title: Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells.
abstract: The sigma-2 receptor is overexpressed in proliferating cells compared to quiescent cells and has been used as a target for imaging solid tumors by positron emission tomography. Recent work has suggested that the sigma-2 receptor may also be an effective therapeutic target for cancer therapy. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage response. In this study, we looked for potential synergy of cytotoxicity between PARP inhibitors and sigma-2 receptor ligands in breast cancer cell lines. We showed that the PARP inhibitor, YUN3-6, sensitized mouse breast cancer cell line, EMT6, to sigma-2 receptor ligand (SV119, WC-26, and RHM-138) induced cell death determined by cell viability assay and colony forming assay. The PARP inhibitor, olaparib, sensitized tumor cells to a different sigma-2 receptor ligand SW43-induced apoptosis and cell death in human triple negative cell line, MDA-MB-231. Olaparib inhibited PARP activity and cell proliferation, and arrested cells in G2/M phase of the cell cycle in MDA-MB-231 cells. Subsequently cells became sensitized to SW43 induced cell death. In conclusion, the combination of sigma-2 receptor ligands and PARP inhibitors appears to hold promise for synergistically triggering cell death in certain types of breast cancer cells and merits further investigation.
authors.affiliation: Department of Radiology, University of Pennsylvania, Perelman School Medicine, Philadelphia, PA, United States.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: McDonald
authors.affiliation: Department of Radiology, University of Pennsylvania, Perelman School Medicine, Philadelphia, PA, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Mankoff
authors.affiliation: Department of Radiology, University of Pennsylvania, Perelman School Medicine, Philadelphia, PA, United States.
authors.forename: Mehran
authors.initials: M
authors.lastname: Makvandi
authors.affiliation: Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Chu
authors.affiliation: Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States.
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Radiology, University of Pennsylvania, Perelman School Medicine, Philadelphia, PA, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Department of Radiology, University of Pennsylvania, Perelman School Medicine, Philadelphia, PA, United States. Electronic address: zengc@mail.med.upenn.edu.
authors.forename: Chenbo
authors.initials: C
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D002219:Carbamates; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017480:Receptors, sigma; C579249:SV119; C106107:sigma-2 receptor; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: Breast cancer; PARP inhibitor; Sigma-2 receptor; Synergy; Synthetic lethal; Therapeutics