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The Human Immunodeficiency Virus Protease Inhibitor Ritonavir Inhibits Lung Cancer Cells, in Part, by Inhibition of Survivin  Anjaiah Srirangam, PhD,

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Presentation on theme: "The Human Immunodeficiency Virus Protease Inhibitor Ritonavir Inhibits Lung Cancer Cells, in Part, by Inhibition of Survivin  Anjaiah Srirangam, PhD,"— Presentation transcript:

1 The Human Immunodeficiency Virus Protease Inhibitor Ritonavir Inhibits Lung Cancer Cells, in Part, by Inhibition of Survivin  Anjaiah Srirangam, PhD, Monica Milani, PhD, Ranjana Mitra, PhD, Zhijun Guo, PhD, Mariangellys Rodriguez, BS, Hitesh Kathuria, PhD, Seiji Fukuda, MD, PhD, Anthony Rizzardi, BS, Stephen Schmechel, MD, PhD, David G. Skalnik, PhD, Louis M. Pelus, PhD, David A. Potter, MD, PhD  Journal of Thoracic Oncology  Volume 6, Issue 4, Pages (April 2011) DOI: /JTO.0b013e31820c9e3c Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 Panel A, Ritonavir inhibits growth of the lung adenocarcinoma lines A549 and H522. Ritonavir inhibited the growth of both lines, exhibiting an half maximal inhibitory concentration (IC50) of 35 μM for A549 (open circles) and 42 μM for H522 (open squares). Results are representative of three consistent experiments. Panel B, Ritonavir reduces the clonogenic efficiency of the lung adenocarcinoma lines A549 and H522. Ritonavir was efficient in reducing the clonogenic efficiency in both the A549 (open circles) and H522 (open squares) lines, exhibiting an IC50 of 30 and 40 μM, respectively. Panel C, Ritonavir induces apoptosis of the lung adenocarcinoma lines A549 and H522. Ritonavir significantly increased early- and late-apoptotic events in both lines. The results are representative of two consistent experiments. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Panel A, Ritonavir causes G0/G1 cell cycle arrest in the A549 and H522 lung adenocarcinoma lines. Ritonavir was able to induce a G0/G1 block as demonstrated by increase of the G0/G1 population and by a corresponding reduction of the S and G2/M populations. Cells grown with ritonavir or vehicle are indicated with (+) and (−), respectively. For quantitation of the flow cytometry analysis, see Table 2S [ Panel B, Ritonavir down-regulates the expression of numerous cell cycle-associated proteins in the lung adenocarcinoma lines A549 and H522. CDK2, CDK4, CDK6, cyclin D1, cyclin A, phospho-retinoblastoma protein (Rb), and Rb levels were reduced in both lines treated with ritonavir. Levels of p53 were reduced in the H522 line but increased in the A549 line. The levels of p27Kip1 were increased in both lines. For quantitation of the Western blots, see Table S3 [ Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Panel A, Ritonavir down-regulates the expression of phospho-c-Src, Src, phospho signal transducer and activator of transcription protein (STAT)3, and survivin and increases cleaved PARP in the lung adenocarcinoma lines A549 and H522. Both in the A549 and H522 line, ritonavir reduced phospho-c-Src, phospho-STAT3, and survivin levels, whereas it increased the cleaved PARP levels; it did not affect total STAT3 levels, and it down-regulated total c-Src only in the H522 line. Cells growth with ritonavir or vehicle are indicated with (+) and (−), respectively. For quantitation of the Western blots, see Table S4a [ Panel B, Ritonavir down-regulates survivin mRNA in the lung adenocarcinoma lines A549 and H522. After 48 hours of treatment, ritonavir drastically reduced the levels of survivin messenger RNA (mRNA) in both lines. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

5 FIGURE 4 Panel A, c-Src, STAT3, and survivin siRNA reduce the levels of their target proteins. The (−) column indicates nontarget siRNA, whereas the (+) column indicates specific siRNA as labeled. The siRNA to c-Src, STAT3, and survivin reduced the level of the corresponding protein in all three lines. For quantitation of the Western blots, see Table S4b [ Panel B, siRNA targeting c-Src, STAT3, and survivin reduces growth of the lung adenocarcinoma lines A549 and H522. Cells treated with siRNA targeting c-Src, STAT3, and survivin exhibited reduced growth, when compared with cells treated with nontargeting siRNA. p value of <0.05 is indicated with an asterisk. Panel C, siRNA targeting c-Src or STAT3 does not reduce ritonavir half maximal inhibitory concentration (IC50) for the lung adenocarcinoma lines A549 and H522. A549 and H522 cells transfected with siRNA targeting c-Src, STAT3, survivin, or nontargeting siRNA were grown in the presence of increasing concentrations of ritonavir. Silencing of survivin mRNA expression increased the cell sensitivity to ritonavir, reducing its IC50 to 25 μM for the A459 line and 27 μM for the H522 line. Panel D, siRNA targeting survivin increases the sensitivity to ritonavir of the lung adenocarcinoma lines A549 and H522. A549 and H522 cells transfected with siRNA targeting survivin were treated with ritonavir at the appropriate IC50. Survivin siRNA and ritonavir acted together to reduce cell growth in both lines. p value of <0.05 is indicated with an asterisk. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

6 FIGURE 5 Panel A, Overexpression of survivin in the lung adenocarcinoma lines A549 and H522. Cells transiently transfected with human survivin complementary DNA (cDNA) had significantly higher levels of survivin, when compared with cells transfected with the empty vector. Panel B, Overexpression of survivin increases resistance of the lung adenocarcinoma lines A549 and H522 to ritonavir. Overexpression of survivin reduced the cell sensitivity to ritonavir, increasing its half maximal inhibitory concentration (IC50) to 45 μM for the A549 line and 55 μM for the H522 line. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

7 FIGURE 6 Panel A, Gemcitabine and ritonavir down-regulate the survivin levels of the lung adenocarcinoma lines A549 and H522. Ritonavir was able to reduce the levels of survivin either when used alone or together with gemcitabine. For quantitation of the Western blots, see Table S5 [ Panel B, Ritonavir and gemcitabine synergize in inhibiting the growth of the lung adenocarcinoma lines A549 and H522. The combination gemcitabine and ritonavir had a synergic effect and was significantly more effective in reducing growth compared with each drug alone. On the other hand, the combined effect of ritonavir and cisplatin was additive for the A549 and H522 lines. Panel C, The combination ritonavir/gemcitabine/cisplatin is synergistic in the A549 line and additive in the H522 line. The concentrations of ritonavir (R), gemcitabine (G), and cisplatin (C) are indicated on the x axis. The combination ritonavir/gemcitabine/cisplatin acted synergistically in the A549 line and additively in the H522 line. The combination gemcitabine/cisplatin was superior to ritonavir/gemcitabine/cisplatin in the H522 line but not in the A549 line. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

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