The Experts below are selected from a list of 33 Experts worldwide ranked by ideXlab platform
Laurent Belec - One of the best experts on this subject based on the ideXlab platform.
-
pre clinical development as microbicide of zinc tetra ascorbo camphorate a novel Terpenoid Derivative potent in vitro inhibitory activity against both r5 and x4 tropic hiv 1 strains without significant in vivo mucosal toxicity
Aids Research and Therapy, 2008Co-Authors: Hela Saidi, Mohammadali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurele Mannarini, Laurent BelecAbstract:Background Terpenoid Derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoTerpenoid Derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells.
-
Pre-clinical development as microbicide of zinc tetra-ascorbo-camphorate, a novel Terpenoid Derivative: Potent in vitro inhibitory activity against both R5- and X4-tropic HIV-1 strains without significant in vivo mucosal toxicity
AIDS Research and Therapy, 2008Co-Authors: Hela Saidi, Mohammadali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurele Mannarini, Laurent BelecAbstract:Background Terpenoid Derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoTerpenoid Derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells. Results The toxicity study was carried out in vitro and also with the New Zealand White rabbit vaginal irritation model. C14 was found to be no cytotoxic at high concentrations (CC50 > 10 μM) and showed to be a potential HIV-1 inhibitor of infection of all the primary cells tested (EC50 = 1 μM). No significant changes could be observed in cervicovaginal tissue of rabbit exposed during 10 consecutive days to formulations containing up to 20 μM of C14. Conclusion Overall, these preclinical studies suggest that zinc tetra-ascorbo-camphorate Derivative is suitable for further testing as a candidate microbicide to prevent male-to-female heterosexual acquisition of HIV-1.
Hela Saidi - One of the best experts on this subject based on the ideXlab platform.
-
pre clinical development as microbicide of zinc tetra ascorbo camphorate a novel Terpenoid Derivative potent in vitro inhibitory activity against both r5 and x4 tropic hiv 1 strains without significant in vivo mucosal toxicity
Aids Research and Therapy, 2008Co-Authors: Hela Saidi, Mohammadali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurele Mannarini, Laurent BelecAbstract:Background Terpenoid Derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoTerpenoid Derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells.
-
Pre-clinical development as microbicide of zinc tetra-ascorbo-camphorate, a novel Terpenoid Derivative: Potent in vitro inhibitory activity against both R5- and X4-tropic HIV-1 strains without significant in vivo mucosal toxicity
AIDS Research and Therapy, 2008Co-Authors: Hela Saidi, Mohammadali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurele Mannarini, Laurent BelecAbstract:Background Terpenoid Derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoTerpenoid Derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells. Results The toxicity study was carried out in vitro and also with the New Zealand White rabbit vaginal irritation model. C14 was found to be no cytotoxic at high concentrations (CC50 > 10 μM) and showed to be a potential HIV-1 inhibitor of infection of all the primary cells tested (EC50 = 1 μM). No significant changes could be observed in cervicovaginal tissue of rabbit exposed during 10 consecutive days to formulations containing up to 20 μM of C14. Conclusion Overall, these preclinical studies suggest that zinc tetra-ascorbo-camphorate Derivative is suitable for further testing as a candidate microbicide to prevent male-to-female heterosexual acquisition of HIV-1.
Pothana Saikumar - One of the best experts on this subject based on the ideXlab platform.
