Antiandrogenic and growth inhibitory effects of ring‐substituted analogs of 3,3′‐diindolylmethane (Ring‐DIMs) in hormone‐responsive LNCaP human prostate cancer cells

Abdelbaqi, Khalil; Lack, Nathan A.; Guns, Emma Tomlinson; Kotha, Leela; Safe, Stephen; Sanderson, J. Thomas

doi:10.1002/pros.21356

Cited by 37 publications

(26 citation statements)

References 58 publications

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“…1), as previously reported [31]. The brominated and chlorinated derivatives of DIM inhibited AR-dependent cellular signalling through different mechanisms, and results of this study show that their effects on cellular proliferation also differ.…”

Section: Ring-dims Structure-dependently Inhibit Androgen-dependent Psupporting

confidence: 82%

“…We previously showed that ring-DIMs are potent inhibitors of androgen-dependent LNCaP prostate cancer cell growth and that these effects could, in part, be explained by antagonistic actions at the level of androgen receptor nuclear translocation, transactivation and gene transcription [31]. Our present study expands these findings by demonstrating that the ringDIMs, at slightly greater concentrations than those that inhibit androgen-dependent cell proliferation, induce cell death in androgen-independent PC-3 cells as well as LNCaP cells and that this occurs via apoptotic and necrotic mechanisms in both cell types.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we showed that ring-DIMs inhibited the growth of DHT-stimulated LNCaP cells [31] with IC 50 values between 2-and 3.5-fold lower than DIM. In this earlier study, cell growth was assessed by measuring mitochondrial re-ductase activity after a 96 h exposure to the ring-DIMs.…”

Section: Ring-dims Inhibit Dht-stimulated Lncap Cell Proliferation Wimentioning

confidence: 93%

“…Moreover, the search for compounds exhibiting higher potency and specificity towards prostate tumours is ongoing, and we have studied a number of methyl-substituted derivatives of DIM in other cancerous tissues [19,[25][26][27][28][29][30]. More recently, we have begun to test halogenated forms of the compound in AD prostate cancer cell models [31].…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that a series of 4,4′-and 7,7′-dichlorinated and -dibrominated ring-substituted DIM analogs (ring-DIMs) inhibits the growth of LNCaP AD human prostate cancer cells [31] and that all four ring-DIMs were able to selectively inhibit AR transactivation up to 9 times more effectively than DIM itself. Although the four compounds inhibited androgen-stimulated LNCaP cell proliferation and PSA secretion, only the brominated ring-DIMs decreased expression of AR protein and mRNA as well as nuclear AR accumulation, whereas the chlorinated ring-DIMs did not affect AR expression and nuclear translocation, suggesting these compounds exert their antiandrogenic and growth inhibitory effects via different sets of cellular targets.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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SummaryWe 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 dichlorosubstituted 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 asindependent (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 immuno-blotting 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 CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript 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.

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Section: Ring-dims Structure-dependently Inhibit Androgen-dependent Psupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Ring-dims Inhibit Dht-stimulated Lncap Cell Proliferation Wimentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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Oxidative Coupling of Benzylamines with Indoles in Aqueous Medium to Realize Bis‐(Indolyl)Methanes Using a Water‐Soluble Cobalt Catalyst and Air as the Oxidant

Saini

Kumari

Hazra

et al. 2019

Chemistry An Asian Journal

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Oxidative coupling of benzylamines with indoles to bis‐(indolyl)methanes (BIMs) was achieved using an inexpensive water‐soluble cobalt complex, Co(bpb). The catalyst was found to be quite effective when air was used as the oxidant and water as solvent under mild reaction conditions. Aromatic amines were successfully converted to the corresponding BIMs with yields up to 85 %. We have successfully carried out a 1 gram scale reaction, and few pharmaceutically relevant compounds were also synthesised by this method in good yields. Control experiments have also been carried out to understand the possible reaction mechanism.

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pH‐Controlled Transition from Disaggregation to Reaggregation of Bis‐indolyl(phenyl)methane−β‐CD Conjugate Appended with Multi‐logic Operations

Paul,

Samanta,

Mondal

et al. 2023

ChemNanoMat

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Multifunctional molecular logic system is designed based on the pH responsive emission properties of Bis‐indolyl(phenyl)methane (BIPM)–β‐CD conjugates in aqueous medium. In our previous studies, BIPM molecules in water were found to form large molecular self‐aggregates that disaggregated in presence of β‐CD molecules through inclusion complexation. In the present study, transition from the disaggregated to reaggregated form of Bis‐indolyl(phenyl)methane–β‐CD conjugate was followed through alteration of the local pH from 7 to 13.2. The BIPM molecules are expected to reaggregate at high alkaline medium due to the expulsion of probes from the nano‐cages of β‐CD. The pH dependent emission spectroscopic changes are harvested to design a multi‐functional molecular logic system. The molecular system can mimic the functions of several fundamental logic gates and an ‘erase‐read‐write‐read’ memory unit. A macro‐molecular security system based on three chemical inputs is also presented here that can authenticate all‐active‐all‐possible (33) three‐character passwords with the respective unique fluorescence trajectories. Designing of molecular logic system based on the pH responsive emission properties of the aggregated and disaggregated forms of an organic probe is rather uncommon and the multifunctional logic, memory and security applications of the present system will carry significant importance in the molecular logic research.

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Antiandrogenic and growth inhibitory effects of ring‐substituted analogs of 3,3′‐diindolylmethane (Ring‐DIMs) in hormone‐responsive LNCaP human prostate cancer cells

Abstract: The antiandrogenic effects of ring-DIMs suggest they may form the basis for the development of novel agents against hormone-sensitive prostate cancer, alone or in combination with other drugs.

Cited by 37 publications

References 58 publications

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

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

Oxidative Coupling of Benzylamines with Indoles in Aqueous Medium to Realize Bis‐(Indolyl)Methanes Using a Water‐Soluble Cobalt Catalyst and Air as the Oxidant

pH‐Controlled Transition from Disaggregation to Reaggregation of Bis‐indolyl(phenyl)methane−β‐CD Conjugate Appended with Multi‐logic Operations

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