Therapeutic Potential of Mitotic Kinases’ Inhibitors in Cancers of the Gastrointestinal System

Javed, Aadil; Malagraba, Gianluca; Yarmohammadi, Mahdieh; Perelló-Reus, Catalina M.; Barceló, Carles; Rubio-Tomás, Teresa

doi:10.3390/futurepharmacol2030015

Cited by 5 publications

(11 citation statements)

References 137 publications

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“…Some mitotic kinase inhibitors, their targets and effects. Mitotic kinases are essential in the advancement of gastric cancer (GC) and present as potential targets for anti-cancer pharmacotherapeutics [43]. Several mitotic kinases have been used in GC including (i) Cyclin-Dependent Kinases (CDKs): are crucial regulators of the cell cycle and DNA damage response, and their overexpression is observed in various cancers, including GC [44].…”

Section: Mitotic Kinase Inhibitorsmentioning

confidence: 99%

“…The following mitotic kinase inhibitors show promise as potential therapeutic options for liver, pancreatic, and colorectal cancers [43]. Further research and clinical trials are ongoing to explore their efficacy and safety in combination anti-cancer therapy.…”

Section: Mitotic Kinase Inhibitors Used Against Gastric Cancersmentioning

confidence: 99%

“…Aurora Kinase Inhibition (MLN8237, SNS-314) with sorafenib reduces tumor growth. PLK1 Inhibition (Volasertib, GSK461364, Rigosertib, Danusertib) targets p53-mutated cells and may enhance treatment with BIRC5 inhibitor [43].…”

Section: Mitotic Kinase Inhibitors Used Against Liver Cancermentioning

confidence: 99%

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Mitotic Poisons In Cancer Pharmacotherapy

Mohamed,

Boye

2024

Preprint

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Background: Cell proliferation and the cell cycle are fundamental to tumor development, with mitosis playing a crucial role in cell division. Understanding the complexities of the cell cycle and mitosis is critical for cancer research, especially in the context of developing therapeutic strategies. Objective: This review highlights mitotic poisons as potential anti-cancer pharmacotherapeutics, particularly their structural and functional group diversity presenting opportunity for semi-synthesis of new derivatives with multi-target mechanisms relevant for cancer pharmacotherapeutics. Also, the review explores naturally occurring mitotic poisons and inhibitors of microtubule-dependent molecular motors as promising cancer pharmacotherapeutics. Methods: A comprehensive review of literature from 2004 to 2023 was conducted, covering studies on cell proliferation, mechanism of cell cycle regulation, mitosis, cytokinesis, and anti-cancer drug development. The published literature was collected primarily from PubMed, Scopus, Medline, Web of Science Core Collections, Google Scholar and other relevant scientific databases using keywords including but not limited to mitotic poisons and cancer, sources of mitotic poisons, mechanism of mitotic poisons, targets of mitotic poisons and structural diversity of mitotic poisons. The efficacy and limitations of various mitotic poisons and their impact on different cancer types were examined. Recent advancements in targeted therapeutic interventions for various cancers were also explored. Results: The effectiveness and limitations of mitotic poisons, including Taxanes, Epothilones, Colchicine, Vinca alkaloids, Berberine, Laulimalide, and Pseudolaric acid B, were highlighted. Drugs targeting mitotic kinases such as CDKs, Aurora kinases, PLK1, and WEE1 inhibitors were reported. Inhibiting kinesin motor proteins such as Eg5 and KIF15 to interfere with spindle formation and cell division were discussed, along with specific genomic alterations in KIF genes and the discovery of KIFC1 as potential for future research and drug development. Conclusion: Targeting microtubules and mitotic kinases, along with inhibiting kinesin motor proteins, show promise for cancer pharmacotherapeutics. The combination of targeted therapies, patient stratification based on biomarkers (such as low alpha-1 acid glycoprotein and high p63 expression), and exploration of alternative natural sources of mitotic poisons and analogues can significantly advance cancer pharmacotherapy to improve patient outcomes.

