A Novel Synthetic Analog of 5, 8-Disubstituted Quinazolines Blocks Mitosis and Induces Apoptosis of Tumor Cells by Inhibiting Microtubule Polymerization

Tian, Wei; Qin, Lili; Song, Qiaoling; He, Li; Ai, Midan; Jin, Yi; Zhou, Zuyu; You, Song; Long, Ya‐Qiu; Yu, Qiang

doi:10.1371/journal.pone.0010499

Cited by 9 publications

(6 citation statements)

References 32 publications

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“…In the search for cell growth inhibitors with the potential for use as anticancer therapies, many inhibitors of microtubule dynamics have been investigated, including colchicine and paclitaxel (Taxol). 3, 4, 5, 6, 7 Taxol binds and stabilizes microtubules, thereby suppressing their dynamic rearrangements, which are necessary for cell growth. 8 In contrast, colchicine is a Vinca alkaloid that binds to tubulin and inhibits its polymerization by blocking the cell cycle at the G2/M phase and triggering apoptosis.…”

Section: Introductionmentioning

confidence: 99%

The colchicine derivative CT20126 shows a novel microtubule-modulating activity with apoptosis

et al. 2013

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New colchicine analogs have been synthesized with the aim of developing stronger potential anticancer activities. Among the analogs, CT20126 has been previously reported to show immunosuppressive activities. Here, we report that CT20126 also shows potential anticancer effects via an unusual mechanism: the modulation of microtubule integrity and cell cycle arrest at the G2/M phase before apoptosis. When we treated COS-7 cells with CT20126 (5 μℳ), the normal thread-like microtubules were disrupted into tubulin dimers within 10 min and thereafter repolymerized into short, thick filaments. In contrast, cells treated with the same concentration of colchicine exhibited microtubule depolymerization after 20 min and never underwent repolymerization. Furthermore, optical density (OD) analysis (350 nm) with purified tubulin showed that CT20126 had a higher repolymerizing activity than that of Taxol, a potent microtubule-polymerizing agent. These results suggest that the effects of CT20126 on microtubule integrity differ from those of colchicine: the analog first destabilizes microtubules and then stabilizes the disrupted tubulins into short, thick polymers. Furthermore, CT20126 induced a greater level of apoptotic activity in Jurkat T cells than colchicine (assessed by G2/M arrest, caspase-3 activation and cell sorting). At 20 nℳ, CT20126 induced 47% apoptosis among Jurkat T cells, whereas colchicine induced only 33% apoptosis. Our results suggest that the colchicine analog CT20126 can potently induce apoptosis by disrupting microtubule integrity in a manner that differs from that of colchicine or Taxol.

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Section: Introductionmentioning

confidence: 99%

The colchicine derivative CT20126 shows a novel microtubule-modulating activity with apoptosis

et al. 2013

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“…When cells were exposed to alkaloid at a concentration of 20 μg/l for 2, 5, 10, 15 or 20 minutes, no noticeable changes occurred in the microtubule network (data not shown). The 30 min treatment at concentration of 20 μg/ml did not cause an obvious disruption of the treated cell microtubules Figure (7).When exposed toZephyranthes candida alkaloid extract at a concentration of 800 μg/ml for 5 minutes, the treated cells showed a severely defected microtubules network. In this time and concentration the network was thinned down, and singular fibers had a granulated wavelike shape Figure (8).…”

Section: Resultsmentioning

confidence: 93%

“…Interaction of antitumor agents with components of the cytoskeleton is a theme studied in many researches (5)(6)(7)(8)(9)(10)(11)(12).Targeting cancer cells microtubules is one of many strategiesutilized to defeat deferent types of this disease (17). Natural products were of the realist chemicals to be recognized as potent antitumor drugs as a result of their interaction withcancer cells microtubules (18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Effect of extraction Alkaloids from Zephyranthes candida induces cell death through destruction microtubules in (China hamster cell line)