-
Abstract P3-14-09: Targeting TMEPAI/ PMEPA1 inhibited triple negative breast cancer cell growth and metastasis through growth suppressive TGF-β signaling
Cancer Research, 2016Co-Authors: Prajjal K. Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam, Pothana SaikumarAbstract:Background: Triple negative breast cancers (TNBC) that lack estrogen receptor (ER), progesterone receptor (PR) and hormone epidermal growth factor receptor 2 (HER-2/neu) are aggressive and cause high mortality among breast cancer patients. Transforming growth factor beta (TGF-β) dependency for their aggressive behavior (growth and metastasis) has been well established in many of these tumors. Although targeting TGF-β signaling has major potential to treat TNBCs, however it carries the risk of disturbing the tumor suppressive effects of TGF-β in early tumors and its homeostatic control of normal tissues. Hence there is a need to identify novel targets to impede tumor progression without compromising the beneficial effects of TGF-β signaling. To satisfy this unmet need, earlier we identified that transmembrane prostate androgen induced (TMEPAI/PMEPA1), a direct target gene of TGF-β could act as a "molecular switch" that converts TGF-β from a tumor suppressor to promoter in TNBC. Thus, we undertook the present study that identified a novel compound that blocked TMEPAI expression. Materials and Methods: All cell lines were cultured according to the ATCC recommendations. Cell proliferation was measured by quantitation of total cellular DNA. Immunoblotting, migration, invasion, tumor xenografts and lung metastasis were performed using standard methods. Results: We identified a Terpenoid Derivative (TD) which inhibited the expression of TMEPAI, enhanced TGF-β signaling and blocked proliferation, migration and invasion of several triple negative breast cancer cells in vitro. Our results showed that TD increased phosphorylation of Smad2/3 and increased PTEN, p21 and p27 proteins that cause growth suppression. Concomitantly, TD decreased Akt phosphorylation and reduced Snail and Slug that are required for cell growth and metastasis. Interestingly, TD did not affect the growth of normal human mammary epithelial cells and failed to cause associated molecular changes that can result in growth suppression. Notably, using mice models (nude mice and syngeneic BALB/c mice), we showed that TD reduced tumor burden significantly with little or no toxicity. Consistent with its ability to inhibit Akt phosphorylation and induction of Snail and Slug proteins, TD suppressed lung metastasis of TNBC in mice model. Importantly, reduced tumors derived from TD treated mice exhibited increased expression of pSmad2/3, PTEN, p21, p27 and reduced expression of pAkt compared to tumors obtained from vehicle treated mice. Conclusions: Our results have two important dimensions: On one hand, TD inhibited TMEPAI induction to promote growth suppressive TGF-β dependent Smad signaling in TNBC but not in normal cells. On the other hand, TD also inhibited non-Smad signaling that promotes growth and metastasis of TNBC both in vitro and in vivo. Hence our findings suggest that drugs that target TMEPAI will not only inhibit growth and metastasis of TNBC but will also restore homeostatic functions of TGF-β to prevent new tumor development. Citation Format: Singha PK, Pandeswara S, Venkatachalam MA, Saikumar P. Targeting TMEPAI/ PMEPA1 inhibited triple negative breast cancer cell growth and metastasis through growth suppressive TGF-β signaling. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-09.
-
Abstract P4-15-06: TMEPAI, a novel drug target in breast cancer therapy and prevention
Cancer Research, 2013Co-Authors: Prajjal K. Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam, Pothana SaikumarAbstract:Background: Triple negative (ER, PR and Her2 –negative) breast cancers (TNBC) depend on transforming growth factor beta (TGF-b) signaling activity for their late growth and metastasis. Thus TGF-β signaling antagonism has major potential in treating TNBC. However, this approach carries the risk of disturbing the tumor suppressive homeostatic control of TGF-β in normal tissues and early tumors. In this context, we identified that Transmembrane prostate androgen induced (TMEPAI) could act as a “molecular switch” that converts TGF-β from a tumor suppressor to promoter. Therefore, we hypothesized that therapeutic targeting of TMEPAI will impede tumor progression without compromising TGF-β dependent homeostasis of normal cells. Hence, we undertook the present study to evaluate the role of TMEPAI in the regulation of TGF-β signaling in breast cancer progression and screened drugs that can block TMEPAI expression as well as breast cancer cell growth and metastasis. Materials and Methods: All cell lines were cultured according to the recommended standard procedures. Lentiviral mediated expression vector was used to stably knockdown endogenous TMEPAI expression. DNA transfections and luciferase assays were performed according to vendor instructions. Cell proliferation was measured by quantitation of total cellular DNA. Immunoblotting, tumor xenografts, migration, invasion and immunohistochemical assays were performed using standard methods. Results: Our