Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

Loong, Herbert H.; Park, Yeon Hee

doi:10.2147/ott.s46019

Cited by 41 publications

(32 citation statements)

References 99 publications

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“…Three clusters identified in PPI network mainly functioned in cell division and metabolic processes. These findings were consistent with our knowledge (Jiang et al, 2015;Kastan & Bartek, 2004;Liu et al, 2016;Loong & Yeo, 2014;Shoieb et al, 2019). Among 30 hub genes, upregulated ASPM, AURKA, CCNB2, CDC20, PRC1 and TOP2A and downregulated AOX1, CAT, CYP2E1, CYP3A4 and HP, were considered key biomarkers in HCC.…”

Section: Discussionsupporting

confidence: 89%

Transcriptome analysis revealed key prognostic genes and microRNAs in hepatocellular carcinoma

Zhou

Zheng

2020

PeerJ

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Background. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, the molecular mechanisms involved in HCC remain unclear and are in urgent need of elucidation. Therefore, we sought to identify biomarkers in the prognosis of HCC through an integrated bioinformatics analysis. Methods. Messenger RNA (mRNA) expression profiles were obtained from the Gene Expression Omnibus database and The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) for the screening of common differentially expressed genes (DEGs). Function and pathway enrichment analysis, protein-protein interaction network construction and key gene identification were performed. The significance of key genes in HCC was validated by overall survival analysis and immunohistochemistry. Meanwhile, based on TCGA data, prognostic microRNAs (miRNAs) were decoded using univariable and multivariable Cox regression analysis, and their target genes were predicted by miRWalk. Results. Eleven hub genes (upregulated ASPM, AURKA, CCNB2, CDC20, PRC1 and TOP2A and downregulated AOX1, CAT, CYP2E1, CYP3A4 and HP) with the most interactions were considered as potential biomarkers in HCC and confirmed by overall survival analysis. Moreover, AURKA, PRC1, TOP2A, AOX1, CYP2E1, and CYP3A4 were considered candidate liver-biopsy markers for high risk of developing HCC and poor prognosis in HCC. Upregulation of hsa-mir-1269b, hsa-mir-518d, hsa-mir-548aq, hsa-mir-548f-1, and hsa-mir-6728, and downregulation of hsa-mir-139 and hsa-mir-4800 were determined to be risk factors of poor prognosis, and most of these miRNAs have strong potential to help regulate the expression of key genes. Conclusions. This study undertook the first large-scale integrated bioinformatics analysis of the data from Illumina BeadArray platforms and the TCGA database. With a comprehensive analysis of transcriptional alterations, including mRNAs and miRNAs, in HCC, our study presented candidate biomarkers for the surveillance and prognosis of the disease, and also identified novel therapeutic targets at the molecular and pathway levels.How to cite this article Ma X, Zhou L, Zheng S. 2020. Transcriptome analysis revealed key prognostic genes and microRNAs in hepatocellular carcinoma. PeerJ 8:e8930 http://doi.org/10.7717/peerj.8930 Ma et al. (2020), PeerJ, DOI 10.7717/peerj.8930 2/22 Ma et al. (2020), PeerJ, DOI 10.7717/peerj.8930 3/22 PPI network construction and cluster identificationThe PPI network of DEGs was constructed using STRING (version 11.0, http://stringdb.org) and a combined score > 0.7 (high confidence) was set as the cut-off criterion. Cytoscape (version 3.7.2, https://cytoscape.org/), an open source platform, was applied to the visualization of molecular interaction networks based on the results from STRING. The Molecular Complex Detection (MCODE) plugin (version 1.5.1) in Cytoscape was used for identifying densely interconnected clusters. The selection criteria were as follows: degree ≥ 2, node score ≥ 0.2, K-core ≥ 2, and max depth = 100.

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Section: Discussionsupporting

confidence: 89%

Transcriptome analysis revealed key prognostic genes and microRNAs in hepatocellular carcinoma

Zhou

Zheng

2020

PeerJ

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“…They have demonstrated high potency against the proliferation of various cancer cells, as well as in multidrug-resistant cancers (21,22). …”

Section: Resultsmentioning

confidence: 99%

“…In the current study, we first investigated whether the EGFP/HAC-based assay could be used to rank compounds that affect microtubule dynamics (21,22). HT1080 cells with an autonomously propagated EGFP-HAC were treated with six well established microtubule-stabilizing drugs: pacilitaxel, docetaxel, peloruside A, ixabepilone, dactylolide, zampanolide, and eight microtubule-destabilizing drugs: nocodazole, vincristine, combretastatin A4, maytansine, cryptophycin, vindesine, vinorelbine, and eribuline mesylate (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Effects of Anticancer Drugs on Chromosome Instability and New Clinical Implications for Tumor-Suppressing Therapies

Lee

Kouprina

et al. 2016

Cancer Research

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Whole-chromosomal instability (CIN), manifested as unequal chromosome distribution during cell division, is a distinguishing feature of most cancer types. CIN is generally considered to drive tumorigenesis, but a threshold level exists whereby further increases in CIN frequency in fact hinder tumor growth. While this attribute is appealing for therapeutic exploitation, drugs that increase CIN beyond this therapeutic threshold are currently limited. In our previous work, we developed a quantitative assay for measuring CIN based on the use of a non-essential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene. Here, we used this assay to rank 62 different anticancer drugs with respect to their effects on chromosome transmission fidelity. Drugs with various mechanisms of action such as antimicrotubule activity, histone deacetylase (HDAC) inhibition, mitotic checkpoint inhibition, and targeting of DNA replication and damage responses were included in the analysis. Ranking of the drugs based on their ability to induce HAC loss revealed that paclitaxel, gemcitabine, dactylolide, LMP400, talazoparib, olaparib, peloruside A, GW843682, VX-680, and cisplatin were the top ten drugs demonstrating HAC loss at a high frequency. Therefore, identification of currently used compounds that greatly increase chromosome mis-segregation rates should expedite the development of new therapeutic strategies to target and leverage the CIN phenotype in cancer cells.

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“…Microtubule targeting agents (MTAs) are used therapeutically to induce either polymerization or depolymerization of microtubules and are categorized into two groups, known as stabilizers (including taxanes and epothilones) and destabilizers (including Vinca alkaloids, halichondrins and combretastatins) [1]. Microtubules are found in both interphase and dividing cells and play a key role in mitosis, intracellular trafficking, cell signaling, migration, secretion, angiogenesis, among other critical cell functions [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors

et al. 2019

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Purpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15-21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70 mg/m 2. Three grade 3 DLTs occurred: hypotension (70 mg/m 2), hyponatremia and neutropenia (both 90 mg/m 2). The MTD for 48-h IV BAL101553 was 70 mg/m 2. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the C max was 144 ng/ mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.

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Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

Cited by 41 publications

References 99 publications

Transcriptome analysis revealed key prognostic genes and microRNAs in hepatocellular carcinoma

Transcriptome analysis revealed key prognostic genes and microRNAs in hepatocellular carcinoma

Effects of Anticancer Drugs on Chromosome Instability and New Clinical Implications for Tumor-Suppressing Therapies

A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors

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