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Section: Mitotic Kinase Inhibitorsmentioning

confidence: 99%

Section: Mitotic Kinase Inhibitors Used Against Gastric Cancersmentioning

confidence: 99%

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Mitotic Poisons In Cancer Pharmacotherapy

Mohamed,

Boye

2024

Preprint

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“…132 In addition, this can alter the expression of cell cycle regulators, such as cyclin D1 and CDK4, which control the progression of cells through the cell cycle, and promote the development of cancer. 133,134 These changes in gene expression contribute to the development of liver damage and HCC, making it important to limit or avoid alcohol consumption, in order to reduce the risk of this disease.…”

Section: Alcohol Consumptionmentioning

confidence: 99%

Unraveling Key Signaling Pathways Altered in Hepatocellular Carcinoma

Shiragannavar¹,

Karunakara²,

Puttahanumantharayappa³

et al. 2023

Gene Expr

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Hepatocellular carcinoma (HCC) is becoming one of the major health problems, and the leading cause of cancer-related mortality globally. Its multifactorial risk factors remain as paramount challenges to the treatment of this deadly disease. The conventionally known risk factors that trigger HCC include hepatitis C virus (HCV), hepatitis B virus (HBV), excess alcohol consumption, and environmental toxins, such as aflatoxin, aristolochic acid, etc. All these risk factors activate the oncogenic signaling in the liver, and transform the normal liver into an HCC liver. Recently, globalization and the Western sedentary lifestyle have newly emerged as risk factors for HCC, which include obesity, metabolic syndrome, and associated clinical and pathological modalities. In addition, a number of cellular signaling pathways are derailed in HCC, and these pathways, which are altered in HCC, are known to be directly controlled by oncogenes, such as KRAS, BRAF, c-MYC, astrocyte elevated gene-1 (AEG-1), staphylococcal nuclease domain containing 1 (SND1), late SV40 factor (LSF), apoptosis-antagonizing transcription factor (AATF), WNT/β-catenin, TGF-β, etc. All these oncogenes activate the oncogenic signaling in HCC, and suppress the important cellular tumor suppressor protein activity, playing a prominent role in hepatocarcinogenesis, and its development and progression. The present review established a novel interconnected network between all these oncogene-associated proteins, in order to determine its role in deregulating normal cellular signaling pathways, and transforming these into oncogenic signaling. A number of these oncogenes regulate the miRNA-RISC-associated oncogenic signaling, and trigger oncogenic miRNA singling by downregulating various tumor suppressor genes.Therefore, therapeutically targeting these oncogenes and associated proteins would aid in the development of new drugs to treat HCC.

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“…Prostate cancer is a major health concern worldwide, particularly among men [1]. There are several proteins, which are overexpressed in Prostate cancer, associated with cell cycle-regulating pathways [2,3]. Cell cycle regulatory proteins are key targets for therapeutic interventions in various cancers [4].…”

Section: Introductionmentioning

confidence: 99%

HN1 Is Enriched in the S-Phase, Phosphorylated in Mitosis, and Contributes to Cyclin B1 Degradation in Prostate Cancer Cells

Javed

Özduman

Varisli

et al. 2023

Biology

Self Cite

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HN1 has previously been shown as overexpressed in various cancers. In Prostate cancer, it regulates AR signaling and centrosome-related functions. Previously, in two different studies, HN1 expression has been observed as inversely correlated with Cyclin B1. However, HN1 interacting partners and the role of HN1 interactions in cell cycle pathways have not been completely elucidated. Therefore, we used Prostate cancer cell lines again and utilized both transient and stable inducible overexpression systems to delineate the role of HN1 in the cell cycle. HN1 characterization was performed using treatments of kinase inhibitors, western blotting, flow cytometry, immunofluorescence, cellular fractionation, and immunoprecipitation approaches. Our findings suggest that HN1 overexpression before mitosis (post-G2), using both transient and stable expression systems, leads to S-phase accumulation and causes early mitotic exit after post-G2 overexpression. Mechanistically, HN1 interacted with Cyclin B1 and increased its degradation via ubiquitination through stabilized Cdh1, which is a co-factor of the APC/C complex. Stably HN1-expressing cells exhibited a reduced Cdt1 loading onto chromatin, demonstrating an exit from a G1 to S phenotype. We found HN1 and Cdh1 interaction as a new regulator of the Cyclin B1/CDK1 axis in mitotic regulation which can be explored further to dissect the roles of HN1 in the cell cycle.

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Therapeutic Potential of Mitotic Kinases’ Inhibitors in Cancers of the Gastrointestinal System

Cited by 5 publications

References 137 publications

Mitotic Poisons In Cancer Pharmacotherapy

Mitotic Poisons In Cancer Pharmacotherapy

Unraveling Key Signaling Pathways Altered in Hepatocellular Carcinoma

HN1 Is Enriched in the S-Phase, Phosphorylated in Mitosis, and Contributes to Cyclin B1 Degradation in Prostate Cancer Cells

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