ABT-737

ABT-737, as a BH3 analog, is an inhibitor of the Bcl-2 family that suppresses the activity of Bcl-2, Bcl-xL, and Bcl-w^[1], with an IC₅₀ value <1nM^[2].Bcl-2 and Bcl-xL are two key anti-apoptotic proteins within the Bcl-2 family. They localize to mitochondria and regulate mitochondrial outer membrane permeability. These proteins inhibit apoptosis, and their overexpression is closely associated with the onset and progression of various diseases^[3]. ABT737 competitively binds to the BH3 domain, specifically inhibiting the interaction between Bcl-2/Bcl-xL and Bak/Bax, thereby inducing apoptosis through the mitochondrial pathway^[4].

In vitro, treatment of cisplatin-resistant ovarian cancer cells A2780/DDP with ABT-737 (0-80μM) for 24-48 hours resulted in a time- and dose-dependent decrease in cell survival rate, while significantly enhancing cisplatin-induced activation levels of JNK and ASK1^[4]. Treatment of human UC cells (UMUC3 and 5637) with ABT-737 (0–40μM) for 12 hours significantly inhibited cell survival in a dose-dependent manner^[5]. Co-treatment of DLD1 cells with an immunotoxin targeting human transferrin receptor (1ng/mL) and ABT-737 (10μM) for 48 hours resulted in caspase-3 activation, indicating cell death via the apoptotic pathway ^[6].

In vivo, intra-tracheal administration of 50μL carrier solution containing 100μg ABT-737 significantly alleviated AHR symptoms in mice with airway inflammation models and promoted eosinophil apoptosis^[7].In vivo, treatment with ABT-737 (100mg/kg) via intraperitoneal injection for 21 days in patient-derived xenograft (PDX) mouse models of small cell lung cancer (SCLC) resulted in minor tumor shrinkage during the treatment period. Combination therapy with ABT-737 and rapamycin (20mg/kg) produced sustained antitumor activity, leading to tumor regression, with efficacy persisting beyond the treatment period ^[8].

References:
[1] Ou YC, Li JR, Wang JD, et al. Liao SL, Lu HC and Chen CJ: Aspirin restores ABT737mediated apoptosis in human renal carcinoma cells. Biochem Biophys Res Commun 502: 187193, 2018.
[2] Oltersdorf, T., et al. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 435(7042), 677-681.
[3] Li X, Guo Y, Xing Z, et al. ABT737 increases cisplatin sensitivity through the ROSASK1JNK MAPK signaling axis in human ovarian cancer cisplatinresistant A2780/DDP cells[J]. Oncol Rep. 2024 Sep;52(3):122.
[4] Whitecross KF, Alsop AE, Cluse LA, et al.Lindemann RK and Johnstone RW: Defining the target specificity of ABT737 and synergistic antitumor activities in combination with histone deacetylase inhibitors. Blood 113: 19821991, 2009.
[5] Cheng R, Liu X, Wang Z,et al. a Bcl2 family inhibitor, has a synergistic effect with apoptosis by inducing urothelial carcinoma cell necroptosis. Mol Med Rep. 2021 Jun;23(6):412.
[6] Fitzgerald DJ, Moskatel E, Ben-Josef G,et al.Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737. Leuk Lymphoma. 2011 Jun;52 Suppl 2(Suppl 2):79-81. doi: 10.3109/10428194.2011.569961.
[7] Tian BP, Xia LX, Bao ZQ, et al. Bcl-2 inhibitors reduce steroid-insensitive airway inflammation. J Allergy Clin Immunol. 2017 Aug;140(2):418-430. doi: 10.1016/j.jaci.2016.11.027. Epub 2016 Dec 31. Erratum in: J Allergy Clin Immunol. 2021 Jul;148(1):281.
[8] Gardner EE, Connis N, Poirier JT,et al.Rapamycin rescues ABT-737 efficacy in small cell lung cancer. Cancer Res. 2014 May 15;74(10):2846-56. doi: 10.1158/0008-5472.CAN-13-3460. Epub 2014 Mar 10.