MPT0B169, a New Tubulin Inhibitor, Inhibits Cell Growth and Induces G2/M Arrest in Nonresistant and Paclitaxel-Resistant Cancer Cells

Lee, Wei Hwa; Liu, Hsinjin Eugene; Chang, Jang Yang; Liou, Jing Ping; Huang, Huei Mei

doi:10.1159/000351852

Cited by 16 publications

(16 citation statements)

References 25 publications

(32 reference statements)

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“…MPT0B169 and MPT0B002 were synthesized as previously described [9,10] and dissolved in dimethyl sulfoxide (DMSO; SigmaAldrich, St. Louis, MO, USA).…”

Section: Chemicalsmentioning

confidence: 99%

“…In our previous studies, we synthesized 2 indole-based compounds, 2-di- Fig. 1a) [9] and (1-methyl-1H-indol-5-yl)-(3,4,5-trimethoxy-phenyl)-methanone (MPT0B002; Fig. 1b) [10] as novel tubulin inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…1b) [10] as novel tubulin inhibitors. MPT0B169 inhibited cell growth and arrested cell cycle progression at the G2/M phase in acute myeloid leukemia (AML) cells [9]. MPT0B002 induced growth inhibition and apoptosis of chronic myeloid leukemia (CML) cells [10].…”

Section: Introductionmentioning

confidence: 99%

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MPT0B169 and MPT0B002, New Tubulin Inhibitors, Induce Growth Inhibition, G2/M Cell Cycle Arrest, and Apoptosis in Human Colorectal Cancer Cells

et al. 2018

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We previously synthesized new tubulin inhibitors, MPT0B169 and MPT0B002, which induced growth inhibition and apoptosis in leukemia cells. However, their effects on solid tumor cells have not been determined. In this study, we investigated the effects of MPT0B169 and MPT0B002 on glioblastoma, breast, lung, and colorectal cancer (CRC) cell lines. A cell viability analysis showed that MPT0B169 and MPT0B002 were more effective in inhibiting the proliferation of COLO205 and HT29 CRC cells than U87MG and GBM8401 glioblastoma, MCF-7 and MDA-MB-231 breast cancer, and A549 lung cancer cells. MPT0B169 and MPT0B002 inhibited growth of COLO205 and HT29 cells in dose- and time-dependent manners. A colony-formation assay confirmed the growth inhibitory effects of MPT0B169 and MPT0B002 on COLO205 and HT29 cells. MPT0B169 and MPT0B002 disrupted tubulin polymerization and arrested the cell cycle at the G2/M phase, with a concomitant increase of the cyclin B1 level. MPT0B169 and MPT0B002 induced apoptosis, accompanied by induction of the intrinsic apoptotic pathway, as shown by a reduction in the caspase-9 level and increases in cleaved caspase-3 and cleaved PARP. These results suggest that MPT0B169 and MPT0B002, new tubulin inhibitors, induced growth inhibition, G2/M arrest, and apoptosis in COLO205 and HT29 cells, and they could potentially be anticancer agents for CRC cells.

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“…MPT0B169 and MPT0B002 were synthesized as previously described [9,10] and dissolved in dimethyl sulfoxide (DMSO; SigmaAldrich, St. Louis, MO, USA).…”

Section: Chemicalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MPT0B169 and MPT0B002, New Tubulin Inhibitors, Induce Growth Inhibition, G2/M Cell Cycle Arrest, and Apoptosis in Human Colorectal Cancer Cells

et al. 2018

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“…In addition, antitumor drugs are liable to the development of drug resistance, which restricts clinical treatment (17). Therefore, treatment methods that target specific cell signaling pathways require investigation, and studies have identified novel targets for targeted therapy of tumor molecules, including the regulation of miRs (18,19). Therefore, miRs provide a novel method for treating malignant tumors, and it has been observed that treating cancer by regulating the level of miRs in the cancerous cells is possible (20).…”

