Simultaneous Drug Targeting of the Promoter MYC G-Quadruplex and BCL2 i-Motif in Diffuse Large B-Cell Lymphoma Delays Tumor Growth
Simultaneous Drug Targeting of the Promoter MYC G-Quadruplex and BCL2 i-Motif in Diffuse Large B-Cell Lymphoma Delays Tumor Growth
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DOI：
10.1021/acs.jmedchem.7b00298
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发表时间：
2017-08-10
影响因子：
7.3
通讯作者：
Rimsza, Lisa M.
中科院分区：
文献类型：
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作者：
Kendrick, Samantha;Muranyi, Andrea;Rimsza, Lisa M.
DNA 二级结构因其在开启或关闭基因表达方面的分子开关功能以及蛋白质和小分子相互作用的支架样特性而成为独特的治疗靶点。迄今为止，通过这些结构改变基因转录的策略涉及针对单一 DNA 构象。在这里，我们研究了在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中同时靶向不同二级 DNA 结构来调节两个关键癌基因，细胞骨髓细胞瘤病 (MYC) 和 B 细胞淋巴瘤基因 2 (BCL2) 的可行性。在 DLBCL 细胞系中，与先前鉴定的识别 MYC G-四链体和 BCL2 i-motif 启动子 DNA 结构的玫瑰树碱和孕醇衍生物共同治疗可降低 mRNA 水平，并随后增强对标准化疗药物环磷酰胺的敏感性。体内抑制 MYC 和 BCL2 与环磷酰胺联合也显着减缓了 DLBCL 异种移植小鼠的肿瘤生长。我们的研究结果表明，同时靶向不同的 DNA 二级结构提供了一种有效、精确、基于医学的方法，可以直接阻碍转录并克服侵袭性恶性肿瘤中的异常途径。
Secondary DNA structures are uniquely poised as therapeutic targets due to their molecular switch function in turning gene expression on or off and scaffold-like properties for protein and small molecule interaction. Strategies to alter gene transcription through these structures thus far involve targeting single DNA conformations. Here we investigate the feasibility of simultaneously targeting different secondary DNA structures to modulate two key oncogenes, cellular-myelocy-tomatosis (MYC) and B-cell lymphoma gene-2 (BCL2), in diffuse large B-cell lymphoma (DLBCL). Cotreatment with previously identified ellipticine and pregnanol derivatives that recognize the MYC G-quadruplex and BCL2 i-motif promoter DNA structures lowered mRNA levels and subsequently enhanced sensitivity to a standard chemotherapy drug, cyclophosphamide, in DLBCL cell lines. In vivo repression of MYC and BCL2 in combination with cyclophosphamide also significantly slowed tumor growth in DLBCL xenograft mice. Our findings demonstrate concurrent targeting of different DNA secondary structures offers an effective, precise, medicine-based approach to directly impede transcription and overcome aberrant pathways in aggressive malignancies.