Cytotoxic Activity of Novel GnRH Analogs Conjugated with Mitoxantrone in Ovarian Cancer Cells
Christos Markatos,
Georgia Biniari,
Oleg G. Chepurny,
Vlasios Karageorgos,
Nikos Tsakalakis,
Georgios Komontachakis,
Zacharenia Vlata,
Maria Venihaki,
George G. Holz,
Theodore Tselios,
George Liapakis
Affiliations
Christos Markatos
Department of Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece
Georgia Biniari
Department of Chemistry, University of Patras, 26504 Rion, Greece
Oleg G. Chepurny
Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY 13210, USA
Vlasios Karageorgos
Department of Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece
Nikos Tsakalakis
Department of Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece
Georgios Komontachakis
Department of Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece
Zacharenia Vlata
Flow Cytometry Facility, Institute of Molecular Biology and Biotechnology of the Foundation for Research and Technology Hellas (IMBB-FORTH), 70013 Heraklion, Greece
Maria Venihaki
Department of Clinical Chemistry, School of Medicine, University of Crete, 71003 Heraklion, Greece
George G. Holz
Department of Medicine and Pharmacology, State University of New York (SUNY), Upstate Medical University, Syracuse, NY 13210, USA
Theodore Tselios
Department of Chemistry, University of Patras, 26504 Rion, Greece
George Liapakis
Department of Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece
The gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) is highly expressed in ovarian cancer cells (OCC), and it is an important molecular target for cancer therapeutics. To develop a new class of drugs targeting OCC, we designed and synthesized Con-3 and Con-7 which are novel high-affinity GnRH-R agonists, covalently coupled through a disulfide bond to the DNA synthesis inhibitor mitoxantrone. We hypothesized that Con-3 and Con-7 binding to the GnRH-R of OCC would expose the conjugated mitoxantrone to the cellular thioredoxin, which reduces the disulfide bond of Con-3 and Con-7. The subsequent release of mitoxantrone leads to its intracellular accumulation, thus exerting its cytotoxic effects. To test this hypothesis, we determined the cytotoxic effects of Con-3 and Con-7 using the SKOV-3 human OCC. Treatment with Con-3 and Con-7, but not with their unconjugated GnRH counterparts, resulted in the accumulation of mitoxantrone within the SKOV-3 cells, increased their apoptosis, and reduced their proliferation, in a dose- and time-dependent manner, with half-maximal inhibitory concentrations of 0.6–0.9 µM. It is concluded that Con-3 and Con-7 act as cytotoxic “prodrugs” in which mitoxantrone is delivered in a GnRH-R-specific manner and constitute a new class of lead compounds for use as anticancer drugs targeting ovarian tumors.
