Ring-substituted analogs of 3,3′-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and –independent prostate cancer cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-05-25

AUTHORS

A. A. Goldberg, V. I. Titorenko, A. Beach, K. Abdelbaqi, S. Safe, J. T. Sanderson

ABSTRACT

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 addition, 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 concentrations of DIM and ring-DIMs (0.3–30 μM) and effects on cell proliferation were measured in real-time using an xCELLigence cellular analysis system. Chromatin condensation and loss of membrane integrity were determined by Hoechst and propidium iodide staining, respectively. Apoptotic protein markers were measured by immunoblotting and activation of caspases determined using selective fluorogenic substrates. Intra- and extracellular concentrations 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 compounds was decreased by an inhibitor of caspase −3. The 4,4′-dibromoDIM was primarily found in the extracellular medium, whereas all other compounds 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 compounds have clinical potential as chemopreventive and chemotherapeutic agents in prostate cancer, regardless of hormone-dependency. More... »

PAGES

25-36

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10637-013-9979-y

DOI

http://dx.doi.org/10.1007/s10637-013-9979-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1014998588

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23709189


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88 electrospray ionization tandem mass spectrometry
89 elevated expression
90 expression
91 extent
92 extracellular concentration
93 extracellular medium
94 fluorogenic substrate
95 greater potency
96 growth
97 human prostate cancer cells
98 immunoblotting
99 independent prostate cancer cells
100 inhibitors
101 inhibitors of caspases
102 inhibitory effect
103 integrity
104 intra
105 iodide staining
106 ionization tandem mass spectrometry
107 large extent
108 lines
109 loss
110 markers
111 mass spectrometry
112 medium
113 membrane integrity
114 monitoring techniques
115 necrosis
116 necrotic cell death
117 objective
118 pathway
119 potency
120 potential
121 proliferation
122 propidium iodide staining
123 prostate cancer
124 prostate cancer cell growth
125 prostate cancer cells
126 protein
127 protein markers
128 real-time monitoring technique
129 ring-substituted analogues
130 selective fluorogenic substrates
131 spectrometry
132 staining
133 study
134 substrate
135 system
136 tandem mass spectrometry
137 technique
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