The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform

Yang Liao - One of the best experts on this subject based on the ideXlab platform.

  • Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to Mitotic inhibitor induced cell death.
    American journal of cancer research, 2014
    Co-Authors: Jiong Zhao, Zhenyu Zhang, Yang Liao
    Abstract:

    The retinoblastoma gene Rb is a prototype tumor suppressor, which encodes a protein that is inactivated in a broad range of human cancers through different mechanisms. Rb functions to regulate cell proliferation, differentiation, as well as cell death. Therefore, even though Rb inactivation promotes cancer development, this may also open up certain vulnerabilities of cancers that can potentially be targeted with drug intervention. Based on the assumption that cancers that have mutation, deletion, or rearrangement in the Rb locus represent strong loss of Rb function while cancers with WT Rb on average retain some Rb function, we searched Genomics of Drug Sensitivity in Cancer database to identify cancer drugs that are particularly effective to cancers with Rb genomic alterations. Three Mitotic Inhibitors were identified from this analysis. We further tested the effects of two Mitotic Inhibitors, Taxol and STLC, on prostate and breast cancer cells. We demonstrate that the Rb status affects cancer cell sensitivity to these Mitotic drugs and that the sensitizing effects of Rb are mediated in part by its regulation of the cell cycle checkpoint protein Mad2. Since the Mitotic Inhibitors identified in our analysis inhibit mitosis through distinct targets, it is possible that the Rb functional status may serve as a general biomarker for cancer sensitivity to Mitotic Inhibitors. Because the Rb pathway is inactivated in a large number of human cancers, identification of agents that are particularly effective or ineffective based on the Rb status in cancers can potentially be used generally to matching patients with appropriate treatments to achieve better therapeutic outcome.

  • Original Article Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to Mitotic inhibitor induced cell death
    2014
    Co-Authors: Jiong Zhao, Zhenyu Zhang, Yang Liao, Ben May
    Abstract:

    * Equal contributors. Received October 14, 2013; Accepted November 18, 2013; Epub January 15, 2014; Published January 30, 2014 Abstract: The retinoblastoma gene Rb is a prototype tumor suppressor, which encodes a protein that is inactivated in a broad range of human cancers through different mechanisms. Rb functions to regulate cell proliferation, dif- ferentiation, as well as cell death. Therefore, even though Rb inactivation promotes cancer development, this may also open up certain vulnerabilities of cancers that can potentially be targeted with drug intervention. Based on the assumption that cancers that have mutation, deletion, or rearrangement in the Rb locus represent strong loss of Rb function while cancers with WT Rb on average retain some Rb function, we searched Genomics of Drug Sensitivity in Cancer database to identify cancer drugs that are particularly effective to cancers with Rb genomic alterations. Three Mitotic Inhibitors were identified from this analysis. We further tested the effects of two Mitotic Inhibitors, Taxol and STLC, on prostate and breast cancer cells. We demonstrate that the Rb status affects cancer cell sensi- tivity to these Mitotic drugs and that the sensitizing effects of Rb are mediated in part by its regulation of the cell cycle checkpoint protein Mad2. Since the Mitotic Inhibitors identified in our analysis inhibit mitosis through distinct targets, it is possible that the Rb functional status may serve as a general biomarker for cancer sensitivity to Mitotic Inhibitors. Because the Rb pathway is inactivated in a large number of human cancers, identification of agents that are particularly effective or ineffective based on the Rb status in cancers can potentially be used generally to match- ing patients with appropriate treatments to achieve better therapeutic outcome.

Michael A. Teitell - One of the best experts on this subject based on the ideXlab platform.

