AT-101 (R-(-)-gossypol acetic acid) is a polyphenolic compound isolated from cottonseeds. AT-101 induces Apoptosis through activation of caspase-9, -3, and -7 in VCaP cells. It inhibits Bcl-2 by acting as a BH3 mimetic and disrupts the heterodimerization of Bcl-2 with proapoptotic family members. AT-101 was found to mimic the proapoptosis proteins and is able to bind to the BH3 domains of Bcl-2, Mcl-1, and Bcl-xL. AT-101 has been shown to be therapeutically active as a single agent in several mouse models including breast, prostate, colon, and non-small cell lung cancer. We demonstrate that AT-101 administration delays the onset of androgen-independent prostate cancer in vivo. The use of AT-101 and ADT may further delay the onset of AI disease, resulting in prolonged progression-free survival of prostate cancer.
|Cell lines||HDMEC, OSCC3, UM-SCC-17B, UM-SCC-74A cells line|
|Preparation method||SRB assay
Sulforhodamine B (SRB) cytotoxicity assays were done as described (25). Briefly, cells were seeded at 2×103 cells per well of 96-well plates, allowed to attach overnight, and treated with AT101 and/or taxotere for 72–96 hours. Cells were fixed with 10% trichloroacetic acid, stained with 0.4% SRB (Sigma-Aldrich, St. Louis, MO) in 1% acetic acid, and plates were read in a microplate reader at 560 nm (GENios; Tecan, Graz, Austria). Test results were normalized against initial plating density and drug-free controls. Data were obtained from triplicate wells per condition and is representative of three independent experiments.
|Incubation time||72-96 h|
|Animal models||SCID Mouse Model of Human Tumor Angiogenesis|
|Formulation||resuspended in carboxymethyl cellulose and sonicated for 30 minutes|
|Dosages||10mg/kg daily or 70mg/kg weekly|
|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.
Metronomic dosing of BH3 mimetic small molecule yields robust antiangiogenic and antitumor effects.
Imai A, et al. Cancer Res. 2012 Feb 1;72(3):716-25. PMID: 22158856.
A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer.
Baggstrom et al. J Thorac Oncol. 2011 Oct;6(10):1757-60. PMID: 21918390.
Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer.
Ready et al. J Thorac Oncol. 2011 Apr;6(4):781-5. PMID: 21289522.
AT-101 (R-(-)-gossypol acetic acid) enhances the effectiveness of androgen deprivation therapy in the VCaP prostate cancer model.
McGregor et al. J Cell Biochem. 2010 Aug 1;110(5):1187-94. PMID: 20589722.
AT-101, a pan-Bcl-2 inhibitor, leads to radiosensitization of non-small cell lung cancer.
Moretti et al. J Thorac Oncol. 2010 May;5(5):680-7. PMID: 20354451.
AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis.
Zerp et al. Radiat Oncol. 2009 Oct 23;4:47. PMID: 19852810.
|Related Bcl-2 Products|
BH3I-1 is a Bcl-XL-BH3 domain interaction inhibitor with Ki of 2.4 μM (by fluorescence polarization ).It is a selective inhibitor of Bcl-2 family proteins.
Obatoclax is an antagonist of Bcl-2 family members containing four Bcl-2 homology domains, including Bcl-2, Bcl-W, Bcl-XL, and Mcl-1 (KD = ~500 nM).
HA14-1 is a Bcl-2 inhibitor that is widely used for studies of apoptosis with IC50 of ~9 μM.
Sabutoclax(BI-97C1) is a pan-Bcl-2 inhibitor, including Bcl-xL, Bcl-2, Mcl-1 and Bfl-1 with IC50 of 0.31 μM, 0.32 μM, 0.20 μM and 0.62 μM, respectively.
BM-1074 is a potent and efficacious Bcl-2/Bcl-xL inhibitor with Ki of <1 nM, inactive to Mcl-1.
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