Background
ABT-263 (Navitoclax) is a inhibitor of Bcl-xL, Bcl-2 and Bcl-w, with Ki ≤0.5 nM, ≤1 nM and ≤1 nM respectively[1].
ABT-263 (Navitoclax) is senolytic in some, but not all types of senescent cells: Navitoclax reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs)[2]. Navitoclax (1μM ; 60 hours) accelerates apoptosis mainly by inhibiting Bcl-xL[8].
ABT-263 (Navitoclax)exhibited modest (IC50=3-8 μM) single agent potency in 8 ovarian cancer cell lines. Navitoclax(0.4μM;30h) enhanced the activation of caspase 3/7 induced by carboplatin and/or paclitaxel in Igrov-1 cells [3]. Multiple lymphoid subpopulations isolated from the thymi or BM of vavP-Bcl-2 transgenic mice were markedly more sensitive to ABT-263 (Navitoclax)[4].
ABT-263 (Navitoclax) (100 mg/kg/d;p.o;once daily for 21 days) treated a mouse model inoculated with H345 cells, and significant antitumor efficacy was observed [6]. Navitoclax with venetoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma[5]. In 44 xenograft models representing 9 different histologies, ABT-263 (Navitoclax) (100 mg/kg/d;i.g; 21 days)demonstrated limited single agent in vivo activity against the PPTP's(pediatric preclinical testing program)solid tumor panels but showed significant activity against xenografts in the ALL panel [7].
参考文献:
[1]. Tse C, Shoemaker AR, et,al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008 May 1;68(9):3421-8. doi: 10.1158/0008-5472.CAN-07-5836. PMID: 18451170.
[2]. Zhu Y, Tchkonia T, et,al.Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016 Jun;15(3):428-35. doi: 10.1111/acel.12445. Epub 2016 Mar 18. PMID: 26711051; PMCID: PMC4854923.
[3]. Stamelos VA, Robinson E, et,al. Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells. Gynecol Oncol. 2013 Feb;128(2):377-82. doi: 10.1016/j.ygyno.2012.11.019. Epub 2012 Nov 17. PMID: 23168176.
[4]. Mérino D, Khaw SL, et,al. Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood. 2012 Jun 14;119(24):5807-16. doi: 10.1182/blood-2011-12-400929. Epub 2012 Apr 26. PMID: 22538851; PMCID: PMC3382939.
[5]. Pullarkat VA, Lacayo NJ, et,al.Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Cancer Discov. 2021 Jun;11(6):1440-1453. doi: 10.1158/2159-8290.CD-20-1465. Epub 2021 Feb 16. PMID: 33593877; PMCID: PMC9533326.
[6]. Shoemaker AR, Mitten MJ, et,al. Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res. 2008 Jun 1;14(11):3268-77. doi: 10.1158/1078-0432.CCR-07-4622. PMID: 18519752.
[7]. Lock R, Carol H, et,al. Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Jun;50(6):1181-9. doi: 10.1002/pbc.21433. PMID: 18085673.
[8].Shi J, Zhou Y, Huang HC, Mitchison TJ. Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. Cancer Res. 2011 Jul 1;71(13):4518-26. doi: 10.1158/0008-5472.CAN-10-4336. Epub 2011 May 5. PMID: 21546570; PMCID: PMC3129452.
