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Cell Cycle and Cell Cycle Targeting Cancer Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 22623

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Special Issue Editor

Prof. Dr. Sibylle Mittnacht

E-Mail Website
Guest Editor

UCL Cancer Institute, University College London, London WC1E 6DD, UK
Interests: cell cycle; cell cycle checkpoints; DNA damage response; radiation biology; molecular targeted cancer therapy; solid tumour biology

Special Issue Information

Dear Colleagues,

Stringent control of the cell division cycle is a prerequisite for the precise formation of organs during metazoan development and is vital in adults for tissue renewal and tissue repair. In turn, cell cycle deregulation leads to diseases including Alzheimer’s and cancer. Understanding the molecular events involved in the control of cell division cycle is of fundamental relevance to understanding these processes.

While the principle of cell cycle control is a textbook matter, detailed studies continue to yield unexpected discoveries that challenge established textbook views. For example, cell cycle control appears to substantially differ between lineage-committed and pluripotent cells, with questions on how these differences come about molecularly, and whether they are the consequence or the cause of pluripotency and/or its dissolution. How the cell cycle machinery integrates information from the plethora of events known to control cell proliferation, how cell cycle exit into quiescence is facilitated, and to what extent events that facilitate quiescence are involved in driving permanent, irreversible exit, typified by senescence and terminal differentiation, lack definite answers.

There is now firm recognition that cell cycle defects cause genomic instability and determine therapy response in cancer, and hence contribute to cancer outcomes in ways beyond the deregulated production of cell progeny. A growing number of therapeutic strategies seek to rectify or exploit cell cycle defects for cancer treatment. For example, pharmacological inhibitors targeting the cell cycle-regulatory CDK4/6 kinases are transforming the treatment of hormone-dependent breast cancer, yet strategies involving these inhibitors have not yet been successful in other cancer types. Genomic and pharmacological screens highlight vulnerabilities caused by cell cycle defects and checkpoint overuse with the promise of selective therapeutic potential in cancers with these specific features. This Special Issue seeks to capture evolving novel insight into cell cycle control, to showcase new technologies that drive discovery in cell cycle research and to highlight opportunities and challenges of cell-cycle-targeting strategies for the rational treatment of diseases including cancer.

Prof. Dr. Sibylle Mittnacht
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cell cycle checkpoint
cell cycle control
cell cycle dynamics
mitosis
endoreplication
ploidy
interphase
high content analysis
systems biology
network biology
cell fate
senescence
quiescence
pluripotency
restriction point
self-renewal
cancer
cancer therapy response
cell cycle targeting therapeutics
synthetic lethality
DNA replication
DNA replication stress
DNA damage checkpoint
ploidy checkpoint
mitotic instability
mitotic nondisjunction
genomic instability

Published Papers (6 papers)

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Research

Jump to: Review

36 pages, 5777 KiB

Open AccessArticle

Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones

by Magdalena Perużyńska, Aleksandra Borzyszkowska-Ledwig, Jacek G. Sośnicki, Łukasz Struk, Tomasz J. Idzik, Gabriela Maciejewska, Łukasz Skalski, Katarzyna Piotrowska, Paweł Łukasik, Marek Droździk and Mateusz Kurzawski

Int. J. Mol. Sci. 2021, 22(5), 2462; https://doi.org/10.3390/ijms22052462 - 28 Feb 2021

Cited by 4 | Viewed by 2441

Abstract

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine analogue (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC₅₀ equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells. Full article

(This article belongs to the Special Issue Cell Cycle and Cell Cycle Targeting Cancer Therapies)

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14 pages, 1455 KiB

Open AccessArticle

Silencing DNA Polymerase β Induces Aneuploidy as a Biomarker of Poor Prognosis in Oral Squamous Cell Cancer

by Hui-Ching Wang, Leong-Perng Chan, Chun-Chieh Wu, Shu-Jyuan Chang, Sin-Hua Moi, Chi-Wen Luo and Mei-Ren Pan

Int. J. Mol. Sci. 2021, 22(5), 2402; https://doi.org/10.3390/ijms22052402 - 27 Feb 2021

