title: ERα-targeted therapy in ovarian cancer cells by a novel estradiol-platinum(II) hybrid.
abstract: As we previously showed, we have synthesized a new family of 17β-estradiol-platinum(II) hybrids. Earlier studies revealed the VP-128 hybrid to show high efficiency compared with cisplatin toward hormone-dependent breast cancer cells. In the present research, we have studied the antitumor activity of VP-128 in vitro and in vivo against ovarian cancer. In nude mice with ovarian xenografts, VP-128 displayed selective activity toward hormone-dependent tumors and showed higher efficiency than cisplatin to inhibit tumor growth. Similarly, in vitro, transient transfection of estrogen receptor (ER)-α in ERα-negative A2780 cells increased their sensitivity to VP-128-induced apoptosis, confirming the selectivity of VP-128 toward hormone-dependent tumor cells. In agreement, Western blot analysis revealed that VP-128 induced higher caspase-9, caspase-3, and poly (ADP-ribose) polymerase cleavage compared with cisplatin. The activation of caspase-independent apoptosis was also observed in ERα-negative A2780 cells, in which VP-128 rapidly induced the translocation of apoptosis-inducing factor to the nucleus. Conversely, subcellular localization of apoptosis-inducing factor was not modified in ERα-positive Ovcar-3 cells. We also discovered that VP-128 induces autophagy in ovarian cancer cells because of the formation of acidic vesicular organelles (AVOs) and increase of Light Chain 3B-II protein responsible for the formation of autophagosomes; pathways related to autophagy (AKT and mammalian target of rapamycin) were also down-regulated, supporting this mechanism. Finally, the inhibition of autophagy using chloroquine increased VP-128 efficiency, indicating a possible combination therapy. Altogether these results highlight the beneficial value of VP-128 for the treatment of hormone-dependent ovarian cancers and provide preliminary proof of concept for the efficient targeting of ERα- by 17β-estradiol-Pt(II)-linked chemotherapeutic hybrids in these tumors.
authors.affiliation: Research Group in Molecular Oncology and Endocrinology, Department of Medical Biology, Canada Research Chair in Molecular Gyneco-Oncology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada G9A 5H7.
authors.forename: K
authors.initials: K
authors.lastname: Brasseur
authors.forename: V
authors.initials: V
authors.lastname: Leblanc
authors.forename: F
authors.initials: F
authors.lastname: Fabi
authors.forename: S
authors.initials: S
authors.lastname: Parent
authors.forename: C
authors.initials: C
authors.lastname: Descôteaux
authors.forename: G
authors.initials: G
authors.lastname: Bérubé
authors.forename: E
authors.initials: E
authors.lastname: Asselin
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017671:Platinum Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D017304:Annexin A5; D016588:Anticarcinogenic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D017671:Platinum Compounds; D004958:Estradiol