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.