Cited by 3 | Viewed by 2040

Abstract

Most patients with oral squamous cell cancer (OSCC) have a locally advanced stage at diagnosis. The treatment strategies are diverse, including surgery, radiotherapy and chemotherapy. Despite multimodality treatment, the response rate is unsatisfactory. DNA repair and genetic instability are highly associated with carcinogenesis and treatment outcomes in oral squamous cell cancer, affecting cell growth and proliferation. Therefore, focusing on DNA repair and genetic instability interactions could be a potential target for improving the outcomes of OSCC patients. DNA polymerase-β (POLB) is an important enzyme in base excision repair and contributes to gene instability, leading to tumorigenesis and cancer metastasis. The aim of our study was to confirm POLB regulates the growth of OSCC cells through modulation of cell cycle and chromosomal instability. We analyzed a tissue array from 133 OSCC patients and discovered that low POLB expression was associated with advanced tumor stage and poor overall survival. In multivariate Cox proportional hazards regression analysis, low POLB expression and advanced lymph node status were significantly associated with poor survival. By performing in vitro studies on model cell lines, we demonstrated that POLB silencing regulated cell cycles, exacerbated mitotic abnormalities and enhanced cell proliferation. After POLB depletion, OSCC cells showed chromosomal instability and aneuploidy. Thus, POLB is an important maintainer of karyotypic stability in OSCC cells. Full article

(This article belongs to the Special Issue Cell Cycle and Cell Cycle Targeting Cancer Therapies)

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18 pages, 3544 KiB

Open AccessArticle

Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death against Human Non-Small Cell Lung Cancers

by Ya-Ching Chang, Yu-Ling Tseng, Wohn-Jenn Leu, Chi-Min Du, Yi-Huei Jiang, Lih-Ching Hsu, Jui-Ling Hsu, Duen-Ren Hou and Jih-Hwa Guh

Int. J. Mol. Sci. 2020, 21(16), 5608; https://doi.org/10.3390/ijms21165608 - 05 Aug 2020

Cited by 2 | Viewed by 2507

Abstract

Non-small cell lung cancer (NSCLC) accounts about 80% of all lung cancers. More than two-thirds of NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities of chemotherapeutic drugs are in high demand. YL-9 was a novel and non-cytotoxic compound with the structure related to sildenafil but showing much less activity against phosphodiesterase type 5 (PDE5). NCI-H460, an NSCLC cell line with low PDE5 expression, was used as the cell model. YL-9 synergistically potentiated vinorelbine-induced anti-proliferative and apoptotic effects in NCI-H460 cells. Vinorelbine induced tubulin acetylation and Bub1-related kinase (BUBR1) phosphorylation, a necessary component in spindle assembly checkpoint. These effects, as well as BUBR1 cleavage, were substantially enhanced in co-treatment with YL-9. Several mitotic arrest signals were enhanced under combinatory treatment of vinorelbine and YL-9, including an increase of mitotic spindle abnormalities, increased cyclin B1 expression, B-cell lymphoma 2 (Bcl-2) phosphorylation and increased phosphoproteins. Moreover, YL-9 also displayed synergistic activity in combining with vinorelbine to induce apoptosis in A549 cells which express PDE5. In conclusion. the data suggest that YL-9 is a novel agent that synergistically amplifies vinorelbine-induced NSCLC apoptosis through activation of spindle assembly checkpoint and increased mitotic arrest of the cell cycle. YL-9 shows the potential for further development in combinatory treatment against NSCLC. Full article

(This article belongs to the Special Issue Cell Cycle and Cell Cycle Targeting Cancer Therapies)

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Graphical abstract

20 pages, 1887 KiB

Open AccessArticle

Reversible Growth-Arrest of a Spontaneously-Derived Human MSC-Like Cell Line

by Catharina Melzer, Roland Jacobs, Thomas Dittmar, Andreas Pich, Juliane von der Ohe, Yuanyuan Yang and Ralf Hass

Int. J. Mol. Sci. 2020, 21(13), 4752; https://doi.org/10.3390/ijms21134752 - 03 Jul 2020