results showed increased stimulation and prolonged sustenance of Smad2 and Smad3 phosphorylation and Smad-driven luciferase reporter activity by TGF-β in TMEPAI knock-down MDA-MB-231 triple negative breast cancer cells. In contrast, exogenous expression of TMEPAI in normal human mammary epithelial cells (HMEC) or TMEPAI-deficient MDA-MB-231 cells reduced Smad dependent TGF-β signaling. While proliferation of HMEC is inhibited by TGF-β, MDA-MB-231 cells showed a biphasic growth response to TGF-β, which is inhibited by TMEPAI-deficiency. Moreover, TMEPAI subverts tumor suppressive TGF-β mediated Smad signaling into tumor promotive non-Smad signaling through stimulation of mammalian mitogen-activated protein kinases (MAPKs), pAkt and reduced PTEN while TMEPAI-deficiency prevented MAPKs, Akt activation and enhanced PTEN. Furthermore, immunohistochemistry revealed high TMEPAI expression in several aggressive human breast tumor samples but not in the matched normal human breast tissue specimens. Interestingly, drug screening resulted in the identification of a Terpenoid Derivative (TD) that blocked the expression of TMEPAI and inhibited the proliferation, migration and invasion of cancer cells in vitro and lung metastasis of breast cancer cells in vivo. Notably, TD did not affect the growth of normal human mammary epithelial cells. Remarkably, TD enhanced TGF-β mediated Smad signaling and inhibited growth promoting non-Smad-signaling in breast cancer cells. Conclusions: Hence our findings suggest that TMEPAI not only serves as a novel biomarker but also as a suitable therapeutic target for aggressive breast cancers. Drugs that target TMEPAI may develop an effective anti-TGF-β therapy against aggressive breast cancers without disturbing the growth suppressive homeostatic control of TGF-β in normal tissues and early tumors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-06.
-
Abstract 562: Targeting TMEPAI in breast cancer therapy and prevention
Cancer Research, 2012Co-Authors: Prajjal K. Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam, Pothana SaikumarAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL We earlier identified that TMEPAI (Transmembrane prostate androgen induced) as a novel TGF-β inducible gene that converts tumor suppressive TGF-β into a tumor promoter in breast cancer. The objective of the present study was to assess the role of TMEPAI in the regulation of TGF-β mediated canonical and non-canonical signaling pathways and evaluate the effect of novel drugs, which block TMEPAI expression, in controlling breast tumor progression. Knockdown of endogenous TMEPAI expression was achieved by Lentiviral shRNA expression vectors. DNA transfections, luciferase assays, cell culture, cell proliferation, immunoblotting, immunohistochemistry and in vivo tumor studies using nude mice were done using standard methods. Here, we show that TMEPAI knock-down in MDA-MB-231 triple negative breast cancer cells increased TGF-β mediated Smad signaling with prolonged activation of Smad2 and Smad3 proteins measured by their phosphorylation and Smad-driven luciferase reporter activity. In contrast, exogenous expression of TMEPAI in normal human mammary epithelial cells (HMEC) or TMEPAI-deficient MDA-MB-231cells reduced Smad signaling. While proliferation of HMEC is inhibited by TGF-β, MDA-MB-231 cells showed a biphasic growth response to TGF-β, which is blocked by TMEPAI-deficiency. This led us to test the role of TMEPAI in regulating the canonical and non-canonical pathways of TGF- ≤ signaling. Our studies identified that TMEPAI subverts tumor suppressive TGF-β mediated Smad signaling into tumor promotive non-Smad signaling through stimulation of all three groups of mammalian mitogen-activated protein kinase (MAPK) pathways and Akt pathway. TMEPAI-deficiency prevented the activation of these MAPKs in breast cancer cells. Importantly, TMEPAI-deficiency increased PTEN and reduced pAkt levels in MDA-MB-231 cells. Furthermore, evaluation of TMEPAI as a prognostic biomarker by immunohistochemistry (IHC) revealed high TMEPAI expression in several aggressive human breast tumor samples but not in the matched normal human breast specimens. In addition, drug screening identified a Terpenoid Derivative (TD) that blocked the expression of TMEPAI and inhibited the proliferation, migration and invasion of MDA-MB-231 cells. Notably, TD did not block the growth of normal human mammary epithelial cells. In addition, TD enhanced TGF-β-mediated Smad signaling but inhibited growth promoting activation of MAPKs and Akt in MDA-MB-231 cells. Importantly, administration of TD (at 2mg/Kg body weight by i.p.) markedly reduced the mass of tumors in mice harboring MDA-MB-231-derived xenograft tumors. Our findings suggest that TMEPAI is a novel biomarker and a therapeutic target for TGF-β dependent aggressive breast cancers. In addition to reducing the tumor mass, drugs that block TMEPAI expression may also prevent nascent tumor formation by their ability to stimulate growth suppressive TGF-β signaling and inhibit growth promoting signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 562. doi:1538-7445.AM2012-562
Aurele Mannarini - One of the best experts on this subject based on the ideXlab platform.
