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Maximiscin Induces DNA damage Activates DNA Damage Response Pathways and Has Selective Cytotoxic Activity against a Subtype of Triple-Negative Breast Cancer

机译：Maximiscin诱导DNA损伤激活DNA损伤应答途径并具有针对三阴性乳腺癌亚型的选择性细胞毒活性。

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Triple-negative breast cancers are highly aggressive, and patients with these types of tumors have poor long-term survival. These breast cancers do not express estrogen or progesterone receptors and do not have gene amplification of human epidermal growth factor receptor 2; therefore, they do not respond to available targeted therapies. The lack of targeted therapies for triple-negative breast cancers stems from their heterogeneous nature and lack of a clear definition of driver defects. Studies have recently identified triple-negative breast cancer molecular subtypes based on gene expression profiling and representative cell lines, allowing for the identification of subtype-specific drug leads and molecular targets. We previously reported the identification of a new fungal metabolite named maximiscin (>1) identified through a crowdsourcing program. New results show that >1 has selective cytotoxic efficacy against basal-like 1 MDA-MB-468 cells compared to cell lines modeling other triple-negative breast cancer molecular subtypes. This compound also exhibited antitumor efficacy in a xenograft mouse model. The mechanisms of action of >1 in MDA-MB-468 cells were investigated to identify potential molecular targets and affected pathways. Compound >1 caused accumulation of cells in the G1 phase of the cell cycle, suggesting induction of DNA damage. Indeed, treatment with >1 caused DNA double-strand breaks with concomitant activation of the DNA damage response pathways, indicated by phosphorylation of p53, Chk1, and Chk2. Collectively, these results suggest basal-like triple-negative breast cancer may be inherently sensitive to DNA damaging agents relative to other triple-negative breast cancer subtypes. These results also demonstrate the potential of our citizen crowdsourcing program to identify new lead molecules for treating the subtypes of triple-negative breast cancer.
机译：三阴性乳腺癌具有高度的侵袭性，患有这类肿瘤的患者长期生存率很低。这些乳腺癌不表达雌激素或孕激素受体，也没有人类表皮生长因子受体2的基因扩增。因此，他们对可用的靶向疗法没有反应。缺乏针对三阴性乳腺癌的靶向疗法是由于它们的异质性和缺乏明确的驾驶员缺陷定义。最近的研究基于基因表达谱和代表性细胞系鉴定了三阴性乳腺癌分子亚型，从而可以鉴定亚型特异性药物和分子靶标。我们之前曾报道过通过众包计划鉴定出一种名为maximiscin（> 1 ）的新真菌代谢物。新结果表明，与模拟其他三阴性乳腺癌分子亚型的细胞系相比，> 1 对基底样1 MDA-MB-468细胞具有选择性的细胞毒性作用。该化合物在异种移植小鼠模型中也显示出抗肿瘤功效。研究了> 1 在MDA-MB-468细胞中的作用机制，以确定潜在的分子靶标和受影响的途径。化合物> 1 在细胞周期的G1期引起细胞蓄积，提示诱导DNA损伤。实际上，用> 1 进行治疗会导致DNA双链断裂，并伴随DNA损伤反应途径的激活，这由p53，Chk1和Chk2的磷酸化指示。总体而言，这些结果表明，相对于其他三阴性乳腺癌亚型，基底样三阴性乳腺癌可能对DNA损伤剂具有内在敏感性。这些结果还证明了我们的公民众包计划有潜力识别新的治疗三阴性乳腺癌亚型的先导分子。

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