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

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

A prostate cancer-targeted “all-purpose” radiosensitive nanostrategy based on dose deposition enhancement, G2/M phase arrest, DNA damage, and ROS production, can provides effective radiosensitive efficiency and has high potential for clinical translation.

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.

The DNA Methyltransferase Inhibitor Decitabine Induces DNA Damage, Cell Cycle Arrest and Apoptosis in Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1833-1833
Author(s):  
Ken Maes ◽  
Miguel Lemaire ◽  
Jordan Gauthier ◽  
Hendrik De Raeve ◽  
Eline Menu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
Damage Response ◽  
M Phase

Abstract Abstract 1833 Multiple myeloma (MM) is still an incurable plasma cell malignancy, thus highlighting the need for alternative treatment options. Currently, strategies for therapy are being developed targeting epigenetic modification using epigenetic modulating agents like histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi). 5-aza-2'-deoxycitidine or decitabine (DAC) is a DNMTi and is FDA approved for treatment of myelodysplastic syndrome and has beneficial clinical effects against leukemia. The anti-tumor effects are ascribed to two non-mutual exclusive modes of action. Relative low doses are thought to lead to passive CpG demethylation resulting in re-expression of genes silence by DNA methylation and apoptosis, while relative high doses are cytotoxic by inducing a DNA damage response together with cell cycle arrest and apoptosis. In multiple myeloma (MM), preclinical data regarding the effects of DAC is, however, limited. Therefore, we investigated the cytotoxic effects of DAC in MM both in vitro and in vivo. In addition, we evaluated the combination of DAC with the pan-HDAC inhibitor JNJ-26481585. First, we assessed the effects of DAC on cell cycle progression and apoptosis on a panel of MM cell lines. We used one murine (5T33MMvt) and 5 human (OPM-2, RPMI 8226, LP-1, KMS-11 and NCI-H929) MM cell lines. In general, DAC could affect cell cycle progression by inducing either a G0/G1-phase arrest or a G2/M-phase arrest. The 5T33MMvt and LP-1 cells were arrested in the G2/M-phase, while OPM-2 and NCI-H929 cells underwent a G0/G1-phase arrest. Subsequently, apoptosis occurred in all cell lines. Interestingly, the 5T33MMvt cells were relatively sensitive, as nM doses of DAC were sufficient to induce massive apoptosis in a relative short incubation time (2 days). The human cell lines were less sensitive since higher doses (μM range) and longer incubation time (3–5 days) were necessary to induce apoptosis, with the OPM-2 cells being the least sensitive. To determine the potential mechanisms more in detail, we focused on the 5T33MMvt and OPM-2 cells. In both cell lines, DAC-mediated apoptosis was associated with caspase activation and PARP cleavage, Bim upregulation and posttranslational changes in Mcl-1 expression. The G2/M-phase arrest in the 5T33MMvt cells was accompanied by phosphorylation of CDK-1 and an increase in cyclinB1 expression. In both cell lines, p27 protein expression was increased, what may contribute to the cell cycle arrest. Furthermore, in the 5T33MMvt cells, a DNA damage response was activated as evidenced by a clear induction of ATM and H2AX phosphorylation. This was not the case for the OPM-2 cells, in which we observed no ATM activation and only a modest H2AX phosphorylation upon DAC treatment. In addition, the tumor suppressor p53 was phosphorylated on ser15 upon DAC treatment in both cell lines, indicating a potential role of p53. However, a p53 inhibitor, pifithrin-α, could not abrogate DAC-induced apoptosis indicating that p53 transactivation is not essential in this process. Next, we used the syngeneic 5T33 murine MM model (5T33MM) to investigate the in vivo effects of DAC. 5T33MM mice were daily treated with 0.1, 0.2 and 0.5 mg/kg DAC. We observed a significant decrease in serum M-protein, bone marrow plasmacytosis and spleno- and hepatomegaly compared to vehicle treated mice. These effects led to a significant increase in survival probability of DAC treated mice (p≤0.001). Lastly, we evaluated the possibility of combining DAC with a pan-HDAC inhibitor JNJ-26481585 (JNJ-585). DAC and JNJ-585 synergistically induced cell death in RPMI-8226, OPM-2 and 5T33MMvt cells. We further demonstrated the combinatory effects of DAC and JNJ-585 in the 5T33MM murine model. Here, we observed enhanced effects of DAC and JNJ-585 on serum M-protein, BM tumor load and survival (p≤0.001) compared to either agent alone. In conclusion, DAC shows potent anti-MM effects both in vitro and in vivo. Mechanistically, we observed induction of a DNA damage response and/or cell cycle arrest. Apoptosis was caspase-mediated but independent of the transactivation of p53. DAC was also efficient in the murine 5T33MM model in which DAC treatment led to a survival benefit. In addition, DAC showed useful in a combination with the HDAC inhibitor JNJ-585. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dietary Isothiocyanates Inhibit Caco-2 Cell Proliferation and Induce G2/M Phase Cell Cycle Arrest, DNA Damage, and G2/M Checkpoint Activation

2004 ◽  
Vol 134 (11) ◽  
pp. 3121-3126 ◽  
Author(s):  
James M. Visanji ◽  
Susan J. Duthie ◽  
Lynn Pirie ◽  
David G. Thompson ◽  
Philip J. Padfield
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Phase Cell ◽  
Checkpoint Activation ◽  
Cycle Arrest ◽  
M Phase

Natural borneol enhances bisdemethoxycurcumin-induced cell cycle arrest in the G2/M phase through up-regulation of intracellular ROS in HepG2 cells

