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Antiproliferative, antiandrogenic and cytotoxic effects of novel caffeic acid derivatives in LNCaP human androgen-dependent prostate cancer cells

Sanderson, J. Thomas; Clabault, Hélène; Patton, Cody; Lassalle-Claux, Grégoire; Jean-Francois, Jacques; Paré, Aurelie F; Hébert, Martin J G; Surette, Marc E; Touaibia, Mohamed (2013). Antiproliferative, antiandrogenic and cytotoxic effects of novel caffeic acid derivatives in LNCaP human androgen-dependent prostate cancer cells Bioorganic and Medicinal Chemistry , vol. 21 , nº 22. p. 7182-93. DOI: 10.1016/j.bmc.2013.08.057.

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Résumé

Caffeic acid and its naturally occurring derivative caffeic acid phenethyl ester (CAPE) have antiproliferative and cytotoxic properties in a variety of cancer cell lines without displaying significant toxicity toward healthy cells, and are considered to be potential anticancer agents. However, little is known about their effects on prostate cancer cells. We synthesized and evaluated the effects of caffeic acid, CAPE (2) and 18 synthetic derivatives on cell viability and androgen-dependent cell proliferation, subcellular localisation and expression of androgen receptor (AR) and secretion of prostate-specific antigen (PSA) in LNCaP human hormone-dependent prostate cancer cells. Several synthetic derivatives of CAPE were strong, concentration-dependent cytotoxic agents in LNCaP cells with IC50 values in the 6.8-26.6 muM range, potencies that were up to five-fold greater than that of CAPE (33.7+/-4.0 muM). A number of caffeic acid derivatives were inhibitors of androgen-stimulated LNCaP cell proliferation with concomitant inhibition of DHT-stimulated PSA secretion. Compound 24 was the most cytotoxic and antiproliferative caffeic acid derivative (IC50 values of 6.8+/-0.3 and 2.4+/-0.8 muM, respectively) inhibiting DHT-stimulated cell proliferation and PSA secretion statistically significantly at concentrations as low as 0.3 muM. Exposure to DHT increased cytoplasmic and nuclear AR levels and co-treatment with increasing concentrations of compound 24 or CAPE (2), notably, further increased these levels. In conclusion, a number of synthetic derivatives of caffeic acid are potent inhibitors of androgen-dependent prostate cancer cell proliferation and viability, acting, at least in part, via an antiandrogenic mechanism that involves increased nuclear accumulation of (presumably inactive) AR.

Type de document:
Mots-clés libres: Caffeic acid; CAPE; Synthetic derivatives; Androgen receptor; LNCaP; Prostate cancer; Prostate specific antigen; Cytotoxicity; Real-time cell proliferation; Concentration–response; Structure–activity
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 31 mai 2017 19:33
Dernière modification: 31 mai 2017 19:33
URI: http://espace.inrs.ca/id/eprint/2970

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