Identification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin

Peng, Ting; Wu, Jianhui; Tong, Linjiang; Li, Mengyuan; Chen, Fang; Leng, Yi-xin; Qu, Rong; Han, Kun; Su, Yi; Chen, Yi; Duan, Wenhu; Xie, Hua; Ding, Jian

doi:10.1038/aps.2014.33

Cited by 23 publications

(16 citation statements)

References 30 publications

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“…The medium was replaced with DI (12 or 30 μmol/L) or paclitaxel (0.5 μmol/L) 11 and cultured for 24 h. The cells were then rinsed with PBS twice before fixation by 4% formaldehyde for 20 min at room temperature. The cells were rinsed with PBS three times and permeabilized with 0.2% Triton X-100 for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Deacetylisovaltratum disrupts microtubule dynamics and causes G2/M-phase arrest in human gastric cancer cells in vitro

Zhang

Zhou

et al. 2016

Acta Pharmacol Sin

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Aim:Deacetylisovaltratum (DI) is isolated from the traditional Chinese herbal medicine Patrinia heterophylla Bunge, which exhibits anti-cancer activity. Here, we investigated the effects of DI on human gastric carcinoma cell lines in vitro and elucidated its anti-cancer mechanisms.Methods:Human gastric carcinoma AGS and HGC-27 cell lines were treated with DI, and cell viability was detected with MTT assay. Cell cycle stages, apoptosis and mitochondrial membrane potential were measured using flow cytometry. Protein levels were analyzed by Western blotting. Tubulin polymerization assays and immunofluorescence were used to characterize the tubulin polymerization process.Results:DI inhibited the cell viability of AGS and HGC-27 cells in a dose- and time-dependent manner with IC50 values of 12.0 and 28.8 μmol/L, respectively, at 24 h of treatment. Treatment with DI (10–100 μmol/L) dose-dependently promoted tubulin polymerization, and induced significant G2/M cell cycle arrest in AGS and HGC-27 cells. Moreover, DI treatment disrupted mitochondrial membrane potential and induced caspase-dependent apoptosis in AGS and HGC-27 cells.Conclusion:DI induces G2/M-phase arrest by disrupting tubulin polymerization in human gastric cancer cells, which highlights its potent anti-cancer activity and potential application in gastric cancer therapy.

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Section: Methodsmentioning

confidence: 99%

Deacetylisovaltratum disrupts microtubule dynamics and causes G2/M-phase arrest in human gastric cancer cells in vitro

Zhang

Zhou

et al. 2016

Acta Pharmacol Sin

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“…The inhibition of other kinases was measured by WuXi AppTec (Shanghai, China) or by enzyme immunosorbent assays [23] .…”

Section: In Vitro Kinase Assaymentioning

confidence: 99%

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

et al. 2016

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Aim: LS-007 is a CDK inhibitor, which exhibits potent antitumor activity against chronic lymphocytic leukemia and ovarian cancer cells. In this study, we further evaluated the antitumor activity of LS-007 alone and in combination with a Bcl-2 inhibitor ABT-199 in acute leukemia (AL) cells. Methods: Cell viability was detected using resazurin assay, and cell apoptosis was examined using Annexin V/PI double staining and flow cytometry. The inhibition of LS-007 on kinases was evaluated with the mobility shift assay or ELISA. The expression of relevant signaling molecules was assessed using Western blotting and RT-PCR. Primary lymphocytes from patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were separated using Ficoll-Paque PLUS. Results: LS-007 inhibited the proliferation of 6 AL cell lines with IC 50 values of 100-200 nmol/L, and decreased the survival of ALL and AML patient-derived lymphocytes with mean LD 50 value of 67 and 102 nmol/L, respectively. In kinase assays in vitro, LS-007 was more selective for the CDK family, inhibiting CDK2, CDK9, CDK1 and CDK4 at low nanomolar concentrations. In HL-60 and CCRF-CEM cells, LS-007 (0.1-0.4 μmol/L) dose-dependently induced cell apoptosis predominantly through CDK9 inhibition-related dephosphorylation at the ser2 residue of RNA pol II and the corresponding depletion of anti-apoptotic proteins, especially Mcl-1 and XIAP. LS-007 (0.2 and 0.4 μmol/L) also induced cell apoptosis in the patient-derived lymphocytes. In HL-60, CCRF-CEM and Molt-4 cells, combined application of LS-007 with ABT-199 (1 or 2 μmol/L) markedly increased cell apoptosis with a maximal decrease in the XIAP levels as compared with either drug used alone. Conclusion: CDK inhibitor LS-007 potently inhibits the established human AL cell lines and primary AL blasts, and it also shows remarkable synergy with Bcl-2 inhibitor

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“…Recently, Peng et al have reported a benzochromenone derivative, TP ‐ DW532 ( 62 ), with promising MOAs against EGFR, VEGFR as well as tubulin polymerization. This candidate demonstrated moderate inhibitory ability of EGFR and VEGFR in lower single digit micromolar range in addition to the ability to dose dependently inhibit tubulin polymerization ranging from 20 to 40 μM.…”

Section: Tubulin Kinase Dual Inhibition In Anticancer Treatmentmentioning

confidence: 99%

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

Medicinal Research Reviews

107

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Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

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Identification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin

Abstract: DW532 is a dual inhibitor against tubulin and tyrosine kinases, and deserves further development as a novel anti-cancer agent.

Cited by 23 publications

References 30 publications

Deacetylisovaltratum disrupts microtubule dynamics and causes G2/M-phase arrest in human gastric cancer cells in vitro

Deacetylisovaltratum disrupts microtubule dynamics and causes G2/M-phase arrest in human gastric cancer cells in vitro

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

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