Resveratrol enhances ionizing radiation-induced premature senescence in lung cancer cells

Radiotherapy is used in >50% of patients during the course of cancer treatment both as a curative modality and for palliation. However, radioresistance is a major obstacle to the success of radiation therapy and contributes significantly to tumor recurrence and treatment failure, highlighting the need for the development of novel radiosensitizers that can be used to overcome tumor radioresistance and, thus, improve the efficacy of radiotherapy. Previous studies indicated that resveratrol (RV) may sensitize tumor cells to chemotherapy and ionizing radiation (IR). However, the mechanisms by which RV increases the radiation sensitivity of cancer cells have not been well characterized. Here, we show that RV treatment enhances IR-induced cell killing in non-small cell lung cancer (NSCLC) cells through an apoptosis-independent mechanism. Further studies revealed that the percentage of senescence-associated β-galactosidase (SA-β-gal)-positive senescent cells was markedly higher in cells treated with IR in combination with RV compared with cells treated either with IR or RV alone, suggesting that RV treatment enhances IR-induced premature senescence in lung cancer cells. Comet assays demonstrate that RV and IR combined treatment causes more DNA double-strand breaks (DSBs) than IR or RV treatment alone. DCF-DA staining and flow cytometric analyses demonstrate that RV and IR combined treatment leads to a significant increase in ROS production in irradiated NSCLC cells. Furthermore, our investigation show that inhibition of ROS production by N-acetyl-cysteine attenuates RV-induced radiosensitization in lung cancer cells. Collectively, these results demonstrate that RV-induced radiosensitization is associated with significant increase of ROS production, DNA-DSBs and senescence induction in irradiated NSCLC cells, suggesting that RV treatment may sensitize lung cancer cells to radiotherapy via enhancing IR-induced premature senescence.

[1]  G. Silvestri,et al.  Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence. , 2013, Lung cancer.

[2]  M. Wargovich,et al.  Resveratrol Induces Premature Senescence in Lung Cancer Cells via ROS-Mediated DNA Damage , 2013, PloS one.

[3]  K. Brown,et al.  Resveratrol in human cancer chemoprevention--choosing the 'right' dose. , 2012, Molecular nutrition & food research.

[4]  G. Calin,et al.  MicroRNA regulation of ionizing radiation-induced premature senescence. , 2011, International journal of radiation oncology, biology, physics.

[5]  R. Bristow,et al.  Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways , 2011, Radiation oncology.

[6]  B. Telfer,et al.  Inhibition of PARP-1 by Olaparib (AZD2281) Increases the Radiosensitivity of a Lung Tumor Xenograft , 2011, Molecular Cancer Therapeutics.

[7]  S. Choi,et al.  Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy. , 2011, Biochemical and biophysical research communications.

[8]  B. Aggarwal,et al.  Chemosensitization of tumors by resveratrol , 2011, Annals of the New York Academy of Sciences.

[9]  Karen Brown,et al.  Clinical trials of resveratrol , 2011, Annals of the New York Academy of Sciences.

[10]  J. Cui,et al.  Antiproliferative effect of resveratrol in pancreatic cancer cells , 2010, Phytotherapy research : PTR.

[11]  David F Jarrard,et al.  Therapy-induced senescence in cancer. , 2010, Journal of the National Cancer Institute.

[12]  A. Takahashi,et al.  Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status. , 2010, International journal of oncology.

[13]  F. Khuri,et al.  Cancer prevention with natural compounds. , 2010, Seminars in oncology.

[14]  S. Pazhanisamy,et al.  Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells. , 2009, Free radical biology & medicine.

[15]  J. Beaudeux,et al.  Resveratrol bioavailability and toxicity in humans. , 2010, Molecular nutrition & food research.

[16]  S. Lowe,et al.  TAp63 induces senescence and suppresses tumorigenesis in vivo , 2009, Nature Cell Biology.

[17]  L. Moretti,et al.  Combined Bcl-2/Mammalian Target of Rapamycin Inhibition Leads to Enhanced Radiosensitization via Induction of Apoptosis and Autophagy in Non–Small Cell Lung Tumor Xenograft Model , 2009, Clinical Cancer Research.

[18]  D. Butkiewicz,et al.  Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1 , 2009, Mechanisms of Ageing and Development.

[19]  Peng Huang,et al.  Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? , 2009, Nature Reviews Drug Discovery.

[20]  M. Minella,et al.  Resveratrol sensitization of DU145 prostate cancer cells to ionizing radiation is associated to ceramide increase. , 2007, Cancer letters.

[21]  A. Maity,et al.  Inhibition of Phosphatidylinositol-3-OH Kinase/Akt Signaling Impairs DNA Repair in Glioblastoma Cells following Ionizing Radiation* , 2007, Journal of Biological Chemistry.

[22]  E. Yorke,et al.  High-Dose Radiotherapy for the Treatment of Inoperable Non–Small Cell Lung Cancer , 2007, Cancer journal.

[23]  J. Crowell,et al.  Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent , 2007, Cancer Epidemiology Biomarkers & Prevention.

[24]  C. Schmitt.  Cellular senescence and cancer treatment. , 2007, Biochimica et biophysica acta.

[25]  Jinsong Liu,et al.  Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. , 2006, Cancer cell.

[26]  Joseph A. Baur,et al.  Therapeutic potential of resveratrol: the in vivo evidence , 2006, Nature Reviews Drug Discovery.

[27]  H. Stein,et al.  Oncogene-induced senescence as an initial barrier in lymphoma development , 2005, Nature.

[28]  A. Gescher,et al.  Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′‐tetramethoxystilbene (DMU‐212) on adenoma development in the ApcMin+ mouse and cyclooxygenase‐2 in human‐derived colon cancer cells , 2005, International journal of cancer.

[29]  L. Elmore,et al.  p53-Dependent accelerated senescence induced by ionizing radiation in breast tumour cells , 2005, International journal of radiation biology.

[30]  C. Ling,et al.  Results of a phase I dose‐escalation study using three‐dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma , 2005, Cancer.

[31]  R. Levine,et al.  Resveratrol-induced apoptotic death in human U251 glioma cells , 2005, Molecular Cancer Therapeutics.

[32]  Yong Wang,et al.  Inhibition of phosphatidylinostol 3-kinase uncouples H2O2-induced senescent phenotype and cell cycle arrest in normal human diploid fibroblasts. , 2004, Experimental cell research.

[33]  M. Mergeay,et al.  Enhanced radiation-induced apoptosis of cancer cell lines after treatment with resveratrol. , 2004, International journal of molecular medicine.

[34]  Robert Almassy,et al.  Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. , 2004, Journal of the National Cancer Institute.

[35]  E. Hall,et al.  Radiation-induced second cancers: the impact of 3D-CRT and IMRT. , 2003, International journal of radiation oncology, biology, physics.

[36]  S. Joel,et al.  DNA damage is able to induce senescence in tumor cells in vitro and in vivo. , 2002, Cancer research.

[37]  D. Gius,et al.  Radiosensitizing and anti-proliferative effects of resveratrol in two human cervical tumor cell lines. , 2002, Cancer letters.

[38]  J. Pezzuto,et al.  Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. , 2001, Cancer research.

[39]  M. Anscher,et al.  Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. , 1998, International journal of radiation oncology, biology, physics.

[40]  A. Miyajima,et al.  Role of reactive oxygen species in cis-dichlorodiammineplatinum-induced cytotoxicity on bladder cancer cells. , 1997, British Journal of Cancer.

[41]  Patrick R. Griffin,et al.  Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis , 1995, Nature.

[42]  Y. Lazebnik,et al.  Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE , 1994, Nature.