ABT-263 (Navitoclax) 是 Bcl-xL、Bcl-2 和 Bcl-w 的抑制剂，Ki 分别≤0.5 nM、≤1 nM 和≤1 nM[1]。
ABT-263 (Navitoclax) 在一些但不是所有类型的衰老细胞中具有衰老作用:Navitoclax 降低衰老的人脐静脉上皮细胞 (HUVEC)、IMR90 人肺成纤维细胞和鼠胚胎成纤维细胞 (MEF) 的活力[2]。 Navitoclax (1μM ; 60 hours)主要通过抑制Bcl-xL[8]加速细胞凋亡。
ABT-263 (Navitoclax) 在 8 种卵巢癌细胞系中表现出适度的 (IC50=3-8 μM) 单药效力。 Navitoclax(0.4μM;30h) 增强 Igrov-1 细胞中卡铂和/或紫杉醇诱导的半胱天冬酶 3/7 的激活[3]。从 vavP-Bcl-2 转基因小鼠的胸腺或 BM 中分离出的多个淋巴亚群对 ABT-263 (Navitoclax)[4] 明显更敏感。
ABT-263 (Navitoclax)（100 mg/kg/d；p.o；每日一次，持续 21 天）处理接种 H345 细胞的小鼠模型，观察到显着的抗肿瘤功效[6] . Navitoclax 联合维奈托克和化疗对复发/难治性急性淋巴细胞白血病或淋巴细胞淋巴瘤患者具有良好的耐受性，并具有良好的疗效[5]。在代表 9 种不同组织学的 44 个异种移植模型中，ABT-263 (Navitoclax)（100 mg/kg/d；i.g；21 天）证明了针对 PPTP（儿科临床前测试程序）实体瘤组的有限单一药剂体内活性，但显示出显着的ALL 面板中针对异种移植物的活性[7]。
Protocol
| Kinase experiment [1]: |
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Preparation Method
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Ki or IC50 values of ABT-263 (Navitoclax) on different subtypes of the Bcl-2 family were determined by competitive fluorescence polarization assay using the following peptide probe pairs or protein pairs :f-bad (1 nM) and Bcl-xL (6 nM), f-Bax (1 nM) and Bcl-2 (10 nM),f-Bax (1 nM) and Bcl-w (40 nM), f-Noxa (2 nM) and Mcl-1 (40 nM),and f-Bax (1 nM) and Bcl-2-A1 (15 nM) were used to determine the binding tightness of ABT-263 and Bcl-xL by time-resolved fluorescence resonance energy transfer method. Bcl-xL with His label was used for 1 nM and 200 nM f-Bak and 1 nMTb-labeled His antibodies were mixed and then treated at room temperature for 30 minutes.
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Applications
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ABT-263 (Navitoclax) is a inhibitor of Bcl-xL, Bcl-2 and Bcl-w, with Ki ??.5 nM, ?? nM and ?? nM respectively.
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| Cell experiment [2]: |
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Cell lines
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HeLa, U2OS, OVCAR-5, and A549 cell
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Preparation Method
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In four cancer cell lines, nvitokera (ABT-263) was treated with 1 |?ol/L alone or in combination with other agents. Individual cells were monitored by phase-contrast and fluorescence time-lapse microscopy, and time from mitotic entry to morphologic death was measured and plotted as cumulative survival curves.
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Reaction Conditions
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1μM ;60 hours
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Applications
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Navitoclax accelerates apoptosis mainly by inhibiting Bcl-xL.
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| Animal experiment [3]: |
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Animal models
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H345 transplanted tumor model(C.B.-17 scid-bg (scid-bg) or C.B.-17 scid (scid) mice)
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Preparation Method
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Mice were implanted with H345 cells maintained by in vivo propagation. Noculation volume was 0.2 mL consisting of 50% Matrigel. When tumors reached the appropriate tumor volume, mice were size matched (day 0) into treatment(ABT-263 (Navitoclax)) and control groups.
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Dosage form
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100 mg/kg/day ABT-263 (Navitoclax);p.o. ;once daily for 21 days
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Applications
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ABT-263 (Navitoclax) treated a mouse model inoculated with H345 cells, and significant antitumor efficacy was observed.
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参考文献:
[1]. Tse C, Shoemaker AR, et,al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008 May 1;68(9):3421-8. doi: 10.1158/0008-5472.CAN-07-5836. PMID: 18451170.
[2].Shi J, Zhou Y, Huang HC, Mitchison TJ. Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. Cancer Res. 2011 Jul 1;71(13):4518-26. doi: 10.1158/0008-5472.CAN-10-4336. Epub 2011 May 5. PMID: 21546570; PMCID: PMC3129452.
[3]. Shoemaker AR, Mitten MJ, et,al.Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res. 2008 Jun 1;14(11):3268-77. doi: 10.1158/1078-0432.CCR-07-4622. PMID: 18519752.
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