title: Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells.
abstract: BACKGROUND
  Oncolytic viruses represent a promising therapy against cancers with acquired drug resistance. However, low efficacy limits its clinical application. The objective of this study is to investigate whether pharmacologically modulating autophagy could enhance oncolytic Newcastle disease virus (NDV) strain NDV/FMW virotherapy of drug-resistant lung cancer cells.
  
  
  METHODS
  The effect of NDV/FMW infection on autophagy machinery in A549 lung cancer cell lines resistant to cisplatin (A549/DDP) or paclitaxel (A549/PTX) was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, formation of double-membrane vesicles and conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). The effects of autophagy inhibitor chloroquine (CQ) and autophagy inducer rapamycin on NDV/FMW-mediated antitumor activity were evaluated both in culture cells and in mice bearing drug-resistant lung cancer cells.
  
  
  RESULTS
  We show that NDV/FMW triggers autophagy in A549/PTX cells via dampening the class I PI3K/Akt/mTOR/p70S6K pathway, which inhibits autophagy. On the contrary, NDV/FMW infection attenuates the autophagic process in A549/DDP cells through the activation of the negative regulatory pathway. Furthermore, combination with CQ or knockdown of ATG5 significantly enhances NDV/FMW-mediated antitumor effects on A549/DDP cells, while the oncolytic efficacy of NDV/FMW in A549/PTX cells is significantly improved by rapamycin. Interestingly, autophagy modulation does not increase virus progeny in these drug resistant cells. Importantly, CQ or rapamycin significantly potentiates NDV/FMW oncolytic activity in mice bearing A549/DDP or A549/PTX cells respectively.
  
  
  CONCLUSIONS
  These results demonstrate that combination treatment with autophagy modulators is an effective strategy to augment the therapeutic activity of NDV/FMW against drug-resistant lung cancers.
authors: Ke
authors: K
authors: Jiang
authors: Yingchun
authors: Y
authors: Li
authors: Qiumin
authors: Q
authors: Zhu
authors: Jiansheng
authors: J
authors: Xu
authors: Yupeng
authors: Y
authors: Wang
authors: Wuguo
authors: W
authors: Deng
authors: Quentin
authors: Q
authors: Liu
authors: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, Dalian 116044, China. zhang.lth@163.com.
authors: Guirong
authors: G
authors: Zhang
authors: Songshu
authors: S
authors: Meng
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002642:Chick Embryo; D002738:Chloroquine / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009368:Neoplasm Transplantation; D009522:Newcastle disease virus / Q000187:drug effects*; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D008869:Microtubule-Associated Proteins; D002738:Chloroquine; D020123:Sirolimus