  • Identifying fates of cancer cells exposed to Mitotic Inhibitors by quantitative phase imaging.
    The Analyst, 2019
    Co-Authors: Dian Huang, Irena J. Roy, Graeme F. Murray, Jason Reed, Thomas A. Zangle, Michael A. Teitell
    Abstract:

    Cell cycle deregulation is a cancer hallmark that has stimulated the development of Mitotic Inhibitors with differing mechanisms of action. Quantitative phase imaging (QPI) is an emerging approach for determining cancer cell sensitivities to chemotherapies in vitro. Cancer cell fates in response to Mitotic Inhibitors are agent- and dose-dependent. Fates that lead to chromosomal instabilities may result in a survival advantage and drug resistance. Conventional techniques for quantifying cell fates are incompatible with growth inhibition assays that produce binary live/dead results. Therefore, we used QPI to quantify post-Mitotic fates of G0/G1 synchronized HeLa cervical adenocarcinoma and M202 melanoma cells during 24 h of escalating-dose exposures to Mitotic Inhibitors, including microtubule Inhibitors paclitaxel and colchicine, and an Aurora kinase A inhibitor, VX-680. QPI determined cell fates by measuring changes in cell biomass, morphology, and mean phase-shift. Cell fates fell into three groups: (1) bipolar division from drug failure; (2) cell death or sustained Mitotic arrest; and (3) aberrant endocycling or multipolar division. In this proof-of-concept study, colchicine was most effective in producing desirable outcomes of sustained Mitotic arrest or death throughout its dosing range, whereas both paclitaxel and VX-680 yielded dose-dependent multipolar divisions or endocycling, respectively. Furthermore, rapid completion of mitosis associated with bipolar divisions whereas prolonged mitosis associated with multipolar divisions or cell death. Overall, QPI measurement of drug-induced cancer cell fates provides a tool to inform the development of candidate agents by quantifying the dosing ranges over which suboptimal inhibitor choices lead to undesirable, aberrant cancer cell fates.

  • Dissection of Melanoma Drug Resistance and Heterogeneity using Live Cell Interferometry
    Biophysical Journal, 2016
    Co-Authors: Dian Huang, Thomas A. Zangle, Michael A. Teitell
    Abstract:

    Cell-cycle dysregulation and increased proliferation are common in cancer. Accordingly, many cancer treatments target mitosis using small molecule Mitotic Inhibitors. In vivo, Mitotic inhibitor levels show great temporal and spatial variability due to many factors, including varied intratumoral vasculature and diffusion rates. Exposure to Mitotic Inhibitors at sub-optimal concentrations can drive cancer cell fates other than the desired apoptosis, senescence, or terminal differentiation, including multi-polar mitoses and cell endocycling. These unwanted fates may pair with chromosomal instability to promote cancer cell drug resistance. We therefore developed a high throughput, quantitative approach based on live cell interferometry (LCI) to dissect dose-dependent cell fate responses to Mitotic Inhibitors. LCI provides precise quantification of cell biophysical properties, such as cell dry mass, by measuring the phase shift of light as it passes through and interacts with cell matter. As proof-of-principle, we tracked thousands of cell-cycle synchronized HeLa cervical carcinoma and M202 patient-derived melanoma cells during 24 hour treatments with escalating doses of taxol, colchicine and VX680, an aurora-kinase B inhibitor. Cell fate, Mitotic entry time and duration of Mitotic arrest were examined for each cell by quantifying cell biomass and average mass per projected area, a sensitive measure of mitosis-associated morphology changes. The data reveal features missed by standard multi-day viability assays, including the percentage of cells exhibiting each identified cell fate. Our results show that LCI can be used to identify optimal drug combinations and concentrations that most efficiently drive cancer cells to death and, more generally, perturbations that drive desired cell fate outcomes. When combined with cell isolation, LCI shows promise to identify and molecularly dissect cells with different fate outcomes, which could provide key information on mechanisms of therapeutic success or resistance.

Mikhail V Blagosklonny - One of the best experts on this subject based on the ideXlab platform.

  • the power of chemotherapeutic engineering arresting cell cycle and suppressing senescence to protect from Mitotic Inhibitors
    Cell Cycle, 2011
    Co-Authors: Mikhail V Blagosklonny
    Abstract:

    Suppose one drug causes lethal Mitotic arrest, another treatment causes irreversible senescence and a third drug inhibits cellular mass growth: Could cells treated with a combination of all three agents magically emerge alive and proliferating? The result of this experiment is presented here. By knowing the mechanisms of cell cycle arrest, death and senescence, we can design "rainbow combinations" that obediently kill or spare desired cells. Knowledge is power.

