Coupling Kinesin Spindle Protein and Aurora B Inhibition with Apoptosis Induction Enhances Oral Cancer Cell Killing

Silva, João P. N.; Pinto, Bárbara; Monteiro, Luís; Silva, Patrícia M. A.; Bousbaa, Hassan

doi:10.3390/cancers16112014

Coupling Kinesin Spindle Protein and Aurora B Inhibition with Apoptosis Induction Enhances Oral Cancer Cell Killing

Journal Article · Sat May 25 00:00:00 EDT 2024 · Cancers (Basel)

DOI:https://doi.org/10.3390/cancers16112014· OSTI ID:2367249

; Pinto, Bárbara; Monteiro, Luís; ;

Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness.

View Journal Article

Sponsoring Organization:: USDOE Office of Energy Efficiency and Renewable Energy (EERE), Transportation Office. Fuel Cell Technologies Office

OSTI ID:: 2367249

Journal Information:: Cancers (Basel), Journal Name: Cancers (Basel) Journal Issue: 11 Vol. 16; ISSN CANCCT; ISSN 2072-6694

Publisher:: MDPI AGCopyright Statement

Country of Publication:: Switzerland

Language:: English

References (45)

Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer Qi, Guangying; Ogawa, Ikuko; Kudo, Yasusei Virchows Archiv, Vol. 450, Issue 3 https://doi.org/10.1007/s00428-006-0360-9	journal	January 2007
A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group trial Lee, Christopher W.; Bélanger, Karl; Rao, Sanjay C. Investigational New Drugs, Vol. 26, Issue 3 https://doi.org/10.1007/s10637-007-9097-9	journal	October 2007
Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck Tang, Patricia A.; Siu, Lillian L.; Chen, Eric X. Investigational New Drugs, Vol. 26, Issue 3 https://doi.org/10.1007/s10637-007-9098-8	journal	November 2007
Human papillomavirus infection and oral squamous cell carcinoma - a systematic review Melo, Bernardo Augusto de Carvalho; Vilar, Luisa Gallo; Oliveira, Natália Rodrigues de Brazilian Journal of Otorhinolaryngology, Vol. 87, Issue 3 https://doi.org/10.1016/j.bjorl.2020.10.017	journal	May 2021
Suppression of spindly delays mitotic exit and exacerbates cell death response of cancer cells treated with low doses of paclitaxel Silva, Patrícia M. A.; Ribeiro, Nilza; Lima, Raquel T. Cancer Letters, Vol. 394 https://doi.org/10.1016/j.canlet.2017.02.024	journal	May 2017
Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling Roy, Babhrubahan; Han, Simon J. Y.; Fontan, Adrienne N. Current Biology, Vol. 32, Issue 1 https://doi.org/10.1016/j.cub.2021.10.049	journal	January 2022
Novel therapies in the management of oral cancer: An update Nandini, D. B.; Rao, Roopa. S.; Hosmani, Jagadish Disease-a-Month, Vol. 66, Issue 12 https://doi.org/10.1016/j.disamonth.2020.101036	journal	December 2020
Microtubule-targeting agents and their impact on cancer treatment Čermák, Vladimír; Dostál, Vojtěch; Jelínek, Michael European Journal of Cell Biology, Vol. 99, Issue 4 https://doi.org/10.1016/j.ejcb.2020.151075	journal	May 2020
Lip and Oral Cavity Squamous Cell Carcinoma Howard, Adam; Agrawal, Nishant; Gooi, Zhen Hematology/Oncology Clinics of North America, Vol. 35, Issue 5 https://doi.org/10.1016/j.hoc.2021.05.003	journal	October 2021
Artelastin is a cytotoxic prenylated flavone that disturbs microtubules and interferes with DNA replication in MCF-7 human breast cancer cells Pedro, Madalena; Ferreira, Maria Manuel; Cidade, Honorina Life Sciences, Vol. 77, Issue 3 https://doi.org/10.1016/j.lfs.2004.09.049	journal	June 2005
Bcl-xL expression and regulation in the progression, recurrence, and cisplatin resistance of oral cancer Alam, Manzar; Mishra, Rajakishore Life Sciences, Vol. 280 https://doi.org/10.1016/j.lfs.2021.119705	journal	September 2021
Combinatorial approaches targeting the EGFR family and c-Met in SCCHN Wang, Dongsheng; Lu, Yue; Nannapaneni, Sreenivas Oral Oncology, Vol. 112 https://doi.org/10.1016/j.oraloncology.2020.105074	journal	January 2021
Cancer of the Oral Cavity Montero, Pablo H.; Patel, Snehal G. Surgical Oncology Clinics of North America, Vol. 24, Issue 3 https://doi.org/10.1016/j.soc.2015.03.006	journal	July 2015
