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      Phosphodiesterase Type 5 Inhibitors Synergize Vincristine in Killing Castration-Resistant Prostate Cancer Through Amplifying Mitotic Arrest Signaling

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          Abstract

          Combination therapies that display cancer-killing activities through either coexistent targeting of several cellular factors or more efficient suppression of a specific pathway are generally used in cancer treatment. Sildenafil, a specific phosphodiesterase type 5 (PDE5) inhibitor, has been suggested to display both cardioprotective and neuroprotective activities that provide a rationale for the combination with vincristine on the treatment against castration-resistant prostate cancer (CRPC). In the present work, vincristine arrested cells in the metaphase stage of mitosis. Vincristine-induced mitotic arrest was identified by Cdk1 activation (i.e., increased Cdk1 Thr161 phosphorylation and decreased Cdk1 Tyr15 phosphorylation), cyclin B1 upregulation, and increased phosphorylation of multiple mitotic proteins and stathmin. Sildenafil synergistically potentiated vincristine-induced mitotic arrest and a dramatic increase of mitotic index. Furthermore, sildenafil potentiated vincristine-induced mitochondrial damage, including Mcl-1 downregulation, Bcl-2 phosphorylation and downregulation, Bak upregulation and loss of mitochondrial membrane potential, and sensitized caspase-dependent apoptotic cell death. Sildenafil-mediated synergistic effects were mimicked by other PDE5 inhibitors including vardenafil and tadalafil, and also by PDE5A knockdown in cells, suggesting PDE5-involved mechanism. Notably, sildenafil amplified vincristine-induced phosphorylation and cleavage of BUBR1, a protein kinase in spindle assembly checkpoint (SAC) function and chromosome segregation. Sildenafil also significantly decreased kinetochore tension during SAC activation. Moreover, sildenafil synergized with vincristine on suppressing tumor growth in an in vivo model. In conclusion, the data suggest that sildenafil, in a PDE5-dependent manner, potentiates vincristine-induced mitotic arrest signaling, and sensitizes mitochondria damage–involved apoptosis in CRPC. Both in vitro and in vivo data suggest the combination potential of PDE5 inhibitors and vincristine on CRPC treatment.

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          Most cited references37

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          Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2

          The mitotic checkpoint prevents cells with unaligned chromosomes from prematurely exiting mitosis by inhibiting the anaphase-promoting complex/cyclosome (APC/C) from targeting key proteins for ubiquitin-mediated proteolysis. We have examined the mechanism by which the checkpoint inhibits the APC/C by purifying an APC/C inhibitory factor from HeLa cells. We call this factor the mitotic checkpoint complex (MCC) as it consists of hBUBR1, hBUB3, CDC20, and MAD2 checkpoint proteins in near equal stoichiometry. MCC inhibitory activity is 3,000-fold greater than that of recombinant MAD2, which has also been shown to inhibit APC/C in vitro. Surprisingly, MCC is not generated from kinetochores, as it is also present and active in interphase cells. However, only APC/C isolated from mitotic cells was sensitive to inhibition by MCC. We found that the majority of the APC/C in mitotic lysates is associated with the MCC, and this likely contributes to the lag in ubiquitin ligase activity. Importantly, chromosomes can suppress the reactivation of APC/C. Chromosomes did not affect the inhibitory activity of MCC or the stimulatory activity of CDC20. We propose that the preformed interphase pool of MCC allows for rapid inhibition of APC/C when cells enter mitosis. Unattached kinetochores then target the APC/C for sustained inhibition by the MCC.
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            Cohesin cleavage by separase required for anaphase and cytokinesis in human cells.

            Cell division depends on the separation of sister chromatids in anaphase. In yeast, sister separation is initiated by cleavage of cohesin by the protease separase. In vertebrates, most cohesin is removed from chromosome arms by a cleavage-independent mechanism. Only residual amounts of cohesin are cleaved at the onset of anaphase, coinciding with its disappearance from centromeres. We have identified two separase cleavage sites in the human cohesin subunit SCC1 and have conditionally expressed noncleavable SCC1 mutants in human cells. Our results indicate that cohesin cleavage by separase is essential for sister chromatid separation and for the completion of cytokinesis.
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              PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.

              The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement of stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and anti-cancer benefits. Despite mixed results of these clinical trials, there is a continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                07 August 2020
                2020
                : 10
                : 1274
                Affiliations
                [1] 1School of Pharmacy, College of Medicine, National Taiwan University , Taipei, Taiwan
                [2] 2Department of Pharmacy, New Taipei Municipal TuCheng Hospital, Chang Gung Memorial Hospital , New Taipei city, Taiwan
                [3] 3Department of Urology, Shuang Ho Hospital, Taipei Medical University , Taipei, Taiwan
                [4] 4Department of Urology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
                [5] 5Department of Urology, National Taiwan University Hospital College of Medicine , Taipei, Taiwan
                Author notes

                Edited by: Khalid A El Sayed, University of Louisiana at Monroe, United States

                Reviewed by: Victor M. Bolanos-Garcia, Oxford Brookes University, United Kingdom; William Taylor, University of Toledo, United States

                *Correspondence: Shih-Ping Liu spliu@ 123456ntuh.gov.tw

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2020.01274
                7427565
                32850387
                96f2b8dd-86a7-4c66-936a-5e946a5a720f
                Copyright © 2020 Hsu, Leu, Hsu, Ho, Liu and Guh.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 February 2020
                : 19 June 2020
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 42, Pages: 14, Words: 7432
                Funding
                Funded by: Ministry of Science and Technology 10.13039/100007225
                Award ID: MOST 107-2320-B-002-018-MY3
                Award ID: 106-2320-B-002-005-MY3
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                sildenafil,vincristine,castration-resistant prostate cancer,spindle assembly checkpoint,kinetochore tension

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