Endocrine Abstracts

Proliferative inflammatory atrophy and prostatic intraepithelial neoplasia are the first signs of prostate cancer. This inflammatory etiology, together with the infiltration of immune cells, could lead to the binding of the cytokines with cancer cells, forming a population that could initiate tumor growth. [1] Androgens also play an essential role in prostate tumor growth, as is well documented. [2] Androgen deprivation therapy is currently the gold standard for hormone-sensitive metastatic prostate cancer patients.[3] These data have inspired researchers to improve therapy for this disease. Previously, our group prepared a new series of hybrid compounds based on a 5,16-pregnadiene scaffold linked to anti-inflammatory drugs. These derivatives showed important antiproliferative properties. [4] In the present study, we identified the effect of five 5,16-pregnadiene derivatives bound to anti-inflammatory drugs (M1-5) as inhibitors of the 5α-reductase enzyme activity. This enzyme has been recognized as responsible for forming intraprostatic dihydrotestosterone from testosterone. Dihydrotestosterone has also been associated with prostate cell proliferation [5], so blocking this enzyme and preventing prostate inflammation could improve therapies for this disease. Derivatives of M1-5 were tested as inhibitors of 5α-reductase activity by incubating radiolabeled testosterone in the presence or absence of these compounds. A fraction of the human prostate membrane and NADPH were added to this medium. Subsequently, the compounds formed were separated and identified by thin-layer chromatography. Compounds M1-3 and M5 inhibited in vitro formation of dihydrotestosterone, with the highest activity for M1-2, with IC₅₀ values of 24.2 and 0.26 nM, respectively. However, M3 and M5 showed IC₅₀ values too much higher, 15.8 and 6.06 µM, than M1-2, respectively, and M-4 no-displayed activity. Previously, our group demonstrated the inhibitory effect of 5,16-pregnandiene on 5α-reductase activity [6]. This 5, 16 pregnandiene effects was completely diminished by indomethacin moiety attached to this compound, as shown in the M4 derivative.

Reference List

1. Packer JR, Maitland NJ. The molecular and cellular origin of human prostate cancer. Biochim Biophys Acta. 2016;1863(6 Pt A):1238-60.

2. Culig Z, Santer FR. Androgen receptor signaling in prostate cancer. Cancer Metastasis Rev. 2014;33(2-3):413-27.

3. Nevedomskaya E, Baumgart SJ, Haendler B. Recent Advances in Prostate Cancer Treatment and Drug Discovery. Int J Mol Sci. 2018;19(5).

4. Garrido M, González-Arenas A, Camacho-Arroyo I, Cabeza M, Alcaraz B, Bratoeff E. Effect of new hybrids based on 5,16-pregnadiene scaffold linked to an anti-inflammatory drug on the growth of a human astrocytoma cell line (U373). European Journal of Medicinal Chemistry. 2015;93(0):135-41.

5. Ma C, Yoshioka M, Boivin A, Gan L, Takase Y, Labrie F, et al. Atlas of dihydrotestosterone actions on the prostate transcriptome in vivo. Prostate. 2009;69(3):293-316.

6. Cabeza M, Heuze I, Bratoeff E, Ramírez E, Martínez R. Evaluation of new pregnane derivatives as 5alpha-reductase inhibitor. Chem Pharm Bull (Tokyo). 2001;49(5):525-30.