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Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
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Abstract

Introduction

Endometrial cancer is one of the most common gynecological malignancies. Endometrial cancer cells express the gonadotropin-releasing hormone (GnRH) and its receptor (GnRH-R). Among the various therapeutic approaches for the treatment of endometrial cancer is the use of GnRH conjugates, such as the AN-152, created by linking the (D-Lys6) GnRH with the cytotoxic doxorubicin through an ester bond. An undesirable property of these conjugates is their vulnerability to plasma carboxylesterases, which cleave the ester bond to release doxorubicin before reaching the cancer cells.

Methods:

To overcome this problem, we recently developed the Con-3 and Con-7, which are GnRH analogs conjugated through a disulfide bond with the cytotoxic mitoxantrone. In this study, we determined the cytotoxic properties of the Con-3 and Con-7 on the Ishikawa endometrial cancer cells, assuming that their interaction with the GnRH-R of cells exposes the conjugated mitoxantrone to the cellular thioredoxin. The cellular thioredoxin reduces the disulfide bond of Con-3 & Con-7 to release mitoxantrone, which accumulates in the cancer cells and exerts its cytotoxic actions.

Results:

Indeed, treatment of Ishikawa cells with Con-3, Con-7, or the free unconjugated mitoxantrone increased their apoptosis and decreased their proliferation in a dose- and time-dependent manner, displaying half-maximal inhibitory concentrations (IC) of 0.64 - 1.15 µM. In specific, the ICvalues on days 2, 3, and 4 were 1.45, 0.64, and 0.83 μΜ, respectively, for Con-3, 0.91, 0.82 μΜ, and 1.00 μΜ, respectively for Con-7 and 1.15, 0.98, 0.78 μM, respectively for mitoxantrone. In contrast, the free, mitoxantrone-unconjugated peptides did not affect the proliferation of Ishikawa cells.

Conclusion:

The Con-3 and Con-7 could put the basis for the development of a new class of anticancer drugs for endometrial cancer, which will act as “prodrugs” that deliver the cytotoxic mitoxantrone in a GnRH-R-specific manner.

© 2024 The Author(s).
© 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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Two GnRH-mitoxantrone Conjugates, Con-3 and Con-7, Target Endometrial Cancer Cells
Curr Mol Pharmacol 17, E18761429343090 (2024); https://doi.org/10.2174/0118761429343090250121052955
/content/journals/cmp/10.2174/0118761429343090250121052955
/content/journals/cmp/10.2174/0118761429343090250121052955
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  • Article Type:     Research Article
Keyword(s): Anticancer drugs; Endometrial cancer; Gonadotropin-releasing hormone; Mitoxantrone; Prodrugs; Receptor

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