-
pre clinical development as microbicide of zinc tetra ascorbo camphorate a novel Terpenoid Derivative potent in vitro inhibitory activity against both r5 and x4 tropic hiv 1 strains without significant in vivo mucosal toxicity
Aids Research and Therapy, 2008Co-Authors: Hela Saidi, Mohammadali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurele Mannarini, Laurent BelecAbstract:Background Terpenoid Derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoTerpenoid Derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells.
-
Pre-clinical development as microbicide of zinc tetra-ascorbo-camphorate, a novel Terpenoid Derivative: Potent in vitro inhibitory activity against both R5- and X4-tropic HIV-1 strains without significant in vivo mucosal toxicity
AIDS Research and Therapy, 2008Co-Authors: Hela Saidi, Mohammadali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurele Mannarini, Laurent BelecAbstract:Background Terpenoid Derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoTerpenoid Derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells. Results The toxicity study was carried out in vitro and also with the New Zealand White rabbit vaginal irritation model. C14 was found to be no cytotoxic at high concentrations (CC50 > 10 μM) and showed to be a potential HIV-1 inhibitor of infection of all the primary cells tested (EC50 = 1 μM). No significant changes could be observed in cervicovaginal tissue of rabbit exposed during 10 consecutive days to formulations containing up to 20 μM of C14. Conclusion Overall, these preclinical studies suggest that zinc tetra-ascorbo-camphorate Derivative is suitable for further testing as a candidate microbicide to prevent male-to-female heterosexual acquisition of HIV-1.
Charlotte Charpentier - One of the best experts on this subject based on the ideXlab platform.
-
pre clinical development as microbicide of zinc tetra ascorbo camphorate a novel Terpenoid Derivative potent in vitro inhibitory activity against both r5 and x4 tropic hiv 1 strains without significant in vivo mucosal toxicity
Aids Research and Therapy, 2008Co-Authors: Hela Saidi, Mohammadali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurele Mannarini, Laurent BelecAbstract:Background Terpenoid Derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoTerpenoid Derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells.
-
Pre-clinical development as microbicide of zinc tetra-ascorbo-camphorate, a novel Terpenoid Derivative: Potent in vitro inhibitory activity against both R5- and X4-tropic HIV-1 strains without significant in vivo mucosal toxicity
AIDS Research and Therapy, 2008Co-Authors: Hela Saidi, Mohammadali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurele Mannarini, Laurent BelecAbstract:Background Terpenoid Derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoTerpenoid Derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells. Results The toxicity study was carried out in vitro and also with the New Zealand White rabbit vaginal irritation model. C14 was found to be no cytotoxic at high concentrations (CC50 > 10 μM) and showed to be a potential HIV-1 inhibitor of infection of all the primary cells tested (EC50 = 1 μM). No significant changes could be observed in cervicovaginal tissue of rabbit exposed during 10 consecutive days to formulations containing up to 20 μM of C14. Conclusion Overall, these preclinical studies suggest that zinc tetra-ascorbo-camphorate Derivative is suitable for further testing as a candidate microbicide to prevent male-to-female heterosexual acquisition of HIV-1.