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

Slides:

Advertisements

Similar presentations

Volume 66, Issue 6, Pages (June 2017)

Advertisements

Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

Inducible EGFR T790M-Mediated Gefitinib Resistance in Non-small Cell Lung Cancer Cells Does Not Modulate Sensitivity to PI103 Provoked Autophagy Flavia.

Induction of Forkhead Class box O3a and apoptosis by a standardized ginsenoside formulation, KG-135, is potentiated by autophagy blockade in A549 human.

Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.

Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy

Induction of apoptosis of lung and esophageal cancer cells treated with the combination of histone deacetylase inhibitor (trichostatin A) and protein.

INHBA Overexpression Promotes Cell Proliferation and May Be Epigenetically Regulated in Esophageal Adenocarcinoma Christopher W. Seder, MD, Wibisono.

The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild-Type EGFR Non-Small-Cell Lung Cancer Cells to Erlotinib Yiyu Zou, PhD, Yi-He.

MicroRNA-30b is a multifunctional regulator of aortic valve interstitial cells Mi Zhang, MD, Xiaohong Liu, MD, Xiwu Zhang, MD, Zhigang Song, MD, Lin Han,

Yunguang Sun, PhD, Luigi Moretti, MD, Nicholas J

miR-133a positively regulated p53/p21 pathway.

Inactivation of Both FHIT and p53 Cooperate in Deregulating Proliferation-Related Pathways in Lung Cancer Francesca Andriani, PharmD, Elena Roz, MD,

Soy Isoflavones Augment Radiation Effect by Inhibiting APE1/Ref-1 DNA Repair Activity in Non-small Cell Lung Cancer Vinita Singh-Gupta, PhD, Michael.

Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in.

Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo Jessica A. Yu, MD, David Mauchley, MD, Howard Li, MD, Xianzhong.

Marieke A. de Graaff, Shruti Malu, Irma Guardiola, Alwine B

INHBA Overexpression Promotes Cell Proliferation and May Be Epigenetically Regulated in Esophageal Adenocarcinoma Christopher W. Seder, MD, Wibisono.

MET Tyrosine Kinase Inhibitor Crizotinib (PF ) Shows Differential Antitumor Effects in Non-small Cell Lung Cancer According to MET Alterations

A Novel IMP1 Inhibitor, BTYNB, Targets c-Myc and Inhibits Melanoma and Ovarian Cancer Cell Proliferation Lily Mahapatra, Neal Andruska, Chengjian Mao,

A High Content Clonogenic Survival Drug Screen Identifies MEK Inhibitors as Potent Radiation Sensitizers for KRAS Mutant Non–Small-Cell Lung Cancer Steven.

Histone Deacetylase Inhibitors Sensitize Human Non-small Cell Lung Cancer Cells to Ionizing Radiation Through Acetyl p53-Mediated c-myc Down-Regulation

TGM2: A Cell Surface Marker in Esophageal Adenocarcinomas

Volume 134, Issue 1, Pages (January 2008)

The Zinc Ionophore PCI-5002 Radiosensitizes Non-small Cell Lung Cancer Cells by Enhancing Autophagic Cell Death Kwang Woon Kim, PhD, Christina K. Speirs,

Volume 19, Issue 2, Pages (February 2017)

A Histone Deacetylase Inhibitor LBH589 Downregulates XIAP in Mesothelioma Cell Lines Which is Likely Responsible for Increased Apoptosis With TRAIL James.

Interferon-γ Protects from Staphylococcal Alpha Toxin-Induced Keratinocyte Death through Apolipoprotein L1 Anne M. Brauweiler, Elena Goleva, Donald Y.M.

Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.

Combined Radiotherapy and Anti–PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non–Small Cell Lung Cancer Xiaomei Gong, MD, PhD, Xuefei Li,

Volume 141, Issue 2, Pages (August 2011)

Induction of apoptosis of lung and esophageal cancer cells treated with the combination of histone deacetylase inhibitor (trichostatin A) and protein.

Inhibition of Hsp90 Leads to Cell Cycle Arrest and Apoptosis in Human Malignant Pleural Mesothelioma Junichi Okamoto, MD, PhD, Iwao Mikami, MD, PhD,

MET Increases the Sensitivity of Gefitinib-Resistant Cells to SN-38, an Active Metabolite of Irinotecan, by Up-Regulating the Topoisomerase I Activity

Sensitization of Melanoma Cells for Death Ligand TRAIL Is Based on Cell Cycle Arrest, ROS Production, and Activation of Proapoptotic Bcl-2 Proteins Sandra-Annika.

Inducible EGFR T790M-Mediated Gefitinib Resistance in Non-small Cell Lung Cancer Cells Does Not Modulate Sensitivity to PI103 Provoked Autophagy Flavia.

Volume 120, Issue 6, Pages (March 2005)

The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild-Type EGFR Non-Small-Cell Lung Cancer Cells to Erlotinib Yiyu Zou, PhD, Yi-He.

Zoledronic Acid Produces Antitumor Effects on Mesothelioma Through Apoptosis and S- Phase Arrest in p53-Independent and Ras prenylation-Independent Manners

Andreea M. Bujor, Jaspreet Pannu, Shizhong Bu, Edwin A. Smith, Robin C

Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in.

