• Title/Summary/Keyword: Microtubule depolymerization

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Pertussis Toxin Inhibits Colchicine-Induced DNA Synthesis in Human Fibroblast

  • Jang, Won-Hee;Rhee, In-Ja
    • Archives of Pharmacal Research
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    • v.17 no.3
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    • pp.199-203
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    • 1994
  • Several lines evidence indicate that microtubule depolymerization initiates DNA synthesis or enhances the effects of serum or purified growth factors in many types of fibroblasts. Yet little is known about the intracellular events responsible for the mitogenic effect of microtubule disrupting agents. The effects of antitubulin agents on DNA synthesis in sparse and dense cultures in the presence or absence of serum and possible involvement of G-proteins in their mitotic action were examined. In these studies, colchicine by itself appeared to be mitogenic only for confluent quiesecent human lung fibroblasts. In sparse culture, however, colchicine inhibited serum-stimulated DNA synthesis. Colcemid, another antitubulin agent, showed similar effects of growth inhibition and stimulation in sparse and confluent cultures while lumicolhicine, inactive colchicine, did not. The mitogenic effect of two antitubulin agents, colchicine and colcemid, was partially inhibited by pertussis toxin. These data suggest that microtubular integrity is associated with the expression of either negative or positive control on DNA synthesis and mitogenic effect of antitubulin agents may be partially mediated by pertussis toxin-sensitive G protein.

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The Effect of Taxol and Ethyl-N-phenylcarbamate (EPC) on Growth and Gravitropism in Zea mays L

  • Park, Yun-Hee;Choy, Yoon-Hi;Lee, June-Seung
    • Journal of Plant Biology
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    • v.39 no.4
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    • pp.287-293
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    • 1996
  • The effect of taxol and ethyl-N-phenylcarbamate (EPC) on the growth and gravitropism of maize roots and coleoptiles was studied. Taxol is known to promote the assembly of microtubules (MTs) and stabilizes MTs by preventing depolymerization. EPC, on the contrary, is an anti-microtubule drug that promotes disassembly of MTs. Taxol, at 1 $\mu$M, inhibited gravitropic response of maize roots to about 40%, but did not inhibit growth; at 10 $\mu$M, it inhibited the gravitropic response of coleoptile segments of maize by approximately 50%, but did not inhibit growth, while 0.5 mM EPC inhibited both the gravitropic response and growth of maize roots by approximately 50%. Taxol, which inhibited the gravitropic response of maize roots and coleoptile segments, had no effect on either the polar or the bilateral transport of auxin. These results indicated that MT polymerization could not occur normally with taxol or EPC, so that if there was any abnormal rearrangement of MT, the gravitropic response was inhibited, which resulted from the inhibition of neither growth nor auxin transport. This results suggested that gravitropic response was related to the MT arrangement, and that both straight growth and the differential growth in gravitropic response could be regulated by different mechanisms.

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BRI3 associates with SCG10 and attenuates NGF-induced neurite outgrowth in PC12 cells

  • Gong, Yanhua;Wu, Jing;Qiang, Hua;Liu, Ben;Chi, Zhikai;Chen, Tao;Yin, Bin;Peng, Xiaozhong;Yuan, Jiangang
    • BMB Reports
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    • v.41 no.4
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    • pp.287-293
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    • 2008
  • In a yeast two-hybrid screen, we identified the microtubule-destabilizing protein SCG10 as a potential effector protein of $BRI_3$. The association was verified using GST pull-down, Co-IP, and their perinuclear co-localization. The analysis of in vitro microtubule polymerization/depolymerization showed that the binding of $BRI_3$ to SCG10 effectively blocked the ability of SCG10 to induce microtubule disassembly, as determined by turbidimetric assays. In intact PC12 cells, $BRI_3$ exhibited the ability to stabilize the microtubule network and attenuate the microtubule-destabilizing activity of SCG10. Furthermore, co-expression of $BRI_3$ with SCG10 attenuated SCG10-mediated PC12 cell neurite outgrowth induced by NGF. These results identify a novel connection between a neuron-specific BRI protein and the cytoskeletal network, suggesting possible roles of BRI3 in the process of neuronal differentiation.

