Pancreatic cancer is one of the most lethal
malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio.
Pancreatic cancer remains an incurable
malignancy, and current
therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1
pancreatic cancer cell line as CD44+CD24+
EpCAM+ cells. These CSCs form
pancreatic cancer spheres or spheroids and develop
tumors in SCID mice after
subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog
edelfosine inhibited CSC
pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0/G1 region by means of flow cytometry, indicative of
DNA breakdown and apoptosis. This correlated with an increase in
caspase-3 activity and PARP breakdown, as a major substrate of
caspase-3, following PANC-1 CSC treatment with
edelfosine. The antitumor
ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent
edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation.
Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors,
chloroquine or
bafilomycin A1, enhanced
edelfosine-induced apoptosis. Primary cultures from
pancreatic cancer patients were sensitive to
edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and
pancreatic cancer patients are sensitive to
edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.