Biomedical subjects

Sabitha Papineni

Publications and source records attributed to Sabitha Papineni.

6 recordsLinked to original sources

PubMed2006

1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes inhibit growth, induce apoptosis, and decrease the androgen receptor in LNCaP prostate cancer cells through peroxisome proliferator-activated receptor gamma-independent pathways.

1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes (C-DIMs) containing para-trifluoromethyl, t-butyl, and phenyl groups are a novel class of peroxisome proliferator-activated receptor (PPAR)gamma agonists. In LNCaP prostate cancer cells, these compounds induce PPARgamma-dependent transactivation, inhibit cell proliferation, and induce apoptosis. In addition, these PPARgamma agonists modulate a number of antiproliferative and proapoptotic responses, including induction of p27, activating transcription factor 3, and nonsteroidal anti-inflammatory drug-activated gene-1 and down-regulation of cyclin D1 and caveolin-1. Moreover, the PPARgamma antagonist 2-chloro-5-nitrobenzanilide (GW9662) does not inhibit these effects. The C-DIM compounds also abrogate androgen receptor (AR)-mediated signaling and decrease prostate-specific antigen (PSA) and AR protein expression, and these responses were PPARgamma-independent. The effects of C-DIMs on AR and PSA were due to decreased AR and PSA mRNA expression in LNCaP cells. Thus, this series of methylene-substituted diindolylmethane derivatives simultaneously activate multiple pathways in LNCaP cells, including ablation of androgen-responsiveness and down-regulation of caveolin-1. Both of these responses are associated with activation of proapoptotic pathways in this cell line.

Apoptosis↗

PubMed2006

The role of xenoestrogenic compounds in the development of breast cancer.

Lifetime exposure to endogenous steroidal estrogens is an established risk factor for breast cancer, and exposures to other estrogenic and antiestrogenic compounds might also modify the risk of breast cancer. It has been hypothesized that synthetic estrogenic industrial pollutants such as organochlorine compounds and plant-derived estrogenic compounds also modify breast cancer risks; however, recent studies show that levels of organochlorine pollutants are similar in breast cancer patients and controls. There is evidence that synthetic and plant-derived estrogens are selective estrogen receptor modulators, which implies that these compounds can induce tissue-specific, time- and dose-dependent estrogenic or antiestrogenic responses. Therefore, the effects of synthetic or plant-derived estrogens on the incidence of breast cancer depend on both the levels and the timing of exposure to these compounds, particularly during stages of mammary gland development that are extremely sensitive to hormone levels.

Breast Neoplasms↗

PubMed2006

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPARgamma-dependent and PPARgamma-independent pathways.

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing p-trifluoromethyl, t-butyl, and phenyl [1,1-bis(3'-indolyl)-1-(p-phenyl)methane (DIM-C-pPhC(6)H(5))] substituents induce peroxisome proliferator-activated receptor gamma (PPARgamma)-mediated transactivation in SW480 colon cancer cells. These PPARgamma-active compounds also inhibit cell proliferation and modulate some cell cycle proteins. At concentrations from 2.5 to 7.5 micromol/L, the PPARgamma agonists induce caveolin-1 and phosphorylation of Akt and cotreatment with the PPARgamma antagonist GW9662 inhibited the induction response. In contrast, higher concentrations (10 micromol/L) of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing 1,1-bis(3'-indolyl)-1-(p-trifluoromethyl)methane and DIM-C-pPhC(6)H(5) induce apoptosis, which is PPARgamma independent. This was accompanied by loss of caveolin-1 induction but induction of proapoptotic nonsteroidal anti-inflammatory drug activated gene-1. In athymic nude mice bearing SW480 cell xenografts, DIM-C-pPhC(6)H(5) inhibits tumor growth at doses of 20 and 40 mg/kg/d and immunohistochemical staining of the tumors showed induction of apoptosis and nonsteroidal anti-inflammatory drug activated gene-1 expression. Thus, the indole-derived PPARgamma-active compounds induce both receptor-dependent and receptor-independent responses in SW480 cells, which are separable over a narrow range of concentrations. This dual mechanism of action enhances their antiproliferative and anticancer activities.

Animals↗

PubMed2005

1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes are peroxisome proliferator-activated receptor gamma agonists but decrease HCT-116 colon cancer cell survival through receptor-independent activation of early growth response-1 and nonsteroidal anti-inflammatory drug-activated gene-1.

