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Cytotoxic Activity of Novel GnRH Analogs Conjugated with Mitoxantrone in Ovarian Cancer Cells
Christos Markatos1, Georgia Biniari2, Oleg G Chepurny3
1Department of Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece.
Abstract:
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.
Insights
Novel drug conjugates, Con-3 and Con-7, target ovarian cancer cells by delivering the chemotherapy agent mitoxantrone specifically to cancer cells via the gonadotropin-releasing hormone receptor (GnRH-R). This targeted delivery enhances efficacy and reduces side effects.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The gonadotropin-releasing hormone receptor (GnRH-R) is highly expressed in ovarian cancer cells (OCC), making it a promising target for novel cancer therapeutics.
- Developing targeted therapies is crucial for improving treatment outcomes in ovarian cancer.
Purpose of the Study:
- To design and synthesize novel high-affinity GnRH-R agonists (Con-3 and Con-7) conjugated to the DNA synthesis inhibitor mitoxantrone.
- To investigate the hypothesis that Con-3 and Con-7 act as cytotoxic prodrugs, releasing mitoxantrone intracellularly in a GnRH-R-dependent manner.
Main Methods:
- Synthesis of Con-3 and Con-7, novel GnRH-R agonists covalently linked to mitoxantrone via a disulfide bond.
- Evaluation of the cytotoxic effects of Con-3 and Con-7 on SKOV-3 human OCC, including mitoxantrone accumulation, apoptosis, and proliferation assays.
- Dose- and time-dependent analysis of drug efficacy, determining half-maximal inhibitory concentrations (IC50).
Main Results:
- Con-3 and Con-7 demonstrated significant cytotoxic effects on SKOV-3 cells, unlike their unconjugated counterparts.
- Treatment resulted in dose- and time-dependent intracellular accumulation of mitoxantrone, increased apoptosis, and reduced cell proliferation.
- Half-maximal inhibitory concentrations (IC50) for Con-3 and Con-7 were determined to be in the range of 0.6-0.9 µM.
Conclusions:
- Con-3 and Con-7 function as effective cytotoxic prodrugs, delivering mitoxantrone specifically to GnRH-R-expressing ovarian cancer cells.
- These novel compounds represent a new class of lead compounds for targeted anticancer drug development against ovarian tumors.
- Targeted delivery via GnRH-R offers a promising strategy for enhancing the efficacy of chemotherapy in ovarian cancer treatment.
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