Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo

The mammalian target of rapamycin (mTOR), which exists in two functionally distinct complexes, mTORC1 and mTORC2 plays an important role in tumor growth. Whereas the role of mTORC1 has been well characterized in this process, little is known about the functions of mTORC2 in cancer progression. In this study, we explored the specific role of mTORC2 in colon cancer using a short hairpin RNA expression system to silence the mTORC2-associated protein rictor. We found that downregulation of rictor in HT29 and LS174T colon cancer cells significantly reduced cell proliferation. Knockdown of rictor also resulted in a G1 arrest as observed by cell cycle analysis. We further observed that LS174T cells deficient for rictor failed to form tumors in a nude mice xenograft model. Taken together, these results show that the inhibition of mTORC2 reduces colon cancer cell proliferation in vitro and tumor xenograft formation in vivo. They also suggest that specifically targeting mTORC2 may provide a novel treatment strategy for colorectal cancer

Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib

Background: Targeted therapies for metastatic renal cell carcinoma (RCC), including mammalian target of rapamycin (mTOR) inhibitors and small-molecule multikinase inhibitors, have produced clinical effects. However, most patients acquire resistance over time. Thus, new therapeutic strategies need to be developed. Here, we evaluated the effect of the dual PI3K/mTOR inhibitor NVP-BEZ235, in combination with the multikinase inhibitor sorafenib on renal cancer cell proliferation and survival in vitro as well as on tumor growth in vivo.Methods: The renal carcinoma cell lines 786-0 and Caki-1 were treated with NVP-BEZ235 or sorafenib, either alone or in combination. Tumor cell proliferation and apoptosis were investigated in vitro. The anticancer efficacy of NVP-BEZ235 alone, or in combination with sorafenib, was also evaluated on RCC xenografts in nude mice.Results: Treatment of 786-0 and Caki-1 cells with NVP-BEZ235 or sorafenib resulted in reduced tumor cell proliferation and increased tumor cell apoptosis in vitro. The combination of NVP-BEZ235 and sorafenib was more effective than each compound alone. Similarly, in vivo, NVP-BEZ235 or sorafenib reduced the growth of xenografts generated from 786-0 or Caki-1 cells. The antitumor efficacy of NVP-BEZ235 in combination with sorafenib was superior to NVP-BEZ235 or sorafenib alone.Conclusions: Our findings indicate that the simultaneous use of NVP-BEZ235 and sorafenib has greater antitumor benefit compared to either drug alone and thus provides a treatment strategy in RCC

Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells

BACKGROUND: The mammalian target of rapamycin (mTOR) is frequently activated in colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) pathway. Targeting mTOR with allosteric inhibitors of mTOR such as rapamycin reduces colon cancer progression in several experimental models. Recently, a new class of mTOR inhibitors that act as ATP-competitive inhibitors of mTOR, has been developed. The effectiveness of these drugs in colon cancer cells has however not been fully characterized. METHODS: LS174T, SW480 and DLD-1 colon cancer cell lines were treated with PP242 an ATP-competitive inhibitor of mTOR, NVP-BEZ235, a dual PI3K/mTOR inhibitor or rapamycin. Tumor cell growth, proliferation and survival were assessed by MTS assay, 5-bromo-2'-deoxyuridine (BrDU) incorporation or by quantification of DNA fragmentation respectively. In vivo, the anticancer activity of mTOR inhibitors was evaluated on nude mice bearing colon cancer xenografts. RESULTS: PP242 and NVP-BEZ235 reduced the growth, proliferation and survival of LS174T and DLD-1 colon cancer cells more efficiently than rapamycin. Similarly, PP242 and NVP-BEZ235 also decreased significantly the proliferation and survival of SW480 cells which were resistant to the effects of rapamycin. In vivo, PP242 and NVP-BEZ235 reduced the growth of xenografts generated from LS174T and SW480 cells. Finally, we also observed that the efficacy of ATP-competitive inhibitors of mTOR was enhanced by U0126, a MEK inhibitor. CONCLUSIONS: Taken together, these results show that ATP-competitive inhibitors of mTOR are effective in blocking colon cancer cell growth in vitro and in vivo and thus represent a therapeutic option in colon cancer either alone or in combination with MEK inhibitors

Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity.

