Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Abstract

Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspaseand mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH 2 -terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 a-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/ GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.

Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth

“…Since PKCs are considered to be the putative kinases for KRAS Ser181 phosphorylation (13,20,21), we tested whether treatment with two general PKC inhibitors that are clinically relevant (Bryostatin-1 and Edelfosine; refs. [22][23][24][25][26] were able to revert tumor growth in a dephosphorylation-dependent manner.…”

Edelfosine lipid nanosystems overcome drug resistance in leukemic cell lines

“…The exact mechanism of action of ET still remains to be fully elucidated, but it has been proved that it accumulates in membrane lipid rafts by recruiting and promoting clustering of Fas/CD95 receptors [6,[8][9][10]. Moreover, other apoptotic mechanisms involving mitochondria and endoplasmic reticulum have also been hypothesized [11]. Previous studies have demonstrated that ET induces a rapid apoptotic response in leukemia cells [6]; nevertheless, Tidwell et al showed that the cell line K562, established from a patient with chronic myeloid leukemia in blast crisis (CML-BC), presents resistance to the action of the drug [12].…”

Alteration of Plasma Membrane Organization by an Anticancer Lysophosphatidylcholine Analogue Induces Intracellular Acidification and Internalization of Plasma Membrane Transporters in Yeast

“…At the plasma membrane, edelfosine interacts with lipid rafts and induces changes in lipid and protein composition in these microdomains (6,9,10). At the ER, edelfosine can induce ER stress (11,12) and inhibits phosphatidylcholine synthesis (13,14).…”