Cited by 16 | Viewed by 3150

Abstract

Life cycle limitation hampers the production of high amounts of primary human mesenchymal stroma-/stem-like cells (MSC) and limits cell source reproducibility for clinical applications. The characterization of permanently growing MSC544 revealed some differentiation capacity and the simultaneous presence of known MSC markers CD73, CD90, and CD105 even after continuous long-term culture for more than one year and 32 passages. The expression of CD13, CD29, CD44, and CD166 were identified as further surface proteins, all of which were also simultaneously detectable in various other types of primary MSC populations derived from the umbilical cord, bone marrow, and placenta suggesting MSC-like properties in the cell line. Proliferating steady state MSC544 exhibited immune-modulatory activity similar to a subpopulation of long-term growth-inhibited MSC544 after 189d of continuous culture in confluency. This confluent connective cell layer with fibroblast-like morphology can spontaneously contract and the generated space is subsequently occupied by new cells with regained proliferative capacity. Accordingly, the confluent and senescence-associated beta-galactosidase-positive MSC544 culture with about 95% G0/G1 growth-arrest resumed re-entry into the proliferative cell cycle within 3d after sub-confluent culture. The MSC544 cells remained viable during confluency and throughout this transition which was accompanied by marked changes in the release of proteins. Thus, expression of proliferation-associated genes was down-modulated in confluent MSC544 and re-expressed following sub-confluent conditions whilst telomerase (hTERT) transcripts remained detectable at similar levels in both, confluent growth-arrested and proliferating MSC544. Together with the capability of connective cell layer formation for potential therapeutic approaches, MSC544 provide a long term reproducible human cell source with constant properties. Full article

(This article belongs to the Special Issue Cell Cycle and Cell Cycle Targeting Cancer Therapies)

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21 pages, 10647 KiB

Open AccessArticle

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

by Ying-Ming Tsai, Kuan-Li Wu, Yung-Yun Chang, Jen-Yu Hung, Wei-An Chang, Chao-Yuan Chang, Shu-Fang Jian, Pei-Hsun Tsai, Yung-Chi Huang, Inn-Wen Chong and Ya-Ling Hsu

Int. J. Mol. Sci. 2020, 21(5), 1640; https://doi.org/10.3390/ijms21051640 - 28 Feb 2020

Cited by 19 | Viewed by 2780

Abstract

Lung cancer is one of the leading causes of cancer-related death globally, thus elucidation of its molecular pathology is highly highlighted. Aberrant alterations of the spindle assembly checkpoint (SAC) are implicated in the development of cancer due to abnormal cell division. TTK (Thr/Tyr kinase), a dual serine/threonine kinase, is considered to act as a cancer promoter by controlling SAC. However, the mechanistic details of how TTK-mediated signaling network supports cancer development is still a mystery. Here, we found that TTK was upregulated in the tumor tissue of patients with lung cancer, and enhanced tumor growth and metastasis in vitro and in vivo. Mechanistically, TTK exerted a significant enhancement in cancer growth by neurotensin (NTS) upregulation, and subsequently increased the expression of cyclin A and cdk2, which was resulting in the increase of DNA synthesis. In contrast, TTK increased cell migration and epithelial-to-mesenchymal transition (EMT) by enhancing the expression of dihydropyrimidinase-like 3 (DPYSL3) followed by the increase of snail-regulated EMT, thus reinforce metastatic potential and ultimately tumor metastasis. TTK and DPYSL3 upregulation was positively correlated with a poor clinical outcome in patients with lung cancer. Together, our findings revealed a novel mechanism underlying the oncogenic potential effect of TTK and clarified its downstream factors NTS and DPYSL3 might represent a novel, promising candidate oncogenes with potential therapeutic vulnerabilities in lung cancer. Full article

(This article belongs to the Special Issue Cell Cycle and Cell Cycle Targeting Cancer Therapies)

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Review

Jump to: Research

23 pages, 856 KiB

Open AccessReview

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

by Michela Piezzo, Stefania Cocco, Roberta Caputo, Daniela Cianniello, Germira Di Gioia, Vincenzo Di Lauro, Giuseppina Fusco, Claudia Martinelli, Francesco Nuzzo, Matilde Pensabene and Michelino De Laurentiis

Int. J. Mol. Sci. 2020, 21(18), 6479; https://doi.org/10.3390/ijms21186479 - 04 Sep 2020

Cited by 71 | Viewed by 9012

Abstract

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment. Full article

(This article belongs to the Special Issue Cell Cycle and Cell Cycle Targeting Cancer Therapies)

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