Temsirolimus

MCE 国际站：Temsirolimus

产品活性：Temsirolimus 是 mTOR 抑制剂，IC₅₀ 值为 1.76 μM。Temsirolimus 能激活自噬 (autophagy),在动物模型中防止心脏功能恶化。

研究领域：PI3K/Akt/mTOR | Autophagy | Apoptosis | Anti-infection

作用靶点：mTOR | Autophagy | Apoptosis | Bacterial

In Vitro: Temsirolimus potently inhibits mTOR kinase activity with IC₅₀ of 1.76 μM, similar to that of rapamycin with IC₅₀ of 1.74 μM in the absence of FKBP12. Temsirolimus (10 nM to <5 μM) displays a modest and selective antiproliferative activity via FKBP12-dependent mechanism, but can completely inhibit the proliferation of a broad panel of tumor cells at low micromolar concentrations (5-15 μM), involving FKBP12-independent suppression of mTOR signaling. Temsirolimus treatment at micromolar but not nanomolar concentrations (20 μM) causes a marked decline in global protein synthesis and disassembly of polyribosomes, accompanied by rapid increase in the phosphorylation of translation elongation factor eEF2 and the translation initiation factor eIF2A. Temsirolimus inhibits the phosphorylation of ribosomal protein S6, more potently in PTEN-positive DU145 cells than in PTEN-negative PC-3 cells, and inhibits cell growth and clonogenic survival of both cells in a concentration-dependent manner. Temsirolimus (100 ng/mL) potently inhibits proliferation and induces apoptosis in primary human lymphoblastic leukemia (ALL) cells.

In Vivo: CCI-779 (20 mg/kg, i.p.) inhibits the growth of both prostate cancer xenografts, and the rowth of PC-3 tumors is inhibited in a dose-dependent manner and growth inhibition is greater than for DU145 tumors. In the NOD/SCID xenograft models with human ALL, Temsirolimus treatment at 10 mg/kg/day produces a decrease in peripheral blood blasts and in splenomegaly. Administration of Temsirolimus (20 mg/kg, i.p. 5 days/week) significantly delays the growth of DAOY xenografts by 160% after 1 week and 240% after 2 weeks, compared with controls. Single high-dose of Temsirolimus (100 mg/kg, i.p) treatment induces 37% regression of tumor volume within 1 week. Temsirolimus treatment for 2 weeks also delays the growth of rapamycin-resistant U251 xenografts by 148%. Inhibition of mTOR by Temsirolimus improves performance on four different behavioral tasks and decreases aggregate formation in a mouse model of Huntington disease. Administration of Temsirolimus induces significant dose-dependent, antitumor responses against subcutaneous growth of 8226, OPM-2, and U266 xenografts with ED₅₀ of 20 mg/kg and 2 mg/kg for 8226 and OPM-2, respectively, which are associated with inhibited proliferation and angiogenesis, induction of apoptosis, and reduction in tumor cell size.

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