Kinesin-5 Regulation and Function in Mitosis Mann, Barbara J.; Wadsworth, Patricia Trends in Cell Biology, Vol. 29, Issue 1 https://doi.org/10.1016/j.tcb.2018.08.004	journal	January 2019
The Phytochemical Scoulerine Inhibits Aurora Kinase Activity to Induce Mitotic and Cytokinetic Defects Li, Jinhua; Yan, Ziqi; Li, Hongmei Journal of Natural Products, Vol. 84, Issue 8 https://doi.org/10.1021/acs.jnatprod.1c00429	journal	August 2021
Dysregulated expression of bcl‐2 and bax in oral carcinomas: evidence of post‐transcriptional control Chen, Yu; Kayano, Teruo; Takagi, Minoru Journal of Oral Pathology & Medicine, Vol. 29, Issue 2 https://doi.org/10.1034/j.1600-0714.2000.290203.x	journal	February 2000
p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases Marxer, M.; Ma, H. T.; Man, W. Y. Oncogene, Vol. 33, Issue 27 https://doi.org/10.1038/onc.2013.325	journal	August 2013
Kinesin-5 Eg5 is essential for spindle assembly, chromosome stability and organogenesis in development Yu, Wen-Xin; Li, Yu-Kun; Xu, Meng-Fei Cell Death Discovery, Vol. 8, Issue 1 https://doi.org/10.1038/s41420-022-01281-1	journal	December 2022
Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent–induced mitotic arrest Tsuda, Yasuo; Iimori, Makoto; Nakashima, Yuichiro Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-17002-z	journal	December 2017
Mitotic slippage: an old tale with a new twist Sinha, Debottam; Duijf, Pascal H. G.; Khanna, Kum Kum Cell Cycle, Vol. 18, Issue 1 https://doi.org/10.1080/15384101.2018.1559557	journal	January 2019
The proliferation rate paradox in antimitotic chemotherapy Mitchison, Timothy J. Molecular Biology of the Cell, Vol. 23, Issue 1 https://doi.org/10.1091/mbc.e10-04-0335	journal	January 2012
Kinesin molecular motor Eg5 functions during polypeptide synthesis Bartoli, Kristen M.; Jakovljevic, Jelena; Woolford, John L. Molecular Biology of the Cell, Vol. 22, Issue 18 https://doi.org/10.1091/mbc.e11-03-0211	journal	September 2011
Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors Boss, D. S.; Witteveen, P. O.; van der Sar, J. Annals of Oncology, Vol. 22, Issue 2 https://doi.org/10.1093/annonc/mdq344	journal	February 2011
Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases Salmela, Anna-Leena; Pouwels, Jeroen; Mäki-Jouppila, Jenni Carcinogenesis, Vol. 34, Issue 2 https://doi.org/10.1093/carcin/bgs339	journal	October 2012
Navitoclax (ABT-263) Accelerates Apoptosis during Drug-Induced Mitotic Arrest by Antagonizing Bcl-xL Shi, Jue; Zhou, Yuan; Huang, Hsiao-Chun Cancer Research, Vol. 71, Issue 13 https://doi.org/10.1158/0008-5472.CAN-10-4336	journal	June 2011
Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models Tan, Nguyen; Malek, Mehnaz; Zha, Jiping Clinical Cancer Research, Vol. 17, Issue 6 https://doi.org/10.1158/1078-0432.CCR-10-2353	journal	March 2011
Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo Helfrich, Barbara A.; Kim, Jihye; Gao, Dexiang Molecular Cancer Therapeutics, Vol. 15, Issue 10 https://doi.org/10.1158/1535-7163.MCT-16-0298	journal	October 2016
Aurora B Expression as a Prognostic Indicator and Possibile Therapeutic Target in Oral Squamous Cell Carcinoma Pannone, G.; Hindi, S. A. H.; Santoro, A. International Journal of Immunopathology and Pharmacology, Vol. 24, Issue 1 https://doi.org/10.1177/039463201102400110	journal	January 2011
Combining Paclitaxel with ABT-263 Has a Synergistic Effect on Paclitaxel Resistant Prostate Cancer Cells Wang, Chihuei; Huang, Shih-Bo; Yang, Min-Chi PLOS ONE, Vol. 10, Issue 3 https://doi.org/10.1371/journal.pone.0120913	journal	March 2015
Aurora B prevents premature removal of spindle assembly checkpoint proteins from the kinetochore: A key role for Aurora B in mitosis Gurden, Mark D.; Anderhub, Simon J.; Faisal, Amir Oncotarget, Vol. 9, Issue 28 https://doi.org/10.18632/oncotarget.10657	journal	July 2016
Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5 Exertier, Prisca; Javerzat, Sophie; Wang, Baigang Oncotarget, Vol. 4, Issue 12 https://doi.org/10.18632/oncotarget.1490	journal	October 2013
Combination therapy in combating cancer Mokhtari, Reza Bayat; Homayouni, Tina S.; Baluch, Narges Oncotarget, Vol. 8, Issue 23 https://doi.org/10.18632/oncotarget.16723	journal	March 2017
Aurora B: A New Prognostic Marker and Therapeutic Target in Cancer Portella, G.; Passaro, C.; Chieffi, P. Current Medicinal Chemistry, Vol. 18, Issue 4 https://doi.org/10.2174/092986711794480203	journal	February 2011
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries Sung, Hyuna; Ferlay, Jacques; Siegel, Rebecca L. CA: A Cancer Journal for Clinicians, Vol. 71, Issue 3 https://doi.org/10.3322/caac.21660	journal	February 2021
The Evolving Role of Taxanes in Combination With Cetuximab for the Treatment of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck: Evidence, Advantages, and Future Directions Guigay, Joël; Tahara, Makoto; Licitra, Lisa Frontiers in Oncology, Vol. 9 https://doi.org/10.3389/fonc.2019.00668	journal	August 2019
Bcl-xL activity influences outcome of the mitotic arrest Suleimenov, M.; Bekbayev, S.; Ten, M. Frontiers in Pharmacology, Vol. 13 https://doi.org/10.3389/fphar.2022.933112	journal	September 2022
Assessment of MicroRNA (miR)-365 Effects on Oral Squamous Carcinoma Cell Line Phenotypes Coon, Jeffrey; Kingsley, Karl Biomolecules, Vol. 11, Issue 6 https://doi.org/10.3390/biom11060874	journal	June 2021
Cancer Metabolism and the Evasion of Apoptotic Cell Death Sharma, Aditi; Boise, Lawrence; Shanmugam, Mala Cancers, Vol. 11, Issue 8 https://doi.org/10.3390/cancers11081144	journal	August 2019
Eg5 as a Prognostic Biomarker and Potential Therapeutic Target for Hepatocellular Carcinoma Shao, Yu-Yun; Sun, Nai-Yun; Jeng, Yung-Ming Cells, Vol. 10, Issue 7 https://doi.org/10.3390/cells10071698	journal	July 2021
STAT3 and Its Targeting Inhibitors in Oral Squamous Cell Carcinoma Jiang, Mingjing; Li, Bo Cells, Vol. 11, Issue 19 https://doi.org/10.3390/cells11193131	journal	October 2022
Proliferation and Apoptosis Pathways and Factors in Oral Squamous Cell Carcinoma He, Steven; Chakraborty, Rajdeep; Ranganathan, Shoba International Journal of Molecular Sciences, Vol. 23, Issue 3 https://doi.org/10.3390/ijms23031562	journal	January 2022
Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer Borah, Naheed Arfin; Reddy, Mamatha M. Molecules, Vol. 26, Issue 7 https://doi.org/10.3390/molecules26071981	journal	April 2021
Second-Generation Antimitotics in Cancer Clinical Trials Novais, Pedro; Silva, Patrícia M. A.; Amorim, Isabel Pharmaceutics, Vol. 13, Issue 7 https://doi.org/10.3390/pharmaceutics13071011	journal	July 2021
Navitoclax Enhances the Therapeutic Effects of PLK1 Targeting on Lung Cancer Cells in 2D and 3D Culture Systems Pinto, Bárbara; Novais, Pedro; Henriques, Ana C. Pharmaceutics, Vol. 14, Issue 6 https://doi.org/10.3390/pharmaceutics14061209	journal	June 2022
Maximizing Anticancer Response with MPS1 and CENPE Inhibition Alongside Apoptosis Induction Pinto, Bárbara; Silva, João P. N.; Silva, Patrícia M. A. Pharmaceutics, Vol. 16, Issue 1 https://doi.org/10.3390/pharmaceutics16010056	journal	December 2023

Similar Records

Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer

Journal Article · Wed Jun 10 00:00:00 EDT 2009 · Clinical Cancer Research · OSTI ID:1008325

The structure of the ternary Eg5–ADP–ispinesib complex

Journal Article · Mon Oct 01 00:00:00 EDT 2012 · Acta Crystallographica. Section D: Biological Crystallography · OSTI ID:22347861

Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells

Journal Article · Thu Sep 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology · OSTI ID:21587838

Coupling Kinesin Spindle Protein and Aurora B Inhibition with Apoptosis Induction Enhances Oral Cancer Cell Killing

Citation Formats

References (45)

Similar Records

Related Subjects