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Bobel-24 and Derivatives Induce Caspase-Independent Death in Pancreatic Cancer Regardless of Apoptotic Resistance

Grup d'Oncogènesi i Antitumorals of the ¹ Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) and ² Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Barcelona, Spain and ³ Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular-Unidad de Biomedicina del Consejo Superior de Investigaciones Cientificas, Facultad de Medicina, Universidad de Cantabria, Santander, Spain

Requests for reprints: Ramon Mangues, Laboratori d'Investigació Gastrointestinal, Institut de Recerca, Hospital de Sant Pau, Avda Sant Antoni M Claret, 167, 08025 Barcelona, Spain. Phone: 34-93-2919106; Fax: 34-93-4552331; E-mail: rmangues{at}santpau.es.

Key Words: caspase-independent death • mitochondrial dysfunction • AIF • cathepsin B • lysosomal permeabilization • reactive oxygen species

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. [Cancer Res 2008;68(15):6313–23]