Effects of $Taxol^{TM}$ and Cytochalasin B on the Developmental Capacity of Vitrified Porcine Immature Oocytes

  • Kim, S. W;H. T. Cheong;B. K. Yang;Kim, C. I.;Park, C. K.
    • Proceedings of the KSAR Conference
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    • 2004.06a
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    • pp.199-199
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    • 2004
  • This study was conducted to investigate cytoskeleton alterations during vitrified (Open Pulled Straw method) porcine immature oocytes, to utilize Taxol/sup TM/ (polymerization of tubulin molecules) and Cytochalasin B (CB, depolymerization of actin filaments) during vitrification to stabilize microtubule and microfilaments (MT and MF), and to determine in vitro maturation, fertilization and development of cytoskeletal-stabilized and vitrified porcine immature oocytes. (omitted)

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Microtubule Inhibitory Effects of Various SJ Compounds on Tissue Culture Cells

  • Lee Jong Han;Kang Dong Wook;Kwon Ho Suk;Lee Sun Hwan;Park Si Kyung;Chung Sun Gan;Chon Eui Hwan;Paik Soon Young;Lee Joo Hun
    • Archives of Pharmacal Research
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    • v.27 no.4
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    • pp.436-441
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    • 2004
  • SJ compounds (SJ8002 and related compounds) are a group of novel anticancer agents (Cho, Chung, Lee, Kwon, Kang, Joo, and Oh. PCT/KR02/00392). To explore the anticancer mechanism of these compounds, we examined the effect of SJ8002 on microtubules of six human cell lines. At a high concentration ($2\;{\mu}g/mL$), SJ8002 effectively disrupted microtubules of the six cell lines within 1 h. At lower concentrations ($0.05\~1.0\;{\mu}g/mL$), the antimicrotubule activity of SJ8002 varied defending on cell lines. The inhibition of in vitro polymerization of pure tubulin by SJ8002 suggested that SJ8002 acts on free tubulin, inhibits the polymerization of tubulin dimer into microtubules, and hence induces the depolymerization of microtubules.

Paclitaxel Induced Caspase-Independent Mitotic Catastrophe in Rabbit Articular Chondrocyte (Paclitaxel에 의한 관절연골 세포의 capase-비의존적 mitotic catastrophe 유도)

  • Im, Jeong-Hee;Kim, Song-Ja
    • Journal of Life Science
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    • v.20 no.4
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    • pp.519-527
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    • 2010
  • Paclitaxel is known as a potent inhibitor of microtubule depolymerization. It leads to mitotic arrest and cell death by stabilizing the spindle in various cell types. Here, we investigated the effects of paclitaxel on the proliferation and cell death of rabbit articular chondrocytes. Paclitaxel inhibited proliferation in a dose- and time- dependent manner, determined by MTT assay in rabbit articular chondrocytes. We also established paclitaxel-induced G2/M arrest by fluorescent activated cell sorter (FACS) analysis. Paclitaxel increased expression of cyclin B, p53 and p21, while reducing expression of cdc2 and cdc25C in chondrocytes, as detected by Western blot analysis. Interestingly, paclitaxel showed the mitotic catastrophe that leads to abnormal nucleus division and cell death without DNA fragmentation through activation of caspase. Cell death by mitotic catastrophe in cells treated with paclitaxel was suppressed by inhibiting G1/S arrest with 2 mM thymidine. These results demonstrate that paclitaxel induces cell death via mitotic catastrophe without activation of casepase in rabbit articular chondrocytes.

Effects of Epothilone A in Combination with the Antidiabetic Drugs Metformin and Sitagliptin in HepG2 Human Hepatocellular Cancer Cells: Role of Transcriptional Factors NF-κB and p53

  • Rogalska, Aneta;Sliwinska, Agnieszka;Kasznicki, Jacek;Drzewoski, Jozef;Marczak, Agnieszka
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.3
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    • pp.993-1001
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    • 2016
  • Type 2 diabetes mellitus patients are at increased risk of many forms of malignancies, especially of the pancreas, colon and hepatocellular cancer. Unfortunately, little is known of the possible interaction between antidiabetic drugs and anticancer agents. The present study investigates the influence of metformin (MET) and sitagliptin (SITA) on the in vitro anticancer activity of the microtubule depolymerization inhibitor agent epothilone A (EpoA). Hepatocellular liver carcinoma cell line (HepG2) viability and apoptosis were determined by the MTT test and by double staining with PO-PRO-1 and 7-aminoactinomycin D, respectively, after treatment with EpoA, metformin or sitagliptin. The levels of nuclear factor NF-${\kappa}B$ and p53 were evaluated in the presence and absence of inhibitors. While EpoA and MET inhibited HepG2 cell proliferation, SITA did not. EpoA and SITA induced higher p53 levels than MET. All tested drugs increased the level of NF-${\kappa}B$. Only MET enhanced the proapoptotic effect of EpoA. The EpoA+MET combination evoked the highest cytotoxic effect on HepG2 cells and led to apoptosis independent of p53, decreasing the level of NF-${\kappa}B$. These findings support the link between NF-${\kappa}B$ and p53 in the modulation of apoptotic effects in HepG2 cells treated by EpoA. Our studies indicate that the combination of EpoA and MET applied in subtoxic doses has a stronger cytotoxic effect on liver cancer cells than each of the compounds alone. The therapeutic advantages of the combination of EpoA with MET may be valuable in the treatment of patients with diabetes mellitus type 2 (T2DM) and liver cancer.

