XL765 (SAR245409) is an orally bioavailable small molecule targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) kinases in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. XL765 inhibits both PI3K kinase and mTOR kinase, which may result in tumor cell apoptosis and growth inhibition in susceptible tumor cell populations. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy. mTOR, a serine/threonine kinase downstream of PI3K, may also be activated in a PI3K-independent fashion in response to nutrient and energy deprivation. XL765 significantly reduces phosphorylation of the mTOR targets S6, S6K, and 4EBP1, which is associated with greater apoptosis induction rather than to PI3K inhibition alone. In preclinical studies, XL765 slowed tumor growth or caused tumor shrinkage in multiple preclinical cancer models, including breast, lung, ovarian, prostate cancers, and gliomas.
|Cell lines||T3-1, GH3, and MMQ cells|
|Preparation method||Proliferation/viability study
The effect of TMZ, XL765, and TMZ/XL765 combination on cell viability of T3-1, GH3, and MMQ in vitro was accessed using the CCK-8 (AbMole) cell viability assay. The T3-1, GH3, and MMQ cells were centrifuged and resuspended in medium and then plated in 96-well plates at a concentration of 1 *104 cells per 100 uL/well. The T3-1 and GH3 cells were trypsinized before being centrifuged and resuspended because of their adherent properties. After incubation for 24 hours, TMZ alone(15.625, 31.25, 62.5, 125, or 250 uM), XL765 alone (3.125, 6.25, 12.5, 25, 50, 100, and 200 uM), or both agents (15.625, 31.25, 62.5, 125, or 250 uM TMZ 25 or 50 uM XL765) were added into the respective wells, with DMSO serving as the solvent control. Cell viability was evaluated after 72 hours of incubation with the various agents using the CCK-8 assay. Briefly, 10 uL of CCK-8 reagent was added to each well and the cells were then incubated at 37°C for an additional 2 hours. Absorbance was then measured at a wavelength of 450-630 nm using a Victor-2 plate reader (PerkinElmer, Waltham, Massachusetts). Each CCK-8 assay was performed in triplicate. Cell viability was calculated as a percentage of the control, and the median inhibitory concentration (IC50) of TMZ alone, XL765 alone, or both agents (TMZ/XL765) were calculated from growth inhibition curves fitted to the data using the OriginPro 7.5 software (Origin Labs, Northampton, Massachusetts).
|Concentrations||3.125, 6.25, 12.5, 25, 50, 100, and 200 uM|
|Incubation time||72 h|
|Animal models||GH3 cells bearing nude mice|
|Dosages||25, 50, or 100 mg/kg 5 times a 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 ≥15 mg/mL|
Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice.
Dai C, et al. Endocrinology. 2013 Mar;154(3):1247-59. PMID: 23384836.
Targeting the PI3K/mTOR Axis, Alone and in Combination with Autophagy Blockade, for the Treatment of Malignant Peripheral Nerve Sheath Tumors.
Ghadimi et al. Mol Cancer Ther. 2012 Aug;11(8):1758-69. PMID: 22848094.
Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma.
Mirzoeva et al. J Mol Med (Berl). 2011 Sep;89(9):877-89. PMID: 21678117.
Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide.
Prasad et al. Neuro Oncol. 2011 Apr;13(4):384-92. PMID: 21317208.
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