an additional model using castrated mice to mimic the effect of hormone therapy. Additional mechanistic studies are in progress to further investigate the potential for ascorbate and olaparib combination therapy. Conclusions: Ultimately, these data suggest the combination of ascorbate and PARP inhibitors could be an effective treatment for CRPC.

scholarly journals Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death

2019 ◽  
Author(s):  
Vidyavathi Reddy ◽  
Asm Iskander ◽  
Clara Hwang ◽  
George Divine ◽  
Mani Menon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Combined Treatment ◽  
Full Length ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Damage Response

AbstractTelomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.

scholarly journals Primary high-grade serous ovarian cancer cells are sensitive to senescence induced by carboplatin and paclitaxel in vitro

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Paweł Uruski ◽  
Agnieszka Sepetowska ◽  
Corinna Konieczna ◽  
Martyna Pakuła ◽  
Michał Wyrwa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Telomere Length ◽  
Telomerase Activity ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer

Abstract Background Various types of normal and cancer cells undergo senescence in response to carboplatin and paclitaxel, which are considered the gold standard treatments in ovarian cancer management. Surprisingly, the effect of these drugs on ovarian cancer cell senescence remained unknown. Methods The experiments were conducted on primary high-grade serous ovarian cancer cells. Molecular markers of senescence were evaluated using cytochemistry and immunofluorescence. Cell cycle distribution was analyzed using flow cytometry. Expression of cyclins and signaling pathways was tested using western blot. Telomere length and telomerase activity were measured using qPCR, and the colocalization of telomeres with DNA damage foci using immuno-FISH. Oxidative stress-related parameters were quantified using appropriate fluorescence probes. Production of cancerogenic agents was analyzed using qPCR and ELISA. Results Carboplatin applied with paclitaxel induces senescence of ovarian cancer cells in vitro. This activity was reflected by permanent G2/M growth arrest, a high fraction of cells expressing senescence biomarkers (SA-β-Gal and γ-H2A.X), upregulated expression of p16, p21, and p53 cell cycle inhibitors, and decreased expression of cyclin B1. Neither telomere length nor telomerase activity changed in the senescent cells, and the majority of DNA damage was localized outside telomeres. Moreover, drug-treated cancer cells exhibited increased production of STAT3 protein, overproduced superoxide and peroxides, and increased mitochondrial mass. They were also characterized by upregulated ANG1, CCL11, IL-6, PDGF-D, TIMP-3, TSP-1, and TGF-β1 at the mRNA and/or protein level. Conclusions Our findings imply that conventional chemotherapy may elicit senescence in ovarian cancer cells, which may translate to the development of a cancer-promoting phenotype, despite the inability of these cells to divide.

scholarly journals YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Hsiu-Chi Lee ◽  
Chien-Hui Ou ◽  
Yun-Chen Huang ◽  
Pei-Chi Hou ◽  
Chad J. Creighton ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lipid Metabolism ◽  
Critical Issue ◽  
Castration Resistant Prostate Cancer ◽  
Cancer Stemness ◽  
New Treatment ◽  
Underlying Mechanisms ◽  
Transcriptional Complex

AbstractMetastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.

scholarly journals Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3975
Author(s):  
Marco A. De Velasco ◽  
Yurie Kura ◽  
Naomi Ando ◽  
Noriko Sako ◽  
Eri Banno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Late Stage ◽  
Early Stage ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Molecular Features ◽  
Context Specific

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

scholarly journals Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ding-fang Zhang ◽  
Zhi-chun Yang ◽  
Jian-qiang Chen ◽  
Xiang-xiang Jin ◽  
Yin-da Qiu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Cell Adhesion ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Dna Damage And Repair ◽  
Castration Resistant

Abstract Background Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. Methods The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. Results The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. Conclusion Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

scholarly journals Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

2020 ◽  
Vol 148 (2) ◽  
pp. 385-395
Author(s):  
Peter H. J. Slootbeek ◽  
Marleen L. Duizer ◽  
Maarten J. Doelen ◽  
Iris S. H. Kloots ◽  
Malou C. P. Kuppen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Damage Repair ◽  
Aggressive Variant

scholarly journals Focused ultrasound radiosensitizes human cancer cells by enhancement of DNA damage

2021 ◽  
Author(s):  
Xinrui Zhang ◽  
Mariana Bobeica ◽  
Michael Unger ◽  
Anastasia Bednarz ◽  
Bjoern Gerold ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Metabolic Activity ◽  
Focused Ultrasound ◽  
Double Strand Breaks ◽  
High Intensity Focused Ultrasound ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

Abstract Purpose High-intensity focused ultrasound (HIFU/FUS) has expanded as a noninvasive quantifiable option for hyperthermia (HT). HT in a temperature range of 40–47 °C (thermal dose CEM43 ≥ 25) could work as a sensitizer to radiation therapy (RT). Here, we attempted to understand the tumor radiosensitization effect at the cellular level after a combination treatment of FUS+RT. Methods An in vitro FUS system was developed to induce HT at frequencies of 1.147 and 1.467 MHz. Human head and neck cancer (FaDU), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS in ultrasound-penetrable 96-well plates followed by single-dose X‑ray irradiation (10 Gy). Radiosensitizing effects of FUS were investigated by cell metabolic activity (WST‑1 assay), apoptosis (annexin V assay, sub-G1 assay), cell cycle phases (propidium iodide staining), and DNA double-strand breaks (γH2A.X assay). Results The FUS intensities of 213 (1.147 MHz) and 225 W/cm2 (1.467 MHz) induced HT for 30 min at mean temperatures of 45.20 ± 2.29 °C (CEM43 = 436 ± 88) and 45.59 ± 1.65 °C (CEM43 = 447 ± 79), respectively. FUS improves the effect of RT significantly by reducing metabolic activity in T98G cells 48 h (RT: 96.47 ± 8.29%; FUS+RT: 79.38 ± 14.93%; p = 0.012) and in PC-3 cells 72 h (54.20 ± 10.85%; 41.01 ± 11.17%; p = 0.016) after therapy, but not in FaDu cells. Mechanistically, FUS+RT leads to increased apoptosis and enhancement of DNA double-strand breaks compared to RT alone in T98G and PC-3 cells. Conclusion Our in vitro findings demonstrate that FUS has good potential to sensitize glioblastoma and prostate cancer cells to RT by mainly enhancing DNA damage.

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