(R)-(-)-Gossypol acetic acid (AT-101 (acetic acid)) is a novel, orally active Bcl-2 family protein inhibitor that inhibits Bcl-2 (Ki=260±30nM), Mcl-1 (Ki=170±10nM), and Bcl-xL (Ki=480±40nM)[1-2]. (R)-(-)-Gossypol acetic acid can be used in research related to glioblastoma, chronic lymphocytic leukemia, and non-small cell lung cancer, among others[3-4].
In vitro, (R)-(-)-Gossypol acetic acid (2.5–15μM) was co-treated with Trastuzumab in SKBR-3 and MDA-MB-453 HER2-positive breast cancer cells for 72 hours. (R)-(-)-Gossypol acetic acid induced apoptosis by inhibiting the PI3K/AKT signaling pathway[5]. (R)-(-)-Gossypol acetic acid (15μM) was used to treat U87MG and U343 glioma cells for 48 hours. (R)-(-)-Gossypol acetic acid induced mitophagic cell death[6].
In vivo, (R)-(-)-Gossypol acetic acid (35mg/kg) combined with Gefitinib (50mg/kg) was administered orally five times per week to BALB/c nude mice subcutaneously inoculated with PC-9-GR cells (harboring the EGFR T790M mutation). The combination of (R)-(-)-Gossypol acetic acid and Gefitinib significantly inhibited tumor growth and increased the expression of the apoptosis marker cleaved caspase-3 in tumor tissues[7]. (R)-(-)-Gossypol acetic acid (50mg/kg) was administered via daily intraperitoneal injection, five times per week, to NOD/SCID mice subcutaneously inoculated with U937 human leukemia cells for 60 days. (R)-(-)-Gossypol acetic acid significantly inhibited tumor growth and induced tumor cell apoptosis[8].
References:
[1] Oliver CL, Bauer JA, Wolter KG, et al. In vitro effects of the BH3 mimetic, (-)-gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res. 2004 Nov 15;10(22):7757-63.
[2] Sun Y, Wu J, Aboukameel A, et al. Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo. Cancer Biol Ther. 2008 Sep;7(9):1418-26.
[3] Baggstrom MQ, Qi Y, Koczywas M, et al. A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol. 2011 Oct;6(10):1757-60.
[4] Schelman WR, Mohammed TA, Traynor AM, et al. A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer. Invest New Drugs. 2014 Apr;32(2):295-302.
[5] Bulut G, Atmaca H, Karaca B. Trastuzumab in combination with AT-101 induces cytotoxicity and apoptosis in Her2 positive breast cancer cells. Future Oncol. 2020 Jan;16(3):4485-4495.
[6] Meyer N, Zielke S, Michaelis JB, et al. AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells. Autophagy. 2018;14(10):1693-1709.
[7] Zhao R, Zhou S, Xia B, et al. AT-101 enhances gefitinib sensitivity in non-small cell lung cancer with EGFR T790M mutations. BMC Cancer. 2016 Jul 18;16:491.
[8] Li G, Liu L, Shan C, et al. RhoA/ROCK/PTEN signaling is involved in AT-101-mediated apoptosis in human leukemia cells in vitro and in vivo. Cell Death Dis. 2014 Jan 16;5(1):e998. doi: 10.1038/cddis.2013.519. Erratum in: Cell Death Dis. 2025 Apr 3;16(1):243.
(R)-(-)-Gossypol acetic acid (AT-101 (acetic acid))是一种新型的、具有口服活性的Bcl-2家族蛋白抑制剂，可抑制Bcl-2（Ki=260±30nM），Mcl-1（Ki=170±10nM）和Bcl-xL（Ki=480±40nM）[1-2]。(R)-(-)-Gossypol acetic acid可用于胶质母细胞瘤、慢性淋巴细胞白血病和非小细胞肺癌等的相关研究[3-4]。
在体外，(R)-(-)-Gossypol acetic acid（2.5–15μM）与曲妥珠单抗（Trastuzumab）联合处理SKBR-3和MDA-MB-453 HER2阳性乳腺癌细胞72小时。(R)-(-)-Gossypol acetic acid通过抑制PI3K/AKT信号通路诱导细胞凋亡[5]。(R)-(-)-Gossypol acetic acid（15μM）处理U87MG和U343胶质瘤细胞48小时。(R)-(-)-Gossypol acetic acid诱导线粒体自噬性细胞死亡[6]。
在体内，(R)-(-)-Gossypol acetic acid（35mg/kg）联合Gefitinib（50mg/kg）每周五次口服给药，用于处理皮下接种了PC-9-GR细胞（具有EGFR T790M突变）的BALB/c裸鼠。(R)-(-)-Gossypol acetic acid联合Gefitinib显著抑制了肿瘤生长，并增加了肿瘤组织中的细胞凋亡标志物（cleaved caspase-3）表达[7]。(R)-(-)-Gossypol acetic acid（50mg/kg）每日腹腔注射，每周五次，用于处理皮下接种了U937人白血病细胞的NOD/SCID小鼠，持续60天。(R)-(-)-Gossypol acetic acid显著抑制了肿瘤生长并诱导了肿瘤细胞凋亡[8]。