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AT-101, a Pan-Bcl-2 Inhibitor, Leads to Radiosensitization of Non-small Cell Lung Cancer  Luigi Moretti, MD, Bo Li, MD, Kwang Woon Kim, PhD, Heidi Chen,

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Presentation on theme: "AT-101, a Pan-Bcl-2 Inhibitor, Leads to Radiosensitization of Non-small Cell Lung Cancer  Luigi Moretti, MD, Bo Li, MD, Kwang Woon Kim, PhD, Heidi Chen,"— Presentation transcript:

1 AT-101, a Pan-Bcl-2 Inhibitor, Leads to Radiosensitization of Non-small Cell Lung Cancer 
Luigi Moretti, MD, Bo Li, MD, Kwang Woon Kim, PhD, Heidi Chen, MS, Bo Lu, MD, PhD  Journal of Thoracic Oncology  Volume 5, Issue 5, Pages (May 2010) DOI: /JTO.0b013e3181d6e08e Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 Schematic overview showing the action of AT-101 in the apoptotic signaling cascade. Antiapoptotic members of the Bcl-2 family (Bcl-2, Mcl-1, and Bcl-XL) are targeted by AT-101 to allow proapoptotic members (Bax/Bak) to mediate apoptosis. Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181d6e08e) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Clonogenic lung cancer survival after radiotherapy. Clonogenic assay showing sensitivity of A549 and HCC2429 lung cancer cells. Cells were irradiated with the indicated doses of radiation. After 8 days, colonies were stained and scored for colony formation, and the surviving fractions were plotted in a semi-log format. The mean ± standard deviation of three separate repeated experiments are shown. Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181d6e08e) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Radiation-induced apoptosis in lung cancer cell lines. Caspase-3 activation during lung cancer cells apoptosis after radiation treatment. Representative caspase-3 cleavage pattern analyzed using Western blot analysis. Actin was probed to demonstrate equal loading. Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181d6e08e) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

5 FIGURE 4 Bcl-2 family protein expression in lung cancer cell lines. A, Representative Western blot analysis showing relative levels of expression of Bcl-2 family proteins in A549 and HCC2429 lung cancer cell lines. Actin was probed to demonstrate equal loading. B, Densitometry data present relative expression of Bcl-2 family proteins after normalization to actin expression. Data are shown as mean (columns) with standard deviation (bars). Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181d6e08e) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

6 FIGURE 5 Apoptosis after AT-101 treatment with or without radiation in lung cancer cell lines. A549 and HCC2429 cells were pretreated with AT-101 for 2 hours followed by radiation (0 or 6 Gy). A, Caspase-3 activation during A549 and HCC2429 lung cancer cells apoptosis after dimethyl sulfoxide (DMSO), 1 or 10 μM AT-101, at 14 and 26 hours. Actin was probed to demonstrate equal loading. B, Caspase-3 activation during A549 and HCC2429 lung cancer cells apoptosis after DMSO, AT-101 (10 μM for 14 hours), radiation (6 Gy), or combination of both AT-101 and radiation (6 Gy) at 36 hours. Actin was probed to demonstrate equal loading. A549 (C) and HCC2429 (D) cells were stained with Annexin V and propidium iodide and analyzed using flow cytometry. This experiment was performed in triplicate and representative diagrams of Annexin V assays are shown. Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181d6e08e) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

7 FIGURE 6 AT-101 reduces cell proliferation and sensitizes lung cancer cells to radiotherapy. A, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 8 hours treatment with either dimethyl sulfoxide (DMSO) or AT-101 (10 μM) alone, radiation (6 Gy), or combination of both AT-101 (10 μM) and radiation (6 Gy). Data are shown as mean (columns) with standard deviation (bars). B, MTT assay after 14 hours treatment with either DMSO or AT-101 (10 μM) alone, radiation (6 Gy), or combination of both AT-101 (10 μM) and radiation (6 Gy). Data are shown as mean (columns) with standard deviation (bars). Clonogenic assays showing sensitivity of A549 (B) and HCC2429 (C) lung cancer cells. Cells were treated with DMSO or AT-101 (5μM for 14 hours) and then irradiated with the indicated doses of radiation. After 8 days, colonies were stained and scored for colony formation, and the surviving fractions were plotted in a semi-log format. Mean ± SD of three separate repeated experiments are shown. D, Isobologram analysis of the combination of AT-101 and radiation shows an additive interaction in both A549 and HCC2429 cells. The red dot represents the concentrations of both drugs that result in a MTT activity, that is, 50% of control (IC50). Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181d6e08e) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

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