  • exploring long term protection of normal human fibroblasts and epithelial cells from chemotherapy in cell culture
    Oncotarget, 2011
    Co-Authors: Pasha Apontes, Olga V Leontieva, Zoya N Demidenko, Mikhail V Blagosklonny
    Abstract:

    Killing of proliferating normal cells limits chemotherapy of cancer. Several strategies to selectively protect normal cells were previously suggested. Here we further explored the protection of normal cells from cell cycle-specific chemotherapeutic agents such as Mitotic Inhibitors (MI). We focused on a long-term cell recovery (rather than on a short-term cell survival) after a 3-day exposure to MI (paclitaxel and nocodazole). In three normal human cell types (RPE, NKE, WI-38t cells) but not in cancer cells with mutant p53, pre-treatment with nutlin-3a, a non-genotoxic inducer of wt p53, caused G1 and/or G2 arrest, thus preventing lethal Mitotic arrest caused by MI and allowing normal cells to recover after removal of MI. Rapamycin, an inhibitor of the nutrient-sensing mTOR pathway, potentiated the protective effect of nutlin-3a in normal cells. Also, a combination of rapamycin and metformin, an anti-diabetic drug, induced G1 and G2 arrest selectively in normal cells and thereby protected them from MI. A combination of metformin and rapamycin also protected normal cells in low glucose conditions, whereas in contrast it was cytotoxic for cancer cells. Based on these data and the analysis of the literature, we suggest that a rational combination of metformin and rapamycin can potentiate chemotherapy with Mitotic Inhibitors against cancer, while protecting normal cells, thus further increasing the therapeutic window.

Jiong Zhao - One of the best experts on this subject based on the ideXlab platform.

  • Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to Mitotic inhibitor induced cell death.
    American journal of cancer research, 2014
    Co-Authors: Jiong Zhao, Zhenyu Zhang, Yang Liao
    Abstract:

    The retinoblastoma gene Rb is a prototype tumor suppressor, which encodes a protein that is inactivated in a broad range of human cancers through different mechanisms. Rb functions to regulate cell proliferation, differentiation, as well as cell death. Therefore, even though Rb inactivation promotes cancer development, this may also open up certain vulnerabilities of cancers that can potentially be targeted with drug intervention. Based on the assumption that cancers that have mutation, deletion, or rearrangement in the Rb locus represent strong loss of Rb function while cancers with WT Rb on average retain some Rb function, we searched Genomics of Drug Sensitivity in Cancer database to identify cancer drugs that are particularly effective to cancers with Rb genomic alterations. Three Mitotic Inhibitors were identified from this analysis. We further tested the effects of two Mitotic Inhibitors, Taxol and STLC, on prostate and breast cancer cells. We demonstrate that the Rb status affects cancer cell sensitivity to these Mitotic drugs and that the sensitizing effects of Rb are mediated in part by its regulation of the cell cycle checkpoint protein Mad2. Since the Mitotic Inhibitors identified in our analysis inhibit mitosis through distinct targets, it is possible that the Rb functional status may serve as a general biomarker for cancer sensitivity to Mitotic Inhibitors. Because the Rb pathway is inactivated in a large number of human cancers, identification of agents that are particularly effective or ineffective based on the Rb status in cancers can potentially be used generally to matching patients with appropriate treatments to achieve better therapeutic outcome.