AL-Zerkani¹

2018

DJM

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Background:In eukaryotic cells the cytoskeleton network consists of three major structural elements, microtubules, microfilament,and intermediate filaments. Tubulin is the basic protein of the MTs, molecules of tubulin arranged in dimmers consisting of two forms, αtubulin and β-tubulin. They are continuously changeable structures.Taxanes and vinca alkaloids are inhibitors MTC that destabilize microtubules, there by suppressing their dynamics which required for proper mitotic function and effectively blocking cell regulation progression resulting in cell death. Objective: To evaluate the capability of alkaloids taken away from leaves of Zephyranthes candidato divert the MTC network of (CHO), which is an aggressive metastasis cell line. Patients and Methods:In our experiments we used the mouse CHO cell line. This cell line was obtained from the

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“…Microtubule-targeted agents inhibit mitosis in the rapidly dividing cancer cells by interfering with the dynamics of the spindle microtubules, which are required for normal mitotic progression [7]. Microtubule-targeted anti-mitotic compounds are usually classified into two main groups based on their mode of action [8]. One group, known as microtubule-destabilizing agents, inhibits microtubule polymerization and promotes microtubule depolymerization, such as vinca alkaloids, colchicines, podophyllotoxin and nocodazole.…”

Section: Introductionmentioning

confidence: 99%

NMK-TD-100, a Novel Microtubule Modulating Agent, Blocks Mitosis and Induces Apoptosis in HeLa Cells by Binding to Tubulin

et al. 2013

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Thiadiazoles are one of the most widely utilized agents in medicinal chemistry, having a wide range of pharmacologic activity. Microtubules (MTs) have always remained a sought-after target in rapidly proliferating cancer cells. We screened for the growth inhibitory effect of synthetic 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles on cancer cells and identified NMK-TD-100, as the most potent agent. Cell viability experiments using human cervical carcinoma cell line (HeLa cells) indicated that the IC50 value was 1.42±0.11 µM for NMK-TD-100 for 48 h treatment. In further study, we examined the mode of interaction of NMK-TD-100 with tubulin and unraveled the cellular mechanism responsible for its anti-tumor activity. NMK-TD-100 induced arrest in mitotic phase of cell cycle, caused decline in mitochondrial membrane potential and induced apoptosis in HeLa cells. Immunofluorescence studies using an anti-α-tubulin antibody showed a significant depolymerization of the interphase microtubule network and spindle microtubule in HeLa cells in a concentration-dependent manner. However, the cytotoxicity of NMK-TD-100 towards human peripheral blood mononuclear cells (PBMC) was lower compared to that in cancer cells. Polymerization of tissue purified tubulin into microtubules was inhibited by NMK-TD-100 with an IC50 value of 17.5±0.35 µM. The binding of NMK-TD-100 with tubulin was studied using NMK-TD-100 fluorescence enhancement and intrinsic tryptophan fluorescence of tubulin. The stoichiometry of NMK-TD-100 binding to tubulin is 1:1 (molar ratio) with a dissociation constant of ~1 µM. Fluorescence spectroscopic and molecular modeling data showed that NMK-TD-100 binds to tubulin at a site which is very near to the colchicine binding site. The binding of NMK-TD-100 to tubulin was estimated to be ~10 times faster than that of colchicine. The results indicated that NMK-TD-100 exerted anti-proliferative activity by disrupting microtubule functions through tubulin binding and provided insights into its potential of being a chemotherapeutic agent.

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A Novel Synthetic Analog of 5, 8-Disubstituted Quinazolines Blocks Mitosis and Induces Apoptosis of Tumor Cells by Inhibiting Microtubule Polymerization

Cited by 9 publications

References 32 publications

The colchicine derivative CT20126 shows a novel microtubule-modulating activity with apoptosis

The colchicine derivative CT20126 shows a novel microtubule-modulating activity with apoptosis

Effect of extraction Alkaloids from Zephyranthes candida induces cell death through destruction microtubules in (China hamster cell line)

NMK-TD-100, a Novel Microtubule Modulating Agent, Blocks Mitosis and Induces Apoptosis in HeLa Cells by Binding to Tubulin

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