Targeting mTORC1 has been thoroughly explored in cancer therapy. Following encouraging preclinical studies, mTORC1 inhibitors however failed to provide substantial benefits in cancer patients. Several resistance mechanisms have been identified including mutations of mTOR and activation of alternate proliferation pathways. Moreover, emerging evidence discloses intratumoral heterogeneity of mTORC1 activity that further contributes to a reduced anticancer efficacy of mTORC1 inhibitors. Genetic heterogeneity as well as heterogeneous conditions of the tumor environment such as hypoxia profoundly modifies mTORC1 activity in tumors and hence influences the response of tumors to mTORC1 inhibitors. Intriguingly, the heterogeneity of mTORC1 activity also occurs towards its substrates at the single cell level, as mutually exclusive pattern of activation of mTORC1 downstream effectors has been reported in tumors. After briefly describing mTORC1 biology and the use of mTORC1 inhibitors in patients, this review will give an overview on concepts of resistance to mTORC1 inhibition in cancer with a particular focus on intratumoral heterogeneity of mTORC1 activity

Production du vecteur adénoviral dépendant d'un virus auxiliaire

De la première à la troisième génération de vecteurs adénoviraux : quels sont les paramètres gouvernant le rendement de production? -- Un procédé efficace et adaptable à grande échelle utilisant l'adénofection par la polyéthyleneimine pour la production du vecteur adénoviral dépendant d'un virus auxiliaire -- Identification des paramètres critiques d'infection pour contrôler la production du vecteur adénoviral dépendant d'un virus auxiliaire par QPCR -- Production et purification du vecteur adénoviral dépendant d'un virus auxiliaire : comparaison entre les lignées parentale et recombinase HEK293

Fine-Tuning Tumor Endothelial Cells to Selectively Kill Cancer.

Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas initial anti-angiogenic treatments focused mainly on blocking the formation of new blood vessels in cancer, emerging strategies are specifically influencing certain aspects of tumor endothelial cells. For instance, efforts are generated to normalize tumor blood vessels in order to improve tumor perfusion and ameliorate the outcome of chemo-, radio-, and immunotherapy. In addition, treatment options that enhance the properties of tumor blood vessels that support a host's anti-tumor immune response are being explored. Hence, upcoming anti-angiogenic strategies will shape some specific aspects of the tumor blood vessels that are no longer limited to abrogating angiogenesis. In this review, we enumerate approaches that target tumor endothelial cells to provide anti-cancer benefits and discuss their therapeutic potential

Cuidados y educación especial : Aportes de los estudios feministas para pensar los apoyos

La idea de cuidado generalmente se vincula con asistencialismo, invalidez, fragilidad, dependencia. Y si bien algunos de estos vínculos no son inadecuados, intentaremos en las siguientes líneas cambiar el tinte peyorativo de algunas de estas relaciones. Para ello empezaremos por caracterizar qué se entiende por cuidados y cuál será la postura desde la cual nos posicionaremos para pensarlos, para luego vincularlos con la educación y, puntualmente, con la educación especial. Retomaremos, a los fines de este escrito, algunos puntos clave respecto a los cuidado desde la economía feminista, focalizando en la economía del cuidado, que nos permitan pensar algunas causas primordiales del por qué las cuestiones vinculadas a los cuidados son tareas devenidas en tareas femeninas; para luego, desde la ética de los cuidados, abordarlos desde una perspectiva relacional que nos posibilite profundizar en los vínculos de interdependencia como forma toda de relación a fin de poner en tensión las intervenciones en educación especial