title: Novel triterpenoid AECHL-1 induces apoptosis in breast cancer cells by perturbing the mitochondria-endoplasmic reticulum interactions and targeting diverse apoptotic pathways.
abstract: BACKGROUND
  The modus operandi for an anti-cancer drug must allow for an efficient discrimination system between tumorigenic and non-tumorigenic cells. Targeting ER stress and mitochondrial function in cancer cells appears to be a suitable option, as these processes are dysregulated in tumor cells. AECHL-1, a novel triterpenoid, exhibits potent anticancer activity against an array of cancer cell lines however, its mechanism of action remains elusive.
  
  
  METHODS
  Molecular targets of AECHL-1 were investigated using breast adenocarcinoma cells MCF-7, MDA-MB-231 and mammary epithelial cell line MCF 10A in vitro and xenograft tumors in SCID mice in vivo. Western blotting, flow cytometry, and immunohistochemical studies were employed to delineate the molecular pathways.
  
  
  RESULTS
  AECHL-1 caused a transient elevation of ER stress proteins along with a prolonged phosphorylation of eIF2α in breast cancer cells. This was accompanied by a simultaneous release of calcium from ER stores and subsequent mitochondrial accumulation. These effects could be reversed by using ER stress inhibitors. AECHL-1 brings about mitochondria mediated, caspase independent cell death via AIF in MCF-7 cells; MDA-MB-231 succumbed to caspase dependent extrinsic pathway. Xenograft studies closely echoed our in vitro results. AECHL-1 did not alter cellular and molecular parameters in MCF 10A.
  
  
  CONCLUSIONS
  These findings reveal that, AECHL-1 targets the Achilles Heel of cancer cell, namely dysfunctional ER and mitochondria while being non toxic to normal parenchyma and can thus be further explored as a potential chemotherapeutic intervention.
  
  
  CONCLUSIONS
  Aggravation of ER stress by AECHL-1 uncovers a novel pathway for selective elimination of cancer cells.
authors: National Centre for Cell Science, NCCS Complex, S.P. Pune University, Ganeshkhind, Pune 411007, Maharashtra, India.
authors: Mithila A
authors: MA
authors: Sawant
authors: National Centre for Cell Science, NCCS Complex, S.P. Pune University, Ganeshkhind, Pune 411007, Maharashtra, India.
authors: Aparajita
authors: A
authors: Dasgupta
authors: Pharmazz India Private Limited, H-6, Site-C, Surajpur Industrial area, Greater Noida, UP 201307, India.
authors: Manish S
authors: MS
authors: Lavhale
authors: National Centre for Cell Science, NCCS Complex, S.P. Pune University, Ganeshkhind, Pune 411007, Maharashtra, India. Electronic address: ssitaswad@nccs.res.in.
authors: Sandhya L
authors: SL
authors: Sitasawad
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000502:physiology; D020169:Caspases / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: C000606400:AECHL-1 compound; D017382:Reactive Oxygen Species; D014315:Triterpenes; D020169:Caspases; D002118:Calcium
keywords: AECHL-1; AIF; Calcium; ER stress; Mitochondria; Redox regulation