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,

MicroRNA-101 Exerts Tumor-Suppressive Functions in Non-small Cell Lung Cancer through Directly Targeting Enhancer of Zeste Homolog 2 Ji-guang Zhang,

Miral R. Sadaria, MD, Amy E. Reppert, MD, Jessica A

Lovastatin Sensitizes Lung Cancer Cells to Ionizing Radiation: Modulation of Molecular Pathways of Radioresistance and Tumor Suppression Toran Sanli,

Terameprocol (Tetra-O-Methyl Nordihydroguaiaretic Acid), an Inhibitor of Sp1-Mediated Survivin Transcription, Induces Radiosensitization in Non-small.

BCL11B-Mediated Epigenetic Repression Is a Crucial Target for Histone Deacetylase Inhibitors in Cutaneous T-Cell Lymphoma Wenjing Fu, Shengguo Yi, Lei.

BV6, an IAP Antagonist, Activates Apoptosis and Enhances Radiosensitization of Non- small Cell Lung Carcinoma In Vitro Wenyan Li, MD, PhD, Bo Li, MD,

Chadrick E Denlinger, MD, Michael D Keller, BS, Marty W Mayo, PhD, R

Dasatinib, a small molecule inhibitor of the Src kinase, reduces the growth and activates apoptosis in pre-neoplastic Barrett's esophagus cell lines:

Inhibition of CRM1-Mediated Nucleocytoplasmic Transport: Triggering Human Melanoma Cell Apoptosis by Perturbing Multiple Cellular Pathways Gaurav Pathria,

Antiestrogen Fulvestrant Enhances the Antiproliferative Effects of Epidermal Growth Factor Receptor Inhibitors in Human Non–Small-Cell Lung Cancer Edward.

SiRNA Knockdown of Ribonucleotide Reductase Inhibits Melanoma Cell Line Proliferation Alone or Synergistically with Temozolomide Jonathan E. Zuckerman,

Genetic Disruption of KEAP1/CUL3 E3 Ubiquitin Ligase Complex Components is a Key Mechanism of NF-KappaB Pathway Activation in Lung Cancer Kelsie L. Thu,

Inhibition of β-Catenin Enhances the Anticancer Effect of Irreversible EGFR-TKI in EGFR-Mutated Non–small-cell Lung Cancer with a T790M Mutation Yosuke.

Histone Deacetylase Inhibitor Romidepsin Enhances Anti-Tumor Effect of Erlotinib in Non-small Cell Lung Cancer (NSCLC) Cell Lines Wei Zhang, PhD, Michael.

Volume 18, Issue 8, Pages (February 2017)

Schedule-Dependent Interaction between the Proteosome Inhibitor Bortezomib and the EGFR-TK Inhibitor Erlotinib in Human Non-small Cell Lung Cancer Cell.

Mitotic Inhibitors Journal of Thoracic Oncology

Coactivation of Receptor Tyrosine Kinases in Malignant Mesothelioma as a Rationale for Combination Targeted Therapy Marie Brevet, MD, PhD, Shigeki Shimizu,

BCL11B-Mediated Epigenetic Repression Is a Crucial Target for Histone Deacetylase Inhibitors in Cutaneous T-Cell Lymphoma Wenjing Fu, Shengguo Yi, Lei.

MET Increases the Sensitivity of Gefitinib-Resistant Cells to SN-38, an Active Metabolite of Irinotecan, by Up-Regulating the Topoisomerase I Activity

Volume 24, Issue 6, Pages (June 2016)

Volume 23, Issue 4, Pages (April 2015)

Sequence-dependent enhancement of paclitaxel toxicity in non–small cell lung cancer by 17-allylamino 17-demethoxygeldanamycin Dao M. Nguyen, MD, FRCSC,

Elevated Expression of BIRC6 Protein in Non–Small-Cell Lung Cancers is Associated with Cancer Recurrence and Chemoresistance Xin Dong, MD, Dong Lin,

CYP1A1 knockdown increases cell death.

Volume 66, Issue 3, Pages (March 2017)

Signal Transducer and Activator of Transcription 3 as Molecular Therapy for Non–Small- Cell Lung Cancer Cheng-Yi Wang, MD, Ting-Ting Chao, PhD, Wei-Tien.

Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy

Presentation transcript:

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 661-670 (April 2011) DOI: 10.1097/JTO.0b013e31820c9e3c Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

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, 661-670DOI: (10.1097/JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

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 [http://links.lww.com/JTO/A62]. 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 [http://links.lww.com/JTO/A62]. Journal of Thoracic Oncology 2011 6, 661-670DOI: (10.1097/JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

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 [http://links.lww.com/JTO/A62]. 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, 661-670DOI: (10.1097/JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

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 [http://links.lww.com/JTO/A62]. 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, 661-670DOI: (10.1097/JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

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, 661-670DOI: (10.1097/JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

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 [http://links.lww.com/JTO/A62]. 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, 661-670DOI: (10.1097/JTO.0b013e31820c9e3c) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions