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.
Highlights
Pancreatic cancer is one of the most lethal cancers [1]
We tested the antiproliferative activity of the leader compound Bobel-24, named AM-24, and three derivatives (Bobel-16, Bobel-4, and Bobel-30; Fig. 1A) on four human pancreatic carcinoma cell lines (NP9, NP18, NP31, NP29) obtained from pancreatic carcinomas, previously characterized for their mutations [16] and degree of apoptotic induction by diverse genotoxic agents
We describe the induction of caspase-independent cell death by Bobel-24 (AM-24) and its derivative Bobel-16 in all tested pancreatic carcinoma cell lines, bearing different genetic backgrounds, regardless of a concomitant and cell line–dependent degree of apoptotic induction
Summary
Pancreatic cancer is one of the most lethal cancers [1]. A small group of patients are cured by surgery; most patients are candidates to systemic chemotherapy. Pancreatic cancer is exceptionally resistant to the genotoxic therapy that efficiently treats other tumors [2]. Pancreatic carcinoma presents mutations or amplification of oncogenes and inactivation of tumor suppressors that lead to invasiveness and deregulation of cell cycle and apoptosis [2, 3]. The levels of some bcl-2 family members that regulate the mitochondrial pathway have prognostic value in pancreatic cancer patients [2, 4] and play a crucial role in mediating intrinsic or acquired cell resistance to gemcitabine or death receptors [3, 5]. The overexpression of some members of the extrinsic apoptotic pathway (FAP-1, FLIP) is associated with resistance to death receptor–induced apoptosis in pancreatic carcinoma patients and cell lines [2, 3]
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