Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor

  • Authors:
    • Marina Montagnani Marelli
    • Marilena Manea
    • Roberta M. Moretti
    • Monica Marzagalli
    • Patrizia Limonta
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  • Published online on: October 24, 2014     https://doi.org/10.3892/ijo.2014.2730
  • Pages: 243-253
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Abstract

It is well established that gonadotropin-releasing hormone receptors (GnRH-R) are expressed in different types of cancers, including castration-resistant prostate cancer (CRPC) and mediate the antiproliferative effect of GnRH analogs. Thus, these compounds are employed as targeting moieties to selectively deliver chemotherapeutic agents to cancer cells. GnRH-III, the decapeptide isolated from the sea lamprey brain, has lower potency than GnRH in stimulating gonadotropin secretion, but it exerts antiproliferative effects on many tumors expressing the GnRH-R. GnRH-III-based peptides are considered promising targeting moieties for the preparation of anticancer drug delivery systems. These studies were aimed at i) evaluating the antitumor activity of two cytotoxic oxime bond-linked daunorubicin (Dau)-GnRH-III derivative bioconjugates (Dau-GnRH-III, in which daunorubicin was coupled to the 8Lys in the native form of GnRH-III, and Dau-[4Lys(Ac)]-GnRH-III, in which daunorubicin was attached to the 8Lys of a GnRH-III derivative where 4Ser was replaced by an acetylated lysine) on CRPC cells; and ii) to elucidate the involvement of the classical GnRH-R (type I GnRH-R) in this antitumor activity. Our results demonstrated that both Dau-GnRH-III and Dau-[4Lys(Ac)]-GnRH-III were rapidly internalized into DU145 prostate cancer cells and exerted a significant cytostatic effect. Both bioconjugates increased the levels of the active form of caspase-3, indicating the involvement of apoptosis in their antitumor activity. The antiproliferative effect of both Dau-GnRH-III and Dau-[4Lys(Ac)]-GnRH-III was counteracted by the simultaneous treatment of the cells with Antide, an antagonist of the GnRH-R. Moreover, after silencing the type I GnRH-R the antitumor activity of both bioconjugates was completely abolished. These data demonstrate that in CRPC cells, daunorubicin-GnRH-III derivative bioconjugates: i) inhibit tumor cell proliferation, by triggering the apoptosis process; ii) exert their antitumor effect through the activation of the type I GnRH-R expressed on these cells. Cytotoxic-GnRH-III derivative may represent promising targeted chemotherapeutics for the treatment of CRPC patients.
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January 2015
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APA
Montagnani Marelli, M., Manea, M., Moretti, R.M., Marzagalli, M., & Limonta, P. (2015). Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor. International Journal of Oncology, 46, 243-253. https://doi.org/10.3892/ijo.2014.2730
MLA
Montagnani Marelli, M., Manea, M., Moretti, R. M., Marzagalli, M., Limonta, P."Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor". International Journal of Oncology 46.1 (2015): 243-253.
Chicago
Montagnani Marelli, M., Manea, M., Moretti, R. M., Marzagalli, M., Limonta, P."Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor". International Journal of Oncology 46, no. 1 (2015): 243-253. https://doi.org/10.3892/ijo.2014.2730