title: Induction of Autophagic Cell Death in Apoptosis-resistant Pancreatic Cancer Cells using Benzo[α]phenoxazines Derivatives, 10-methyl-benzo[α]phenoxazine-5-one and benzo[α]phenoxazine-5-one.
abstract: BACKGROUND
  Intrinsic resistance to apoptotic cell death due to co-occurrence of mutated KRAS and p53 is frequently reported in pancreatic cancer that renders them aggressive, highly proliferative and metastatic. In addition, these cancer types are less sensitive to apoptosis inducing drugs where promotion of autophagic cell death could be a viable option for treatment under such circumstances.
  
  
  OBJECTIVE
  In this study we examined the potential of three intrinsically fluorescent benzo[α]phenoxazines or BPZs (R=Cl, CH3, H) to induce cytotoxic autophagy in chemo and apoptosis-resistant, KRAS and p53 mutated pancreatic cancer model cell line, MIAPaCa-2.
  
  
  METHODS
  Cells were adapted at in vitro metabolically stressed condition (5% serum) to initiate intrinsic cell survival strategies within. Cell proliferation, colonogenicity, cellular uptake, retention, localization, cellular granularity and presence of both apoptosis and autophagy biomarkers were assessed in BPZ treated/untreated (solvent) cells to validate induction of concentration dependent cytotoxic autophagy and other consequences.
  
  
  RESULTS
  For the first time, we report the ability of this class of compounds to accumulate within cells increasing its granularity, inducing death via autophagy. From different kinetics study, it was observed that the autophagic-cell death was dependent on the ligand type, duration of incubation or working concentrations.
  
  
  CONCLUSIONS
  Among the three BPZ tested, both 3B (benzo[α]phenoxazine-5-one) and 2B (10-methyl-benzo[α] phenoxazine-5-one) induced pro-death autophagy in MIAPaCa-2 cells at an IC50 of 5 μM and 20 μM respectively. Such compounds would be of great interest to explore as novel cytotoxic autophagy inducing agents in apoptosisresistant cancer types.
authors.forename: Sanjima
authors.initials: S
authors.lastname: Pal
authors.forename: Sunita
authors.initials: S
authors.lastname: Salunke-Gawalib
authors.affiliation: School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O. Box:Khurda-752050, Bhimpur-Padanpur, Via- Jatni, Orissa, India.
authors.forename: V Badireenath
authors.initials: VB
authors.lastname: Konkimallaa
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D009154:Mutation; D010078:Oxazines / Q000737:chemistry* / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D010078:Oxazines; D016159:Tumor Suppressor Protein p53; C039203:phenoxazine; D016283:Proto-Oncogene Proteins p21(ras)