1,1-Bis-(3'-indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF3), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC6H5) substituents decrease survival of HCT-116 colon cancer cells and activate peroxisome proliferator-activated receptor (PPAR) gamma in this and other cancer cell lines. These PPARgamma-active compounds had minimal effects on expression of cell cycle proteins and did not induce caveolin-1 in HCT-116 cells. However, these compounds induced nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) and apoptosis in HCT-116 cells, and in time-course studies, the PPARgamma agonists maximally induced early growth response-1 (Egr-1) protein within 2 h, whereas a longer time course was observed for induction of NAG-1 protein. These data, coupled with deletion and mutation analysis of both the Egr-1 and NAG-1 gene promoters, indicate that activation of NAG-1 by these compounds was dependent on prior induction of Egr-1, and induction of these responses was PPARgamma-independent. Results of kinase inhibitor studies also demonstrated that activation of Egr-1/NAG-1 by methylene-substituted diindolylmethanes (C-DIMs) was phosphatidylinositol 3-kinase-dependent, and this represents a novel receptor-independent pathway for C-DIM-induced growth inhibition and apoptosis in colon cancer cells.

Apoptosis↗

PubMed2005

Activation of Nur77 by selected 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induces apoptosis through nuclear pathways.

Nur77 is an orphan receptor and a member of the nerve growth factor-I-B subfamily of the nuclear receptor family of transcription factors. Based on the results of transactivation assays in pancreatic and other cancer cell lines, we have now identified for the first time Nur77 agonists typified by 1,1-bis(3-indolyl)-1-(p-anisyl)methane that activate GAL4-Nur77 chimeras expressing wild-type and the ligand binding domain (E/F) of Nur77. In Panc-28 pancreatic cancer cells, Nur77 agonists activate the nuclear receptor, and downstream responses include decreased cell survival and induction of cell death pathways, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and poly(ADP-ribose) polymerase (PARP) cleavage. Moreover, the transactivation and apoptotic responses are also induced in other pancreatic, prostate, and breast cancer cells that express Nur77. In Panc-28 cells, small inhibitory RNA for Nur77 reverses ligand-dependent transactivation and induction of TRAIL and PARP cleavage. Nur77 agonists also inhibit tumor growth in vivo in athymic mice bearing Panc-28 cell xenografts. These results identify compounds that activate Nur77 through the ligand binding domain and show that ligand-dependent activation of Nur77 through nuclear pathways in cancer cells induces cell death and these compounds are a novel class of anticancer agents.

Active Transport, Cell Nucleus↗

PubMed2005

2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor gamma-dependent and -independent pathways.

2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and the corresponding methyl (CDDO-Me) and imidazole (CDDO-Im) esters induce peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent transactivation in SW-480 colon cancer cells, and these responses were inhibited by small inhibitory RNA for PPARgamma. Moreover, in a mammalian two-hybrid assay using the PPARgamma(2)-VP16 fusion plasmid and GAL4-coactivator/corepressor chimeras and a construct (pGAL4) containing five tandem GAL4 response elements, CDDO, CDDO-Me, and CDDO-IM induce transactivation and PPARgamma interaction with multiple coactivators. A major difference among the three PPARgamma agonists was the higher activity of CDDO-Im to induce PPARgamma interactions with the corepressor SMRT. CDDO, CDDO-Me, and CDDO-Im inhibited SW-480, HCT-116, and HT-29 colon cancer cell proliferation at low concentrations and induced cell death at higher concentrations. Growth inhibition at lower concentrations correlated with induction of the tumor suppressor gene caveolin-1 which is known to inhibit colon cancer cell growth. Induction of caveolin-1 by CDDO, CDDO-Me, and CDDO-Im was inhibited by the PPARgamma antagonist N-(4'-aminopyridyl-2-chloro-5-nitrobenzamide (T007), whereas higher doses induced apoptosis [poly(ADP-ribose) polymerase cleavage], which was not inhibited by T007. These results illustrate that CDDO-, CDDO-Me, and CDDO-Im induce both PPARgamma-dependent and -independent responses in colon cancer cells, and activation of these pathways are separable and concentration-dependent for all three compounds.

Antineoplastic Agents↗