Combining betulinic acid and mithramycin a effectively suppresses pancreatic cancer by inhibiting proliferation, invasion, and angiogenesis.
Combining betulinic acid and mithramycin a effectively suppresses pancreatic cancer by inhibiting proliferation, invasion, and angiogenesis.
复制标题
通过抑制增殖，侵袭和血管生成，结合β酸和毛霉素A可有效抑制胰腺癌。
DOI：
10.1158/0008-5472.can-10-2016
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发表时间：
2011-08-01
期刊：
影响因子：
11.2
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Gao Y;Jia Z;Kong X;Li Q;Chang DZ;Wei D;Le X;Suyun H;Huang S;Wang L;Xie K
桦木酸（BA）和光神霉素A（MIT）通过不同的Sp1抑制机制表现出有效的抗肿瘤活性。然而，尚不清楚这两种化合物的组合是否对胰腺癌生长产生协同抑制作用和/或相对于吉西他滨具有治疗优势。在人胰腺癌的异种移植小鼠模型中，单独用BA或MIT治疗显示出剂量依赖性抗肿瘤活性，但导致全身性副作用，如通过总体体重减轻所测量的。单独使用无毒剂量的任一化合物治疗仅具有边际抗肿瘤作用。重要的是，无毒剂量的BA和MIT的组合治疗产生协同抗肿瘤活性，包括对细胞增殖、侵袭和血管生成的抑制作用。联合治疗产生的副作用也比治疗剂量的吉西他滨更少。此外，BA和MIT的联合治疗导致Sp1募集到Sp1和VEGF启动子的急剧抑制，导致Sp1和VEGF的转录抑制和Sp1和VEGF蛋白表达的下调。Sp1的异位过表达使肿瘤细胞对BA，MIT以及两者的组合具有抗性。总的来说，我们的研究结果表明，Sp1是BA和MIT的重要靶点，它们的组合可以在人类胰腺癌中产生增强的治疗反应。
Both betulinic acid (BA) and mithramycin A (MIT) exhibit potent anti-tumor activity through distinct mechanisms of Sp1 inhibition. However, it is unknown whether a combination of these two compounds results in a synergistic inhibitory effect on pancreatic cancer growth and/or has a therapeutic advantage over gemcitabine. In xenograft mouse models of human pancreatic cancer, treatment with either BA or MIT alone showed dose-dependent antitumor activity, but led to systemic side effects as measured by overall weight loss. Treatment with a nontoxic dose of either compound alone had only marginal antitumor effects. Importantly, combination treatment with nontoxic doses of BA and MIT produced synergistic antitumor activity, including inhibitory effects on cell proliferation, invasion and angiogenesis. The treatment combination also produced less discernible side effects than therapeutic doses of gemcitabine. Moreover, combined treatment of BA and MIT resulted in drastic inhibition of Sp1 recruitment onto Sp1 and VEGF promoters, leading to transcriptional inhibition of both Sp1 and VEGF and downregulation of Sp1 and VEGF protein expression. Ectopic overexpression of Sp1 rendered tumor cells resistant to BA, MIT, and the combination of the two. Overall, our findings argue that Sp1 is important target of BA and MIT and that their combination can produce an enhanced therapeutic response in human pancreatic cancer.