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Ring-substituted analogs of 3,3'-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and -independent prostate cancer cells

Goldberg, Alexander A; Titorenko, Vladimir I; Beach, Adam; Abdelbaqi, K.; Safe, Stephen; Sanderson, J. Thomas (2014). Ring-substituted analogs of 3,3'-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and -independent prostate cancer cells Investigational New Drugs , vol. 32 , nº 1. p. 25-36. DOI: 10.1007/s10637-013-9979-y.

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Résumé

We recently reported that novel ring-substituted analogs of 3,3'-diindolylmethane (ring-DIMs) have anti-androgenic and growth inhibitory effects in androgen-dependent prostate cancer cells. The objectives of this study were to confirm the ability of 4,4'- and 7,7'-dibromo- and dichloro-substituted ring-DIMs to inhibit androgen-stimulated proliferation of androgen-dependent LNCaP human prostate cancer cells using a non-invasive, real-time monitoring technique. In addn., their ability to induce apoptotic and necrotic cell death in androgen-dependent as well as -independent (PC-3) prostate cancer cells was studied. Prostate cancer cells were treated with increasing concns. of DIM and ring-DIMs (0.3-30 μM) and effects on cell proliferation were measured in real-time using an xCELLigence cellular anal. system. Chromatin condensation and loss of membrane integrity were detd. by Hoechst and propidium iodide staining, resp. Apoptotic protein markers were measured by immunoblotting and activation of caspases detd. using selective fluorogenic substrates. Intra- and extracellular concns. of DIM and ring-DIMs were assessed by electrospray ionization tandem mass spectrometry. Ring-DIMs inhibited androgen-stimulated LNCaP cell proliferation and induced apoptosis and necrosis in LNCaP and PC-3 cells with 2-4 fold greater potencies than DIM. DIM and the ring-DIMs increased caspases -3, -8 and -9 activity, elevated expression of Fas, FasL, DR4 and DR5 protein, and induced PARP cleavage in both cell lines. The cytotoxicity of the most potent ring-DIM, 4,4'-dibromoDIM, but not the other compds. was decreased by an inhibitor of caspase -3. The 4,4'-dibromoDIM was primarily found in the extracellular medium, whereas all other compds. were present to a much larger extent in the cell. In conclusion, ring-DIMs inhibited prostate cancer cell growth and induced cell death in LNCaP and PC-3 cells with greater potencies than DIM; they also structure-dependently activated different cell death pathways suggesting that these compds. have clin. potential as chemopreventive and chemotherapeutic agents in prostate cancer, regardless of hormone-dependency.

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Mots-clés libres: Prostate cancer; Androgen-dependent; Androgen-independent; Diindolylmethane; derivatives; LNCaP; PC-3; Apoptosis; Necrosis; Caspase activity; Intracellular; Concentrations
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 31 mai 2017 19:45
Dernière modification: 31 mai 2017 19:45
URI: http://espace.inrs.ca/id/eprint/3044

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