The identification of new therapeutic strategies against osteosarcoma, the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. Osteosarcoma originates from the transformation of mesenchymal stem cells (MSC) and/or osteoblast progenitors, and the loss of differentiation is a common biological osteosarcoma feature, which has strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking osteosarcoma cells in G1 or G2–M phases and induced osteoblastic differentiation through the specific reexpression of genes regulating this physiologic process. Although MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin and cisplatin (CDDP), two major chemotherapeutic agents used to treat osteosarcoma. Specifically, MC3343 increased stable doxorubicin bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this nonnucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for patients with osteosarcoma who respond poorly to preadjuvant chemotherapy. Mol Cancer Ther; 17(9); 1881–92. ©2018 AACR.

中文翻译：

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一种基于喹啉的 DNA 甲基转移酶抑制剂作为骨肉瘤治疗的可能佐剂

确定针对骨肉瘤（最常见的原发性骨肿瘤）的新治疗策略仍然是改善常规化疗难治性患者预后的主要目标。骨肉瘤起源于间充质干细胞（MSC）和/或成骨细胞祖细胞的转化，分化丧失是骨肉瘤常见的生物学特征，对预测肿瘤侵袭性具有重要意义。因此，通过表观遗传重编程恢复分化有可能获得治疗益处。这里，我们证明了新型非核苷 DNMT 抑制剂 (DNMTi) MC3343 通过在 G1 或 G2-M 期阻断骨肉瘤细胞来影响肿瘤增殖，并通过调节该生理过程的基因的特异性再表达诱导成骨细胞分化。尽管 MC3343 具有与 5azadC（FDA 批准的常规 DNA 甲基化核苷抑制剂）相似的抗增殖作用，但其对细胞分化的影响是不同的。当 MC3343 用于治疗源自患者的异种移植物 (PDX) 时，在体内也证实了成熟成骨细胞表型的诱导以及持续的细胞抑制反应。此外，MC3343 与阿霉素和顺铂 (CDDP) 这两种用于治疗骨肉瘤的主要化学治疗剂显示出协同作用。具体来说，MC3343 增加了稳定的阿霉素与 DNA 的结合，和联合治疗导致持续的 DNA 损伤和细胞死亡增加。总体而言，这种非核苷 DNMTi 是一种有效的新型药物，因此是对预辅助化疗反应不佳的骨肉瘤患者的潜在治疗选择。摩尔癌症治疗; 17(9); 1881-92 年。©2018 AACR。