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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
The WEE 1 tyrosine kinase regulates entry into mitosis by arresting cells with DNA damage at the G2 phase. Since tumor cells lack normal DNA repair mechanisms, they rely heavily on this kinase to serve as a DNA damage checkpoint [93]. In conjunction with cytotoxic agents, inhibition of WEE 1 kinase (via the pyrazolopyrimidine derivative MK-1775) has been adopted for the study of adult solid tumors in Phase I/II trials (NCT01748825, NCT02095132, NCT01357161) [94]. In DAOY and UW228 medulloblastoma cell lines, MK-1775 at nanomolar concentrations inhibited colony formation. Furthermore, in nude mice injected with DAOY cells subcutaneously, oral treatment with MK-1775 led to tumor regression. When tested in conjunction with cisplatin, MK-1775 accelerated apoptosis and inhibited repair of cisplatin-induced DNA damage [92].
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Danuta Balicki, Brian Leyland-Jones, Max S. Wicha
Targeting of stem cells is particularly complex since this cellular population is largely quiescent. Thus, therapeutic agents directed against cycling cells are predictably ineffective in this population, which is essentially shielded from these drugs. Cancers that respond to therapy initially may acquire drug resistance during the course of treatment, while other cancers appear to be intrinsically resistant. The cancer stem cell hypothesis suggests that in both of these cases, the resting cancer stem cell, which is both the cancer-initiating cell and its source of replenishment under selective pressure, has innate drug resistance by virtue of its quiescent stem cell phenotype. Acquired drug resistance in more differentiated cancer cells may occur through gene amplification or rearrangement, thereby contributing to an aggressive phenotype. Through the accumulation of mutations that distinguish cancer stem cells from their normal counterparts, these cells may acquire additional features associated with tumor progression, metastases, and therapeutic failure, including genetic instability, radioresistance, and chemoresistance (11,36). In the case of gliomas, cancer stem cells contribute to radioresistance through the preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity (43). Radioresistance may also result from a selective increase of cell survival pathways in progenitor cells, including β-catenin and survivin (36).
CDK Inhibitors in Leukemia and Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Clinical evaluation of UCN-01 in leukemia and lymphoma has been relatively limited. In a recent pilot trial, patients with refractory AML were treated with 1 gm/m2 ara-C as a daily continuous infusion for four days in combination with UCN-01 administered at a dose of 45 mg/m2 as a continuous intravenous infusion starting on day 2 (66). Although UCN-01 potentiated ara-C lethality, in association with abrogation of the DNA-damage checkpoint in blast cells, correlations and clinical responses were not reported in this small pilot study.
Polysaccharides from Hemerocallis citrina Baroni Inhibit the Growth of Hepatocellular Carcinoma Cells by Regulating the Wnt/β-Catenin Pathway
Published in Nutrition and Cancer, 2023
TianYu Sang, Yue Jun Fu, Li Song
The cell cycle is a precisely regulated process that ensures genetic integrity during cell division. Tumor cells are characterized by abnormal cell cycle regulation. Therefore, some antitumor drugs inhibit tumor cell proliferation by modulating the cell cycle and causing cell cycle arrest (29, 30). Our results showed that polysaccharides HcBPS2 significantly inhibited HCC cell proliferation and induced cell cycle arrest in G2/M phase. G2/M phase is an important DNA damage checkpoint. When a cell with DNA damage cannot repair the damage present, the G2/M phase checkpoint prevents the cells from entering M phase (31). Cyclin B1 regulates the transformation from G2 to M phase. Cyclin B1 can bind with the cell cycle-dependent kinase Cdc2 and then promote the cell cycle (16). Cyclin D1 is a crucial regulator during G2 phase (32). Cyclin D1 levels are elevated during G2 phase, which allows the cell to enter the next cycle (32). P21 is a cyclin-dependent kinase inhibitor that promotes G2/M phase arrest by inhibiting the expression of Cdc2 (33). This study found that the level of P21 was significantly increased and the expression levels of cyclin B1 and cyclin D1 were notably decreased in HcBPS2-treated cells. These findings suggested that cyclin B1, cyclin D1 and P21 were involved in HcBPS2-induced G2/M phase arrest.
Inhibitors of cell cycle checkpoint target Wee1 kinase – a patent review (2003–2022)
Published in Expert Opinion on Therapeutic Patents, 2022
Jingxue Yan, Lili Zhuang, Yong Wang, Yiqing Jiang, Zhenlin Tu, Chao Dong, Yadong Chen, Yong Zhu
The ATM-mediated signaling pathway is essential for the activation of the DNA damage checkpoint and cell cycle arrest when DNA damage is induced by endogenous or exogenous factors. In the case of blocked ATM signaling pathways, such as downstream effector p53 mutations, cell cycle checkpoints play an increasingly significant role in blocking the continued replication of damaged DNA, especially the G2-M checkpoint. In addition, the inhibitory effect of Wee1 on histones at the end of the S-phase also contributes to the normal progression of the cell cycle. Based on the critical role of Wee1 in cell cycle, DNA damage repair, and epigenetics, Wee1 is an ideal target for tumor therapy. In addition, the sequence differences between Wee1 and other kinases in the WEE kinase family make it possible to design and synthesize small molecules with high inhibitory activity and high selectivity. As a synthetic lethal target, Wee1 inhibitors have been used in combination with a widening range of DNA-damaging drugs for the treatment of lung, ovarian, triple-negative breast, and colorectal cancers and so on.
Seckel syndrome presenting with complete heart block
Published in Baylor University Medical Center Proceedings, 2021
Mostafa Abohelwa, Mohamed Elmassry, Marina Iskandir, Brandon Rogers, Deephak Swaminath
Seckel syndrome is usually due to recessive mutations in the gene encoding ataxia telangiectasia and Rad3-related protein, a protein kinase responsible for the deoxyribonucleic acid damage response pathway; however, other gene mutations have also been identified.2 The ataxia telangiectasia and Rad3-related protein gene is involved in sensing DNA damage and activating the DNA damage checkpoint, leading to cell cycle arrest.14 This gene is related to a second checkpoint-activating kinase, serine/threonine kinase, an ataxia telangiectasia mutated gene that leads to cell cycle arrest, DNA repair, or apoptosis when activated. It has been described to have a role in cardiac remodeling with different effects early and late post-myocardial infarction.15 Yet, no studies have been done to describe the relationship with specialized cardiac muscle cells and CHB. Could it be apoptosis for specialized cardiac muscle cells?