Amr Ghaleb

Publications of Amr Ghaleb

• Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad.

  Authors: Raluca Rusovici, Amr Ghaleb, Hyunsuk Shim, Vincent W Yang, C Chris Yun

  Biochimica et biophysica acta. 09/2007; 1770(8):1194-203.

  Lysophosphatidic acids (LPA) exert growth factor-like effects through specific G protein-coupled receptors. The presence of different LPA receptors often determines the specific signaling mechanismsLysophosphatidic acids (LPA) exert growth factor-like effects through specific G protein-coupled receptors. The presence of different LPA receptors often determines the specific signaling mechanisms and the physiological consequences of LPA in different environments. Among the four members of the LPA receptor family, LPA(2) has been shown to be overexpressed in colon cancer suggesting that the signaling by LPA(2) may potentiate growth and survival of tumor cells. In this study, we examined the effect of LPA on survival of colon cancer cells using Caco-2 cells as a cell model system. LPA rescued Caco-2 cells from apoptosis elicited by the chemotherapeutic drug, etoposide. This protection was accompanied by abrogation of etoposide-induced stimulation of caspase activity via a mechanism dependent on Erk and PI3K. In contrast, perturbation of cellular signaling mediated by the LPA(2) receptor by knockdown of a scaffold protein NHERF2 abrogated the protective effect of LPA. Etoposide decreased the expression of Bcl-2, which was reversed by LPA. Etoposide decreased the phosphorylation level of the proapoptotic protein Bad in an Erk-dependent manner, without changing Bad expression. We further show that LPA treatment resulted in delayed activation of Erk. These results indicate that LPA protects Caco-2 cells from apoptotic insult by a mechanism involving Erk, Bad, and Bcl-2.

• Protection from murine cysticercosis by immunization with a parasite cysteine protease.

  Authors: Salman Baig, Raymond T Damian, Jorge Morales-Montor, Amr Ghaleb, Amjed Baghdadi, A Clinton White

  Microbes and infection / Institut Pasteur. 11/2006; 8(12-13):2733-5.

  Central nervous system infection by Taenia solium cysts causes neurocysticercosis, a common neurological infection in the Third World. We have previously isolated cysteine proteases from TaeniaCentral nervous system infection by Taenia solium cysts causes neurocysticercosis, a common neurological infection in the Third World. We have previously isolated cysteine proteases from Taenia crassiceps and T. solium. In this study, we immunized BALB/c mice with the purified T. solium cysteine protease and challenged them with Taenia crassiceps. Immunized mice had a 72% reduction in parasite burden compared to mice that received no immunization. Immunized mice developed antigen specific lymphocyte proliferation. These data support further studies of the T. solium cysteine protease as a vaccine candidate.

• Cysteine proteinase inhibitors in murine cysticercosis.

  Authors: Salman Baig, Raymond T Damian, Jorge Morales-Montor, Rupal Thazhath, Amr Ghaleb, Meredith Welch, Jamil Talhouk, A Clinton White

  Antimicrobial agents and chemotherapy. 09/2006; 50(8):2886-8.

  We explored the prophylactic efficacies of two novel protease inhibitors in murine cysticercosis. Our results demonstrated a 95% and 80% reduction in parasite burden for mice injected with Z-LLL-FMKWe explored the prophylactic efficacies of two novel protease inhibitors in murine cysticercosis. Our results demonstrated a 95% and 80% reduction in parasite burden for mice injected with Z-LLL-FMK and Z-LLY-FMK, respectively. Further studies are merited on the role of cysteine proteinase inhibitors in treatment of cysticercosis.

• Rational design of the microtubule-targeting anti-breast cancer drug EM015.

  Authors: Ritu Aneja, Manu Lopus, Jun Zhou, Surya N Vangapandu, Amr Ghaleb, Joyce Yao, James H Nettles, Binfei Zhou, Meenakshi Gupta, Dulal Panda, Ramesh Chandra, Harish C Joshi

  Cancer research. 05/2006; 66(7):3782-91.

  We studied in silico docking of noscapine onto tubulin, combined with calculations of surface charge, pi-pi, van der Waals, and hydrogen bonding interactions, to rationally design a new compound,We studied in silico docking of noscapine onto tubulin, combined with calculations of surface charge, pi-pi, van der Waals, and hydrogen bonding interactions, to rationally design a new compound, EM015. This tubulin-binding semisynthetic compound is a selective and potent anti-breast cancer agent and displays a 20-fold lower IC(50) against many tumor cells compared with our founding compound, (S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]-dioxolo-[4,5-g]isoquinolin-5-yl)isobenzo-furan-1(3H)-one (noscapine). Furthermore, EM015 is also effective against a variety of drug-resistant cells. Surprisingly, the cell cycle profile of nontumorigenic normal cells is not affected. Many antimicrotubule cancer drugs in clinic today, particularly taxanes and Vincas, face challenges including frequent visits to the hospital for prolonged i.v. infusions, toxicities, and tumor recurrences due to drug resistance. EM015, on the other hand, is orally available, regresses breast tumor xenografts in nude mice models, and increases longevity. Furthermore, we have failed to observe any detectable toxicity in tissues, such as liver, kidney, spleen, lung, heart, and brain, as well as neurons, which are common targets of antimicrotubule drug therapy. Thus, EM015 has a great promise in the clinic.

• Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad

  Authors: Raluca Rusovici, Amr Ghaleb, Hyunsuk Shim, Vincent W. Yang, C. Chris Yun

  Biochimica et Biophysica Acta (BBA) - General Subjects.

  Lysophosphatidic acids (LPA) exert growth factor-like effects through specific G protein-coupled receptors. The presence of different LPA receptors often determines the specific signaling mechanismsLysophosphatidic acids (LPA) exert growth factor-like effects through specific G protein-coupled receptors. The presence of different LPA receptors often determines the specific signaling mechanisms and the physiological consequences of LPA in different environments. Among the four members of the LPA receptor family, LPA2 has been shown to be overexpressed in colon cancer suggesting that the signaling by LPA2 may potentiate growth and survival of tumor cells. In this study, we examined the effect of LPA on survival of colon cancer cells using Caco-2 cells as a cell model system. LPA rescued Caco-2 cells from apoptosis elicited by the chemotherapeutic drug, etoposide. This protection was accompanied by abrogation of etoposide-induced stimulation of caspase activity via a mechanism dependent on Erk and PI3K. In contrast, perturbation of cellular signaling mediated by the LPA2 receptor by knockdown of a scaffold protein NHERF2 abrogated the protective effect of LPA. Etoposide decreased the expression of Bcl-2, which was reversed by LPA. Etoposide decreased the phosphorylation level of the proapoptotic protein Bad in an Erk-dependent manner, without changing Bad expression. We further show that LPA treatment resulted in delayed activation of Erk. These results indicate that LPA protects Caco-2 cells from apoptotic insult by a mechanism involving Erk, Bad, and Bcl-2.