Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

Bioinformatic Data Mining for Candidate Drugs Affecting Risk of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) in Cancer Patients

“…Little is yet understood about its risk for BRONJ. The novel endoplasmic reticulum targeted phospholipid Edelfosine promotes apoptosis of tumor cells [ 56 ], but its risk for BRONJ is not documented. The isoflavene Idronoxil was found to enhance tumor cell apoptosis and CD8+ T cell function [ 57 ], but its role in BRONJ is not known.…”

Clusters of apoptotic signaling molecule-enriched rafts, CASMERs: membrane platforms for protein assembly in Fas/CD95 signaling and targets in cancer therapy

“…The antitumor agent edelfosine, which accumulates in lipid rafts as stated above, has also been located in the endoplasmic reticulum [118][119][120][121][122] and mitochondria [50,123,124] in different cancer cells. This could suggest a raft-mediated link between plasma membrane rafts and internal subcellular organelles during the apoptotic response.…”

Photodynamic Therapy Supported by Antitumor Lipids

“…The latter affects critical survival signaling pathways PI3K-Akt and Raf-Erk1/2 [ 15 ]. Another reported effect by these agents was the potent and persistent activation of protein kinase JNK responsible for the phosphorylation of c-Jun transcription factor, known as a component of AP-1 transcription factor complex and associated with its activation [ 16 ]. The plasma membrane appears to be the decisive target for the cytotoxic action of these agents, since they were found to affect the membrane permeability, fluidity, membrane lipid raft function, lipid composition and cholesterol content of these structures [ 16 ].…”

“…Another reported effect by these agents was the potent and persistent activation of protein kinase JNK responsible for the phosphorylation of c-Jun transcription factor, known as a component of AP-1 transcription factor complex and associated with its activation [ 16 ]. The plasma membrane appears to be the decisive target for the cytotoxic action of these agents, since they were found to affect the membrane permeability, fluidity, membrane lipid raft function, lipid composition and cholesterol content of these structures [ 16 ]. Lipid rafts are ordered membrane domains enriched in cholesterol and saturated lipids that influence membrane fluidity, membrane protein trafficking (including receptors clustering), recruit certain lipids and proteins into their structure, and are involved in the formation of endocytic, exocytic, synaptic and other vesicles [ 17 ].…”

“…Lipid rafts are ordered membrane domains enriched in cholesterol and saturated lipids that influence membrane fluidity, membrane protein trafficking (including receptors clustering), recruit certain lipids and proteins into their structure, and are involved in the formation of endocytic, exocytic, synaptic and other vesicles [ 17 ]. The disruption of lipid raft composition by antitumor lipids on the plasma membrane and possibly mitochondrial membrane was suggested to modulate the distribution of death receptor Fas/CD95, enhancing their recruitment and leading to the activation of apoptosis of tumor cells in a ligand-dependent manner [ 16 , 18 ]. Indeed, Fas/CD95 and lipid raft clustering by alkylphospholipid agents was found to promote further recruitment of apoptotic signaling molecules into lipid rafts, culminating in the formation of the major apoptotic complex DISC [ 18 ].…”