1,1-Bis(3′-indolyl)-1-(<i>p</i>-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator–activated receptor–dependent and independent pathways

Lei, Ping; Abdelrahim, Maen; Safe, Stephen

doi:10.1158/1535-7163.mct-06-0184

Cited by 35 publications

(58 citation statements)

References 56 publications

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“…Previous studies have found greater pro-apoptotic responses to other synthetic DIM derivatives. For example, a set of 1,1-bis(3′-indolyl)-1-(p-substituted-phenyl)methanes (C-DIMs), carrying paratrifluoromethyl-, t-butyl-, phenyl-, cyano-, or methoxy-groups have previously been shown to activate anti-proliferative and pro-apoptotic pathways, and this was due in part to their activity as ligands for peroxisome proliferator-activated receptor γ (PPARγ) and NR4A1 (TR3/Nur77); these same compounds also induced ER stress in pancreatic, ovarian and colon cancer cells [19,25,[27][28][29]. Other chemically modified dietary compounds such as brominated vanillin (a flavour compound) and chlorinated flavonoids have been shown to kill Jurkat leukemia cells and hepatocarcinoma cells, respectively, at concentrations lower than the parent molecule by activating down-stream effectors of apoptosis such as caspase-3, resulting in nuclear DNA fragmentation and chromatin condensation [42,43].…”

Section: Ring-dims Induce Death Of Androgen-dependent and -Independenmentioning

confidence: 99%

“…The diverse molecular targets through which DIM is assumed to exert its anti-proliferative and pro-apoptotic effects have not been identified and DIM-induced necrosis has not been examined. 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%

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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 Induce Death Of Androgen-dependent and -Independenmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…20). These PPARg agonists inhibited growth and induced apoptosis in breast, pancreatic, colon, bladder, leukemia, and other cancer cell lines through both receptor-dependent and receptor-independent pathways (20)(21)(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Nur77 Agonists Induce Proapoptotic Genes and Responses in Colon Cancer Cells through Nuclear Receptor–Dependent and Nuclear Receptor–Independent Pathways

et al. 2007

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Nerve growth factor-induced BA (NGFI-BA, Nur77) is an orphan nuclear receptor with no known endogenous ligands; however, recent studies on a series of methylene-substituted diindolylmethanes (C-DIM) have identified 1,1-bis(3 ¶-indolyl)-1-(phenyl)methane (DIM-C-Ph) and 1,1-bis(3 ¶-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH 3 ) as Nur77 agonists. Nur77 is expressed in several colon cancer cell lines (RKO, SW480, HCT-116, HT-29, and HCT-15), and we also observed by immunostaining that Nur77 was overexpressed in colon tumors compared with normal colon tissue. DIM-C-Ph and DIM-C-pPhOCH 3 decreased survival and induced apoptosis in RKO colon cancer cells, and this was accompanied by induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein. The induction of apoptosis and TRAIL by DIM-C-pPhOCH 3 was significantly inhibited by a small inhibitory RNA for Nur77 (iNur77); however, it was evident from RNA interference studies that DIM-C-pPhOCH 3 also induced Nur77-independent apoptosis. Analysis of DIM-C-pPhOCH 3 -induced gene expression using microarrays identified several proapoptotic genes, and analysis by reverse transcription-PCR in the presence or absence of iNur77 showed that induction of programmed cell death gene 1 was Nur77 dependent, whereas induction of cystathionase and activating transcription factor 3 was Nur77 independent. DIM-C-pPhOCH 3 (25 mg/kg/d) also inhibited tumor growth in athymic nude mice bearing RKO cell xenografts. These results show that Nur77-active C-DIM compounds represent a new class of anti-colon cancer drugs that act through receptordependent and receptor-independent pathways. [Cancer Res 2007;67(2):674-83]

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“…23 Furthermore, the effect of rosiglitazone on cancer cells can be either PPARg-dependent or independent, despite it being a potent and highly selective agonist for PPARg. 24,25 Thus, the effect of rosiglitazone on cancer cells may be highly tumor and cell type-specific, and it may not be practical to use it as a monotherapy.…”

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confidence: 99%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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Ligands for peroxisome proliferator-activated receptor gamma (PPARc) possess anticancer properties. However, the efficacy of PPARc ligands varies in different cancers. In colon cancer, the role of PPARc and its ligands is controversial. We recently showed that downregulation of X-linked inhibitor of apoptosis protein (XIAP) could sensitize colon cancer cells to troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether rosiglitazone, another more clinically relevant PPARc ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP 1/1 cells and HCT116-XIAP 2/2 cells were treated with various concentrations of rosiglitazone. The effects of rosiglitazone on cell proliferation, apoptosis and growth of xenograft colon cancers were studied. Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that rosiglitazone strongly suppressed the growth of xenograft colon cancer, especially tumors derived from HCT116-XIAP 2/2 cells. The rosiglitazone-treated tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of PPARc by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP 2/2 cells, as well as in xenograft tumors derived from HCT116-XIAP 2/2 cells. We concluded that rosiglitazone significantly suppresses the growth of xenograft colon cancer, and downregulation of XIAP sensitizes the xenograft tumors to rosiglitazone-induced tumor suppression in vivo via upregulation of PTEN.

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1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator–activated receptor–dependent and independent pathways

Cited by 35 publications

References 56 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

Nur77 Agonists Induce Proapoptotic Genes and Responses in Colon Cancer Cells through Nuclear Receptor–Dependent and Nuclear Receptor–Independent Pathways

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

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