  • Original Article Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to Mitotic inhibitor induced cell death
    2014
    Co-Authors: Jiong Zhao, Zhenyu Zhang, Yang Liao, Ben May
    Abstract:

    * Equal contributors. Received October 14, 2013; Accepted November 18, 2013; Epub January 15, 2014; Published January 30, 2014 Abstract: The retinoblastoma gene Rb is a prototype tumor suppressor, which encodes a protein that is inactivated in a broad range of human cancers through different mechanisms. Rb functions to regulate cell proliferation, dif- ferentiation, as well as cell death. Therefore, even though Rb inactivation promotes cancer development, this may also open up certain vulnerabilities of cancers that can potentially be targeted with drug intervention. Based on the assumption that cancers that have mutation, deletion, or rearrangement in the Rb locus represent strong loss of Rb function while cancers with WT Rb on average retain some Rb function, we searched Genomics of Drug Sensitivity in Cancer database to identify cancer drugs that are particularly effective to cancers with Rb genomic alterations. Three Mitotic Inhibitors were identified from this analysis. We further tested the effects of two Mitotic Inhibitors, Taxol and STLC, on prostate and breast cancer cells. We demonstrate that the Rb status affects cancer cell sensi- tivity to these Mitotic drugs and that the sensitizing effects of Rb are mediated in part by its regulation of the cell cycle checkpoint protein Mad2. Since the Mitotic Inhibitors identified in our analysis inhibit mitosis through distinct targets, it is possible that the Rb functional status may serve as a general biomarker for cancer sensitivity to Mitotic Inhibitors. Because the Rb pathway is inactivated in a large number of human cancers, identification of agents that are particularly effective or ineffective based on the Rb status in cancers can potentially be used generally to match- ing patients with appropriate treatments to achieve better therapeutic outcome.

Trond Stokke - One of the best experts on this subject based on the ideXlab platform.

  • the response of malignant b lymphocytes to ionizing radiation cell cycle arrest apoptosis and protection against the cytotoxic effects of the Mitotic inhibitor nocodazole
    Radiation Research, 2004
    Co-Authors: Kirsti Solberg Landsverk, Heidi Lyng, Trond Stokke
    Abstract:

    Abstract Landsverk, K. S., Lyng, H. and Stokke, T. The Response of Malignant B Lymphocytes to Ionizing Radiation: Cell Cycle Arrest, Apoptosis and Protection against the Cytotoxic Effects of the Mitotic Inhibitor Nocodazole. Radiat. Res. 162, 405–415 (2004). Ionizing radiation and Mitotic Inhibitors are used for the treatment of lymphoma. We have studied cell cycle arrest and apoptosis of three human B-lymphocyte cell lines after X irradiation and/or nocodazole treatment. Radiation (4 and 6 Gy) caused arrest in the G2 phase of the cell cycle as well as in G1 in Reh cells with an intact TP53 response. Reh cells, but not U698 and Daudi cells with defects in the TP53 pathway, died by apoptosis after exposure to 4 or 6 Gy radiation (>15% apoptotic Reh cells and <5% apoptotic U698/Daudi cells 24 h postirradiation). Lower doses of radiation (0.5 and 1 Gy) caused a transient delay in the G2 phase of the cell cycle for the three cell lines but did not induce apoptosis (<5% apoptotic cells at 24 h postirradiation)...

  • The response of malignant B lymphocytes to ionizing radiation: cell cycle arrest, apoptosis and protection against the cytotoxic effects of the Mitotic inhibitor nocodazole.
    Radiation research, 2004
    Co-Authors: Kirsti Solberg Landsverk, Heidi Lyng, Trond Stokke
    Abstract:

    Abstract Landsverk, K. S., Lyng, H. and Stokke, T. The Response of Malignant B Lymphocytes to Ionizing Radiation: Cell Cycle Arrest, Apoptosis and Protection against the Cytotoxic Effects of the Mitotic Inhibitor Nocodazole. Radiat. Res. 162, 405–415 (2004). Ionizing radiation and Mitotic Inhibitors are used for the treatment of lymphoma. We have studied cell cycle arrest and apoptosis of three human B-lymphocyte cell lines after X irradiation and/or nocodazole treatment. Radiation (4 and 6 Gy) caused arrest in the G2 phase of the cell cycle as well as in G1 in Reh cells with an intact TP53 response. Reh cells, but not U698 and Daudi cells with defects in the TP53 pathway, died by apoptosis after exposure to 4 or 6 Gy radiation (>15% apoptotic Reh cells and