Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)
Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)
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DOI：
10.1182/blood-2007-09-113647
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发表时间：
2008-03-15
期刊：
影响因子：
20.3
通讯作者：
Reed, John C.
中科院分区：
文献类型：
--
作者：
Kitada, Shinichi;Kress, Christina L.;Reed, John C.
Bcl-2家族蛋白的表达改变在肿瘤和白血病的细胞凋亡失调中起着核心作用，促进了恶性细胞的扩张，并导致了化疗耐药。在这项研究中，我们比较了天然产物棉酚及其半合成衍生物麦冬酚的毒性和对小鼠的疗效，这些化合物结合和抑制抗细胞凋亡的Bcl-2家族蛋白。日常口服给药研究表明，小鼠对棉酚的耐受量比棉酚高2-4倍。棉酚的主要毒副作用是肝脏毒性和胃肠毒性，而麦冬酚的毒性要小得多。在转基因小鼠身上进行了疗效测试，在转基因小鼠中，B细胞中Bcl2过表达，类似于人类的低度滤泡性淋巴瘤。在体外，转基因小鼠表达Bcl2的B细胞对棉酚的细胞毒性比棉酚更敏感，其LD50值分别为3~5mU M和7.5~10mU M。在体内，以棉酚的最大耐受量连续每日给药，麦冬酚在减少Bcl2转基因小鼠的脾肿大和减少B细胞计数方面显示出优于棉酚的活性。综上所述，这些研究表明，麦冬酚在毒理学和疗效方面优于母体化合物棉酚，表明进一步开发该化合物用于癌症治疗是必要的。
Altered expression of Bcl-2 family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product gossypol and its semisynthetic derivative apogossypol, compounds that bind and inhibit antiapoptotic Bcl-2 family proteins. Daily oral dosing studies showed that mice tolerate doses of apogossypol 2- to 4-times higher than gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of gossypol, with apogossypol far less toxic. Efficacy was tested in transgenic mice in which Bcl-2 is overexpressed in B cells, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2-expressing B cells from transgenic mice were more sensitive to cytotoxicity induced by apogossypol than gossypol, with LD50 values of 3 to 5 mu M and 7.5 to 10 mu M, respectively. In vivo, using the maximum tolerated dose of gossypol for sequential daily dosing, apogossypol displayed superior activity to gossypol in terms of reducing splenomegaly and reducing B-cell counts in spleens of Bcl-2-transgenic mice. Taken together, these studies indicate that apogossypol is superior to parent compound gossypol with respect to toxicology and efficacy, suggesting that further development of this compound for cancer therapy is warranted.