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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
Polo-like kinase 1 (PLK1) facilitates mitotic entry and exit. Overexpression leads to aneuploidy, chromosomal instability, and neoplastic transformation [99]. Likewise, a small molecule inhibitor of PLK1 (BI 2536) suppressed colony and tumor sphere formation, inhibited cell growth, and increased apoptosis in vitro; moreover, PLK1 inhibition enhanced radiosensitivity of high-MYC expressing medulloblastoma cell lines [100]. Finally, the CDK4/6 inhibitor, palbociclib, was shown to decrease tumor cell proliferation, to increase apoptosis, and to improve survival in an orthotopic mouse model of MYC-overexpressing Group 3 MB [101].
Genetics of mammalian meiosis
Published in C. Yan Cheng, Spermatogenesis, 2018
While the identification and characterization of these meiosis-specific structural proteins have elucidated their role in SC formation, the mechanism regulating SC disassembly is poorly understood. In budding yeast, polo-like kinase Cdc5 promotes SC disassembly at the end of the pachytene stage.47 In mouse spermatocytes, polo-like kinase 1 (PLK1) localizes to the SC.48 PLK1 phosphorylates SYCP1 and TEX12. Treatment of spermatocytes with the PLK1 inhibitor prevents removal of SYCP1 and TEX12 from the SC.48 In addition, PLK1 promotes dissociation of REC8 and RAD21L from SC.39 Although a Plk1 mouse mutant is needed to address its in vivo requirement, the PLK1 function in SC disassembly appears to be conserved between yeast and mouse.
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Volasertib is a small molecule polo-like kinase (PLK1) inhibitor which was noted to result in remissions in 31% of patients, compared to 13% in the control arm, with an improved disease-free survival but no overall survival in a randomized phase 2 trial in combination with low-dose cytarabine in newly diagnosed older AML patients considered to be unfit for conventional treatment.32 PLK1 is vital for spindle assembly during cellular mitosis. Based on these response rates and acceptable toxicity, the drug is now being tested in a randomized phase 3 trial (POLO-AML-2) and has been accorded a ‘breakthrough therapy’ designation by the US Food and Drug Administration (FDA).
Polo-like Kinase 1 as an emerging drug target: structure, function and therapeutic implications
Published in Journal of Drug Targeting, 2021
Ilma Shakeel, Neha Basheer, Gulam Mustafa Hasan, Mohammad Afzal, Md. Imtaiyaz Hassan
PLK1 is a mitotic kinase, regulates verities of cellular processes, and is considered as an attractive drug target for cancer therapy. PLK1 inhibition mediates G2/M cell cycle arrest. Overexpression of PLK1 is directly associated with the tumour progression and stages of cancer. Structurally, PLK1 is divided into two distinct domains, one is catalytic kinase and another is regulatory PBD which triggers specific subcellular localisation by interacting with phosphorylation sites of targeted substrates. Inhibition of PLK1 by designed inhibitors of RNAi technology significantly affects the spindle assembly and cell growth. Several in vivo reports in mice models advocating the PLK1 inhibition directly control the tumour growth and metastasis. There are many PLK1 inhibitors are currently in different stages of clinical trials for cancer therapy. However, many of them showed limited selectivity. Several new approaches should be implemented to improve binding affinity, and selectivity of designed inhibitors, while maintaining the stability and bioavailability.
Comparison of cationic liposome and PAMAM dendrimer for delivery of anti-Plk1 siRNA in breast cancer treatment
Published in Pharmaceutical Development and Technology, 2020
Upendra Bulbake, Nagavendra Kommineni, Maksim Ionov, Maria Bryszewska, Wahid Khan
Polo-like kinase 1 is a serine/threonine kinase enzyme encoded by the Plk1 gene (Barr et al. 2004). Activity of Plk1 gene is elevated in proliferating cancer cells (Strebhardt and Ullrich 2006). The significance of Plk1 in tumor and for envisaging effects in patients with cancer results from its involvement in oncogenic transformation (Zhang et al. 2013). The supression of Plk1 with anti-PLk1 siRNA (siPlk1) leads to mitotic arrest, apoptosis and inhibition of tumor growth (Spa¨nkuch-Schmitt et al. 2002). However, delivery of siRNA is difficult because they are highly negatively charged molecules thus they are not able cross cell membranes easily. Moreover, due to their short circulation half-life, degradation by RNase enzyme and poor serum stability, it requires effective delivery system to overcome the number of cellular barriers (Kim and Rossi 2007). TKM-080301 is a lipid nanoparticle formulation of siPlk1 present in phase I clinical trial for the treatment of hepatocellular carcinoma (Bulbake et al. 2017). Patients receive single dose of TKM-080301 given directly into the liver through Hepatic Arterial Infusion (HAI). However, drugs used thus far in HAI have limited efficacy.
Assessment of CEP55, PLK1 and FOXM1 expression in patients with bladder cancer in comparison with healthy individuals
Published in Cancer Investigation, 2018
Saman Seyedabadi, Massoud Saidijam, Rezvan Najafi, Seyed Habibollah Mousavi-Bahar, Mohammad Jafari, Sajjad MohammadGanji, Ali Mahdavinezhad
CEP55 activates PI3K/AKT and FOXM1 dependent pathways in cancer (1). FOXM1 is expressed in actively dividing cells and plays major role in progression of cell cycle (23,24). CEP55 is supposed to be a direct transcriptional target of FOXM1 and linked to the prognosis of breast cancer (25). However, the expression pattern and biological significance of FOXM1 in BC is not known (9). It has been reported that CEP55 enhances expression. Besides, PLK1 and CEP55 are both transcriptional targets of FOXM1. PLK1 phosphorylates FOXM1, thereby making a positive feedback loops as well as phosphorylates CEP55, in turn, supporting its stability (26). PLK1 is a serine/threonine kinase that acts as vital regulator of mitosis and maintains genome stability (27). These mechanisms are supported by our findings so that a direct correlation was observed between higher expression of CEP55 and FOXM1 and between increased expression of FOXM1 and PLK1 in urinary bladder tumor specimens which Waseem et al. reported positive correlation between FOXM1 and CEP55 as a downstream target of FOXM1, too (28).