Therapeutic targeting of pancreatic cancer utilizing sigma-2 ligands
Section snippets
Sigma receptor background
Sigma receptors were identified initially as a subclass of opioid receptors; however, they had low binding affinity to the active stereoisomer of naloxone,11 a potent morphine antagonist, and were, thus, placed subsequently in their own family, consisting of sigma-1 and sigma-2 receptors. Because of the nature of the compounds that bind these receptors, early research focused primarily on neuropharmacology. Sigma-1 and -2 receptors were distinguished classically on the basis of their binding
PGRMC1/sigma-2 receptor in cancer
Identification and cloning of the sigma-2 receptor had remained elusive for many years despite more than a decade of investigation into this protein. Recently, PGRMC1 was identified as the putative sigma-2 receptor binding site by photoaffinity binding with a novel ligand, WC-21, as compared with the known PGRMC1 ligand AG-205.18, 19 This important finding set the stage for validation studies of overexpression of the PGRMC1/sigma-2 receptor and its function in pancreatic cancer, because PGRMC1
Specific uptake in pancreatic cancer cells
Sigma-2 receptor ligands are internalized preferentially by proliferating cancer cells, a characteristic that may limit systemic toxicity. Sigma-2 receptor ligands conjugated with the chromophore 4-chloro-7-nitrobenzo-2-oxa-1, 3-diazole (NBD) were first utilized to show subcellular uptake into proliferating breast cancer cells.10 This study was the first to reveal uptake of these compounds by receptor-mediated endocytosis. Further studies in pancreatic cancer cells with SW120, another
Evidence for sigma-2 ligands as therapy for pancreatic cancer
We first became interested in the use of sigma-2 receptors for pancreatic cancer when it was identified that agents selective for sigma-2 receptors are taken up specifically in tumor cells, as seen on positron emission tomography imaging,17, 48 and that they induce apoptosis.49 Because pancreatic cancer is poorly detected prior to advanced stages and has a poor overall response to chemotherapy, promising agents such as this deserve attention, and the rationale for evaluating selective sigma-2
Sigma-2 ligands augment apoptosis in pancreatic cancer
Drug resistance in pancreatic cancer occurs rapidly through both natural and acquired resistance. Resistance pathways to therapies such as gemcitabine are multiple and include adaptations to cell influx/efflux, nuclear translocation, nucleoside analog conversion by dUTPase, introduction into the DNA strand, DNA editing, cell checkpoint proteins, and further downstream apoptotic pathways.50, 51 Despite this, in our studies of cellular death by sigma-2 ligands in pancreatic cancer, we have
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Cited by (28)
Molecular mechanisms of anti-psychotic drugs for improvement of cancer treatment
2019, European Journal of PharmacologyCitation Excerpt :Sigma-2 receptor ligand acts as a trigger for apoptosis in tumor cells. Also, sigma-2 ligands are rapidly internalized into cancer cells and capable of delivering other small-molecules to anti-cancer agents (Aydar et al., 2004; Hornick et al., 2012). Autophagy is a self-catabolic mechanism which is responsible for the removal of damaged organelles and malformed proteins produced during biosynthesis of lysosome.
Progesterone induced Warburg effect in HEK293 cells is associated with post-translational modifications and proteasomal degradation of progesterone receptor membrane component 1
2019, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :Human Protein Atlas (HPA) based tissue-expression profiles and other studies have shown that PGRMC1 is abundantly expressed in many cell types, tissues and organs [7,8]. PGRMC1 is highly expressed in various types of cancer [9–16] and is implicated in cancer cell proliferation and chemoresistance against anti-cancer drugs [17], drug and hormone metabolism [18], cholesterol biosynthesis [19,20], and DNA damage response (yeast homologue of PGRMC1) [21]. A variety of biological functions, including glucose metabolism [22], progesterone (P4) signaling, steroidogenesis, regulation of cytochrome P450, vesicle trafficking, mitotic spindle and cell cycle regulation, promotion of autophagy, angiogenesis, anchorage-independent growth, invasive growth, and hypoxic biology have been attributed to PGRMC1 [23,24].
The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology
2016, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :S2R ligands preferentially kill dividing cancer cells by unknown mechanisms. The presence of S2R correlates with dividing cancer cells, as well as with various pathological conditions in the nervous system [125,126], and can be used as a vehicle to specifically target anti-cancer drugs to tumor cells, including triple-negative breast [127,128], ovarian [127,129], and pancreatic [130] cancers. In 2011, PGRMC1 was identified as a component of a S2R protein complex using a photo-reactive sigma-2 ligand that chemically cross-linked to PGRMC1 [131].
Comparative evaluation of 4 and 6-carbon spacer conformationally flexible tetrahydroisoquinolinyl benzamide analogues for imaging the sigma-2 receptor status of solid tumors
2016, Nuclear Medicine and BiologyCitation Excerpt :Our group has also reported the localization of σ2 receptors in the mitochondria, lysosomes, endoplasmic reticulum, and plasma membrane of breast cancer cells using two-photon and confocal microscopy probes [25]. In addition to being an excellent biomarker of cell proliferation for imaging studies, the σ2 receptor has also proven to be a promising target either as a monotherapy for treating cancer or as a mechanism for delivering a therapeutic cargo to cancer cells [11,22,26–29]. Therefore, radiolabeled σ2 receptor ligands can be used to assess the proliferative status of solid tumors with positron emission tomography (PET) and single photon emission computed tomography (SPECT), as well as serving as a companion diagnostic for identifying tumors that would respond to σ2 receptor targeting therapeutics [29–33].
Tetrahydroprotoberberine alkaloids with dopamine and σ receptor affinity
2016, Bioorganic and Medicinal ChemistryPotential applications for sigma receptor ligands in cancer diagnosis and therapy
2015, Biochimica et Biophysica Acta - Biomembranes