Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

Borah, Naheed Arfin; Reddy, Mamatha M.

doi:10.3390/molecules26071981

Cited by 81 publications

(60 citation statements)

References 184 publications

(108 reference statements)

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“…In agreement with the existing literature, our data suggest that MYCN promotes RB cell growth and metastasis possibly via regulating the genes involved in the ECM modification. MYCN in addition to the regulation of genes involved in glucose metabolism and migration, has been shown to positively modulate the expression of mitotic protein kinase, aurora kinase B in RB [30] and other tumors [61]. Overall, our data along with the published literature show that MYCN may regulate a plethora of cellular functions in RB and other tumors [62].…”

Section: Discussionsupporting

confidence: 59%

The Oncogene MYCN Modulates Glycolytic and Invasive Genes to Enhance Cell Viability and Migration in Human Retinoblastoma

Sradhanjali

Rout

Tripathy

et al. 2021

Cancers

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Retinoblastoma is usually initiated by biallelic RB1 gene inactivation. In addition, MYCN copy number alterations also contribute to RB pathogenesis. However, MYCN expression, its role in disease progression and correlation with RB histological risk factors are not well understood. We studied the expression of MYCN in enucleated RB patient specimens by immunohistochemistry. MYCN is overexpressed in RB compared to control retina. Our microarray gene expression analysis followed by qRT-PCR validation revealed that genes involved in glucose metabolism and migration are significantly downregulated in MYCN knockdown cells. Further, targeting MYCN in RB cells using small molecule compounds or shRNAs led to decreased cell survival and migration, increased apoptosis and cell cycle arrest, suggesting that MYCN inhibition can be a potential therapeutic strategy. We also noted that MYCN inhibition results in reduction in glucose uptake, lactate production, ROS levels and gelatinolytic activity of active-MMP9, explaining a possible mechanism of MYCN in RB. Taking clues from our findings, we tested a combination treatment of RB cells with carboplatin and MYCN inhibitors to find enhanced therapeutic efficacy compared to single drug treatment. Thus, MYCN inhibition can be a potential therapeutic strategy in combination with existing chemotherapy drugs to restrict tumor cell growth in RB.

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Section: Discussionsupporting

confidence: 59%

The Oncogene MYCN Modulates Glycolytic and Invasive Genes to Enhance Cell Viability and Migration in Human Retinoblastoma

Sradhanjali

Rout

Tripathy

et al. 2021

Cancers

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“…As genes associated with the mitotic spindle formation, we included the Aurora kinases A ( AURKA ) and B ( AURKB ). These upregulated enzymes are serine/threonine kinases that associate with the centrosome and the spindle microtubules during mitosis and play an essential role in various cell division checkpoints ( 85 ) ( Figure 1 and Supplemental Material 5 ). Other transcripts were upregulated, such as the gene TPX2 , a spindle assembly factor that intimately interacts with Aurora A and functions in chromosomes segregation ( 86 ).…”

Section: Resultsmentioning

confidence: 99%

Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration

et al. 2022

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Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the “cytokine storm” observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.

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“…Aurora kinases represent a family of homologous serine/ threonine kinases that play an important role in regulating the mitosis, meisosis, and cell division (Fu et al, 2009; Tang et al, 2017; Willems et al, 2018). The overexpression of Aurora Kinases in leukemia, breast, colon, and prostate cancer cells identifies them as a desirable target in the cancer chemotherapy (Borah & Reddy, 2021; Goos et al, 2013). The rationally developed compounds 51–52 a–e (Figure 14) bear the dicarbonyl mimics of pyrophosphate with adenosine head, and pantetheine based‐tail conserved to mimic the Coenzyme A, a highly selective inhibitor of Aurora Kinase A.…”

Section: Pyrophosphate Mimics Containing Coenzyme a Analogues For Inhibition Of Aurora Kinase Amentioning

confidence: 99%

Medicinal chemistry of pyrophosphate mimics: A mini review

Prasher

Sharma

2021

Drug Development Research

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The pyrophosphate mimicking groups offer rational modification of the pyrophosphate‐bearing natural substrates of the overexpressed enzymes that cause the onset of disease progression. Mainly, the modified substrate interacts differently with the enzyme active site eventually causing its deactivation, or provides the therapeutically active products at the completion of the catalytic cycle that contribute toward the inhibition of the target enzyme. Many of the pyrophosphate mimic‐containing molecules serve as competitive or allosteric inhibitors of the target enzyme to achieve the desirable properties for the mitigation of the target enzyme's pathophysiology. This review presents an epigrammatic overview of the pyrophosphate mimics in medicinal chemistry.

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Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

Cited by 81 publications

References 184 publications

The Oncogene MYCN Modulates Glycolytic and Invasive Genes to Enhance Cell Viability and Migration in Human Retinoblastoma

The Oncogene MYCN Modulates Glycolytic and Invasive Genes to Enhance Cell Viability and Migration in Human Retinoblastoma

Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration

Medicinal chemistry of pyrophosphate mimics: A mini review

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