2015 ◽  
Vol 6 (3) ◽  
pp. 740-748 ◽  
Author(s):  
Jianping Chen ◽  
Lin Li ◽  
Jianyu Su ◽  
Tianfeng Chen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Hepg2 Cells ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
Intracellular Ros ◽  
M Phase

Natural borneol and bisdemethoxycurcumin in combination induces G2/M phase arrest in HepG2 cells.

scholarly journals Pinocembrin flavanone inhibits cell viability in PC-3 human prostate cancer by inducing cellular apoptosis, ROS production and cell cycle arrest

2021 ◽  
Vol 71 (4) ◽  
pp. 669-678
Author(s):  
Linhai Shao ◽  
Yajun Shao ◽  
Yu Yuan
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Human Prostate ◽  
Ros Production ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Dose Dependent

Abstract The main purpose of the present study was to evaluate the antitumor effects of pinocembrin in human prostate cancer cells (PC-3) along with investigating its effects on cell apoptosis, endogenous ROS production and cell cycle. MTT assay and clonogenic assays were used to study the effects on cell viability and cancer colony formation, respectively. Fluorescence microscopy along with Western blotting was used to study apoptotic effects induced by pinocembrin. Flow cytometry was used to study effects on ROS production and cell cycle phase distribution. Results indicated that pinocembrin promoted inhibition cell proliferation along with reducing cancer colony formation of PC-3 cells in a dose-dependent manner. Pinocembrin induced regulatory effects over expressions of caspase-3, caspase-9, Bax and Bcl-2, thereby promoting apoptotic cell death in PC-3 cells. It also led to the dose-dependent G0/G1 cell cycle arrest. In conclusion, pinocembrin exhibits strong anticancer effects in human prostate cancer cells mediated via apoptosis, endogenous ROS production and G0/G1 cell cycle arrest.

scholarly journals Romidepsin Induces G2/M Phase Arrest and Apoptosis in Cholangiocarcinoma Cells

2020 ◽  
Vol 19 ◽  
pp. 153303382096075
Author(s):  
Pihong Li ◽  
Luguang Liu ◽  
Xiangguo Dang ◽  
Xingsong Tian
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Antitumor Effect ◽  
Caspase 3 ◽  
M Cell ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
M Phase

Background: Cholangiocarcinoma (CCA) is an extremely intractable malignancy since most patients are already in an advanced stage when firstly discovered. CCA needs more effective treatment, especially for advanced cases. Our study aimed to evaluate the effect of romidepsin on CCA cells in vitro and in vivo and explore the underlying mechanisms. Methods: The antitumor effect was determined by cell viability, cell cycle and apoptosis assays. A CCK-8 assay was performed to measure the cytotoxicity of romidepsin on CCA cells, and flow cytometry was used to evaluate the effects of romidepsin on the cell cycle and apoptosis. Moreover, the in vivo effects of romidepsin were measured in a CCA xenograft model. Results: Romidepsin could reduce the viability of CCA cells and induce G2/M cell cycle arrest and apoptosis, indicating that romidepsin has a significant antitumor effect on CCA cells in vitro. Mechanistically, the antitumor effect of romidepsin on the CCA cell lines was mediated by the induction of G2/M cell cycle arrest and promotion of cell apoptosis. The G2/M phase arrest of the CCA cells was associated with the downregulation of cyclinB and upregulation of the p-cdc2 protein, resulting in cell cycle arrest. The apoptosis of the CCA cells induced by romidepsin was attributed to the activation of caspase-3. Furthermore, romidepsin significantly inhibited the growth of the tumor volume of the CCLP-1 xenograft, indicating that romidepsin significantly inhibited the proliferation of CCA cells in vivo. Conclusions: Romidepsin suppressed the proliferation of CCA cells by inducing cell cycle arrest through cdc2/cyclinB and cell apoptosis by targeting caspase-3/PARP both in vitro and in vivo, indicating that romidepsin is a potential therapeutic agent for CCA.

Celastrol Induced DNA Damage, Cell Cycle Arrest, and Apoptosis in Human Rheumatoid Fibroblast-Like Synovial Cells

2013 ◽  
Vol 41 (03) ◽  
pp. 615-628 ◽  
Author(s):  
Zengtao Xu ◽  
Guosheng Wu ◽  
Xu Wei ◽  
Xiuping Chen ◽  
Yitao Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Inflammatory Diseases ◽  
Annexin V ◽  
Synovial Fibroblasts ◽  
Damage Cell ◽  
Cycle Arrest ◽  
M Phase

Celastrol is one of the principal active ingredients of Tripterygium wilfordii Hook.f., a toxic Chinese medical herb traditionally prescribed for controlling pain and inhibiting inflammation in various chronic inflammatory diseases, including rheumatoid arthritis (RA). Resistance to apoptosis of fibroblast-like synoviocytes is considered a major characteristic of RA. In this study, we test celastrol's cytotoxic effect and potential mechanisms in human rheumatoid synovial fibroblasts (RA-FLS). In the cytotoxic assay, we found that celastrol dose-dependently decreased RA-FLS viability and increased LDH release. The apoptotic nuclear morphology was observed after celastrol treatment as determined by DAPI fluorescence staining. Flow cytometry analysis with PI and Annexin V revealed that celastrol induced RA-FLS cell cycle arrest in the G2/M phase and apoptosis. Furthermore, celastrol dramatically increased expression of Bax/Bcl-2, proteolytic cleavage of Caspase-3, -9, PARP, and decreased expression of FasR. In addition, celastrol treatment resulted in DNA damage. Collectively, we concluded that celastrol inhibits RA-FLS proliferation by inducing DNA damage, cell cycle arrest, and apoptosis in vitro, which might provide data for its application in RA treatment.

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