title: Bobel-24 and derivatives induce caspase-independent death in pancreatic cancer regardless of apoptotic resistance.
abstract: The poor prognosis of pancreatic cancer and poor sensitivity to current therapeutics, associated with resistance to apoptosis, urge the search for new drugs. We previously described the induction of caspase-independent mithochondrial death in leukemia cells by Bobel-24 (AM-24) and derivatives. Here, we explored whether these compounds induce a similar cytotoxicity in human pancreatic carcinoma cell lines (NP18, NP9, NP31, and NP29). Bobel-24 or Bobel-16 induced cytotoxicity and DNA synthesis inhibition in all cell lines and apoptosis in all lines, except for NP9. Caspase and/or poly(ADP-ribose) polymerase-1 (PARP-1) activity inhibition experiments showed that cytotoxicity was mainly induced through apoptosis in NP18 and through a caspase-independent process in NP9. Moreover, in NP29 or NP31 cell lines, both caspase-dependent and caspase-independent cell death mechanisms coexisted. Cell death was associated with reactive oxygen species (ROS) production, mitochondrial depolarization, cytochrome c and apoptosis-inducing factor (AIF) release, AIF nuclear translocation, and lysosomal cathepsin release. Inhibition of ROS production, mitochondrial pore permeability, PARP-1, or phospholipase A2 partially prevented cell death. Moreover, cathepsin B inhibition or down-regulation by small interfering RNA partially blocked cell death. In conclusion, Bobel-24 and derivatives trigger caspase-independent lysosomal and mitochondrial death in all tested human pancreatic cancer lines, irrespective of their degree of apoptotic sensitivity, becoming the only active cytotoxic mechanism in the apoptosis-resistant NP9 line. This mechanism may overcome the resistance to apoptosis observed in pancreatic carcinoma when treated with current genotoxic drugs.
authors.affiliation: Grup d'Oncogènesi i Antitumorals of the Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Parreño
authors.forename: Isolda
authors.initials: I
authors.lastname: Casanova
authors.forename: María Virtudes
authors.initials: MV
authors.lastname: Céspedes
authors.forename: Jose Pedro
authors.initials: JP
authors.lastname: Vaqué
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Pavón
authors.forename: Javier
authors.initials: J
authors.lastname: Leon
authors.forename: Ramon
authors.initials: R
authors.lastname: Mangues
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010636:Phenols / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D010636:Phenols; C066859:2,4,6-triiodophenol; D020169:Caspases