Temsirolimus (CCI-779) inhibited the growth of xenografts derived from both cell lines with greater effects against PC-3 than DU145 tumors. Temsirolimus caused mild myelosuppression. The activity of mitoxantrone or docetaxel was limited, but CCI-779 given between courses of chemotherapy increased growth delay of PC-3 xenografts. High-dose temsirolimus inhibits mTOR signaling through an FKBP12-independent mechanism that leads to profound translational repression. This distinctive high-dose compound effect could be directly related to the antitumor activities of temsirolimus and other rapalogues in human cancer patients. The rapamycin analogue CCI-779 is an important new agent to investigate in the treatment of human brain tumors, particularly PNET/MB. The rapamycin analogue temsirolimus improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease.
Mol Cell. 2018 Dec 3.
Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression.
Temsirolimus purchased from AbMole
Cell Death and Disease. 2018 Jan 26;9:137-52.
J Agric Food Chem. 2017 Mar 15;65(10):2089-2099.
|Source||Cell Death & Disease (2018). Figure 2. Temsirolimus (Abmole Bioscience)|
|Method||colony formation assays|
|Cell Lines||MDA-MB-231, MDA-MB-157, and MDA-MB-468 cells|
|Incubation Time||24 h|
|Results||But treatment with Temsirolimus in combination with ABT263 or ABT199 only induced modest cell viability inhibition.|
|Source||Cell Death & Disease (2018). Figure 1. Temsirolimus (Abmole Bioscience)|
|Cell Lines||TNBC cell lines|
|Incubation Time||24 h|
|Results||As expected, we found the mTOR inhibitors, especially the BEZ235 and AZD8055, could significantly inhibit the phosphorylation of AKT and 4EBP1 and efficiently led to decreasing MCL-1 expression.|
|Source||APMIS.m (2017). Figure 7. temsirolimus (Abmole Bioscience Inc. Houston, TX, USA)|
|Cell Lines||HeLa cells|
|Results||In addition, exposure with deguelin and temsirolimus could weaken the inhibitory attributes of 10-G on the expression of p-AKT and p-mTOR.|
|Cell lines||A549, H157, H460, H446, HCT116, HT29, SW480, DLD1, Caco2, LNCap, DU145, MDA468, MDA231, HEK293, and PC3-MM2|
|Preparation method||Exposing cells to various concentrations of Temsirolimus for 72 hours. After treatment, using CellTiter AQ assay kit to determing viable cell densities by MTS dye conversion.|
|Concentrations||Dissolved in DMSO, final concentrations ~20 μM|
|Incubation time||72 hours|
|Animal models||Female athymic nude mice injected s.c. with DAOY, or U251 cells|
|Formulation||Prepared in 100% EtOH as a 50 mg/mL stock solution, and diluted in 5% Tween 80 and 5% polyethylene glycol 400|
|Administration||Injection daily 5 times per week|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥180 mg/mL
Ethanol ≥180 mg/mL
A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis.
Shor B, et al. Cancer Res. 2008 Apr 15;68(8):2934-43. PMID: 18413763.
Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts.
Wu L, et al. Cancer Res. 2005 Apr 1;65(7):2825-31. PMID: 15805283.
Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.
Ravikumar B, et al. Nat Genet. 2004 Jun;36(6):585-95. PMID: 15146184.
Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.
Geoerger B, et al. Cancer Res. 2001 Feb 15;61(4):1527-32. PMID: 11245461.
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Zotarolimus (ABT-578) is an analogue of rapamycin, and inhibits FKBP-12 binding with IC50 of 2.8 nM.
LY303511 is a structural analogue of LY294002, which does not inhibit PI3K, increased homotypic GJIC.
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