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.
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.
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DOI：
10.4161/cbt.7.9.6430
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发表时间：
2008-09
影响因子：
3.6
通讯作者：
Mohammad RM
中科院分区：
文献类型：
--
作者：
Sun Y;Wu J;Aboukameel A;Banerjee S;Arnold AA;Chen J;Nikolovska-Coleska Z;Lin Y;Ling X;Yang D;Wang S;Al-Katib A;Mohammad RM
棉酚酮（ApoG2）是棉酚的半合成衍生物。本研究的主要目的是比较ApoG2和棉酚的稳定性和毒性，并评估ApoG2在体外和体内的抗淋巴瘤活性。与外消旋棉酚相比，ApoG2表现出更好的稳定性，并且与棉酚相比，小鼠对ApoG2的耐受性更好。ApoG2对WSU-DLCL2和淋巴瘤患者原代细胞的增殖有明显的抑制作用，而对正常外周血淋巴细胞无毒性。作用72 h后，测定ApoG2对WSU-DLCL2细胞的IC50为350 nM。600 mg/kg ApoG2处理对WSU-DLCL2异种移植物生长有显著抑制作用。当与CHOP联合时，ApoG2表现出更完全的肿瘤生长抑制作用。ApoG2以高亲和力结合纯化的重组Bcl-2、Mcl-1和Bcl-XL蛋白，并被证明可以阻断Bcl-XL和Bim之间异源二聚体的形成。处理72小时，ApoG2最多诱导32%的凋亡细胞死亡。Western blot实验显示，ApoG2处理导致caspase-3、caspase-9和PARP的断裂。此外，用caspase-3、-9和广谱caspase抑制剂预处理DLCL2细胞可显著阻断ApoG2诱导的生长抑制。综上所述，ApoG2至少部分通过诱导凋亡抑制DLCL2细胞的生长。它是一种有吸引力的Bcl-2家族蛋白的小分子抑制剂，有待进一步开发用于治疗弥漫性大细胞淋巴瘤。
Apogossypolone (ApoG2) is a semi-synthesized derivative of gossypol. The principal objective of this study was to compare stability and toxicity between ApoG2 and gossypol, and to evaluate anti-lymphoma activity of ApoG2 in vitro and in vivo. ApoG2 shows better stability when compared with a racemic gossypol and can be better tolerated by mice compared to gossypol. ApoG2 showed significant inhibition of cell proliferation of WSU-DLCL2 and primary cells obtained from lymphoma patients, whereas it displayed no toxicity on normal peripheral blood lymphocytes. For a treatment of 72 h, the IC50 of ApoG2 was determined to be 350 nM against WSU-DLCL2 cells. Treatment with ApoG2 at 600 mg/kg resulted in significant growth inhibition of WSU-DLCL2 xenografts. When combined with CHOP, ApoG2 displayed even more complete inhibition of tumor growth. ApoG2 binds to purified recombinant Bcl-2, Mcl-1 and Bcl-XL proteins with high affinity and is shown to block the formation of heterodimers between Bcl-XL and Bim. For a treatment of 72 h, ApoG2 induced a maximum of 32% of apoptotic cell death. Western blot experiments showed that treatment with ApoG2 led to cleavage of caspase-3, caspase-9 and PARP. Moreover, pretreatment of DLCL2 cells with caspase-3, -9 and broad spectrum caspase inhibitors significantly blocked growth inhibition induced by ApoG2. In conclusion, ApoG2 effectively inhibits growth of DLCL2 cells at least partly by inducing apoptosis. It is an attractive small molecule inhibitor of the Bcl-2 family proteins to be developed further for the treatment of diffuse large cell lymphoma.