Section: Introductionmentioning

confidence: 99%

Role of microRNA-4458 in patients with non-small-cell lung cancer

et al. 2016

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Abstract. Incidence and progression of non-small-cell lung cancer (NSCLC) is a multi-factor, multi-step process. The present study investigated the association between the expression level of microRNA (miR)-4458 in NSCLC and paracarcinoma liver tissues and survival rates, and studied the biological functions of miR-4458 at the cellular and protein level. NSCLC and paracarcinoma tissues were sequenced using a miR expression chip. The association between miR-4458 expression and tumor-node-metastasis staging, total survival rate and relapse-free survival rate was analyzed. miR-4458 was subjected to target gene prediction. The target protein of cyclin D1 (CCND1) was verified with western blot analysis, immunohistochemistry and a luciferase reporter assay. The relative level of miR-4458 in paracarcinoma tissues of 9 NSCLC patients decreased from 2.38 to 0.65 (P<0.001). Total five-year survival rates of the high-expression miR-4458 group (29.21%) significantly exceeded that of the low-expression group (14.37%) (P=0.025). The viability of human lung carcinoma A549 and H460 cells transfected with miR-4458 decreased significantly compared with cells transfected with a normal control (blank control plasmid) within 72 h (P<0.001). The percentage of A549 and H460 cells transfected with a miR-4458 mimic at the cell cycle stage G0/G1 was 69.94±8.05 and 68.15±7.75%, respectively. The percentages increased significantly compared with the control group (46.06±6.93 for A549 cells; 45.22±7.24 for H640 cells; P<0.001). CCND1 mRNA was downregulated significantly in H460 cells 72 h subsequent to the addition of miR-4458 mimics (P<0.001). The activity of mutant-CCND1 altered slightly, while the fluorescence intensity of the wild-type-CCND1 group decreased significantly following the addition of miR-4458 mimics. In conclusion, miR-4458 was expressed at low levels in lung cancer tissues, and it arrested cells in vitro at stage G0/G1 and inhibited cell proliferation. Therefore, miR-4458 may participate in the onset of lung cancer as a suppressor gene by inhibiting CCND1.

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“…In recent years, much effort has been devoted to the identification of new ligands binding to the colchicine site of tubulin, derived not only from natural sources but also by screening of compound libraries in combination with traditional medicinal chemistry [9,10]. Quinoline and benzopyridooxathiazepine (BPT) derivatives are a pharmacologically active class of heterocyclic compounds that have been reported to inhibit tubulin polymerization, leading to cell cycle arrest and apoptosis [8,11,12]. Among the series of synthesized products, 2-dimethylamino-N-[1-(4-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]acetamide was a novel class of quinoline derivative identified as a potent microtubule inhibitor acting through the colchicine-binding site of tubulin [8].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Evaluation of a Novel Benzopyridooxathiazepine Derivative as a Potential Anticancer Agent

Bourdon¹,

Lecoeur²,

Lebegue³

et al. 2014

Pharmacology

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Background/Aims: The in vivo metabolic profile of a benzopyridooxathiazepine (BPT) derivative, a potent tubulin polymerization inhibitor with a promising in vitro activity, was investigated. Methods: The quantification of the BPT derivative and the identification of metabolites in the plasma of Wistar rats after i.p. and oral administration of 10 mg/kg were performed by the HPLC-mass spectrometry method. Results: Following a single i.p. dose of the BPT derivative, the plasma concentrations showed a biexponential decay (with a rapid decline) followed by a slow decay with a terminal half-life of 77.90 min. The area under the concentration-time curve from time 0 to infinity (AUC_0-_∞) was 18.90 µg/ml·min. After oral administration, the plasmatic concentrations reached a peak of 0.06 μg/ml at 35 min and then decayed with a half-life of 108 min. The AUC_0-_∞ was 10.25 µg/ml·min, representing 54.2% of the relative bioavailability. The compound was well distributed in the body, and its elimination seemed to be fast, regardless of the administration route. The major metabolic pathways were demethylation and hydroxylation reactions, both followed by conjugation with glucuronic acid. Conclusion: In rats, the BPT derivative is well distributed and undergoes extensive metabolism, leading to several metabolites. With promising in vitro activity and very good oral bioavailability, this compound seems to be an attractive candidate for further development as an anticancer agent.

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MPT0B169, a New Tubulin Inhibitor, Inhibits Cell Growth and Induces G2/M Arrest in Nonresistant and Paclitaxel-Resistant Cancer Cells

Cited by 16 publications

References 25 publications

MPT0B169 and MPT0B002, New Tubulin Inhibitors, Induce Growth Inhibition, G2/M Cell Cycle Arrest, and Apoptosis in Human Colorectal Cancer Cells

MPT0B169 and MPT0B002, New Tubulin Inhibitors, Induce Growth Inhibition, G2/M Cell Cycle Arrest, and Apoptosis in Human Colorectal Cancer Cells

Role of microRNA-4458 in patients with non-small-cell lung cancer

Pharmacokinetic Evaluation of a Novel Benzopyridooxathiazepine Derivative as a Potential Anticancer Agent

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