Curative Resection of Inoperable, Locally Advanced Gastric Cancer after Neoadjuvant Chemotherapy with Taxotere and Cisplatin (절제 불가능한 국소 진행성 위암 환자에서 Taxotere 및 Cisplatin을 이용한 선행 화학 요법제의 투여 후 근치적 절제가 가능했던 2예)

  • Lee, Han-Hong;Hur, Hoon;Chae, Byung-Joo;Kim, Wook;Jeon, Hae-Myung
    • Journal of Gastric Cancer
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    • v.5 no.1
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    • pp.57-64
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    • 2005
  • At diagnosis, the majority of patients with gastric cancer are found to have local invasion or distant organ metastasis, even though the sole measure for a complete cure is a curative resection. A curative resection is hardly applicable for those with invasion and metastasis; thus, trials with neoadjuvant chemotherapy for downstaging the cancer should be considered. Docetaxel is a semisynthetic taxane that promotes tubulin polymerization and inhibits microtubule depolymerization. In recent studies, many metastatic gastric cancers were treated using neoadjuvant chemotherapy with docetaxel, and the response rates were reported. We report here two cases of locally advanced, non-resectable gastric cancer that were candidates for a curative resection after induction chemotherapy with docetaxel and cisplatin.

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APOPTOTIC EFFECT IN COMBINATION OF CYCLOSPORIN A AND TAXOL ON ORAL SQUAMOUS CELL CARCINOMA CELL LINE THROUGH THE PI-3 KINASE/AKT1 PATHWAY (구강 편평세포암종 세포주에서 Cyclosporin A와 Taxol 투여시 PI-3 kinase/Akt1 Pathway에 의한 세포사멸 병용효과)

  • Kim, Kyu-Young;Lee, Jae-Hoon
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.33 no.5
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    • pp.426-436
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    • 2007
  • Oral cancer take up 2-6% of all carcinomas and squamous cell carcinoma, which is the most common type in oral cancer, has a poor prognosis due to its high metastasis and recurrence rates. In treating oral cancer, chemotherapy to the primary, metastasized and recurrent lesion is a very important and useful treatment, even though its widespread usage is limited due to high general toxicity and local toxicity to other organs. Taxol, a microtubule stabilizing agent, is an anticancer drug that induces cell apoptosis by inhibiting depolymerization of microtubules in between the metaphase and anaphase of the cell mitosis. Recently, its effectiveness and mechanism on various tumor has been reported. However, not much research has been done on the application of Taxol to oral squamous cell carcinoma. Cyclosporin A, which is an immunosuppressant, is being used on cancers and when co-administered with Taxol, effectiveness of Taxol is enhanced by inhibition of Taxol induced multidrug resistance. In this study, Cyclosporin A with different concentration of Taxol was co-administered to HN22, the oral squamous cell carcinomacell line. To observe the cell apoptosis and the mechanisms that take part in this process, mortality evaluation of tumor cell using wortmannin, c-DNA microarray, RT-PCR analysis, cytometry analysis and western blotting were used, and based upon the observation on the effect and mechanism of the agent, the following results were obtained: 1. The HN22 cell line viability was lowest when $100{\mu}M$ of Wortmannin and $5{\mu}g/ml$ of Taxol were co-administered, showing that Taxol participates in P13K-AKT1 pathway. 2. In c-DNA microarray, where $1{\mu}g/ml$ of cyclosporine A and 3mg/ml of Taxol were co-administered, no up regulation of AKT1, PTEN and BAD c-DNA that participate in cell apoptosis was observed. 3. When $1{\mu}g/ml$ of Cyclosporin A was applied alone to HN22 cell line, no difference was found in AKT1, PTEN and BAD mRNA expression. 4. Increased AKT1, mRNA expression was observed when $3{\mu}g/ml$ of Taxol was applied alone to HN22 cell line. 5. When $1{\mu}g/ml$ of Cyclosporin A and Taxol($3{\mu}g/ml\;and\;5{\mu}g/ml$) were co-administered to HN22 cell line, PTEN mRNA expression increased, whereas AKT1 and BAD mRNA decreased. 6. As a result of cytometry analysis, in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration, increased Annxin V was observed, which shows that apoptosis occurred by deformation of plasma membrane. However, no significant difference was observed with vary ing concentration. 7. In western blot analysis, no caspase 3 was observed in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration. From the results of this study, it can be concluded that synergistic effect can be observed in combination therapy of Taxol and Cyclosporin A on oral squamous cell carcinoma cell line, where decreased activity of the cell line was observed. This resulted in decreased AKT1 and BAD mRNA and increased PTEN mRNA expression and when wortmannin and Taxol were co-administered, the viability decreased which confirms that Taxol decreases the viability of tumor cell line. Hence, when Taxol and cyclosporine A are co-administered, it can be assumed that cell apoptosis occurs through AKt1 pathway.