Laboratory of Experimental Oncology, IRCCS - Istituto Ortopedico Rizzoli, Bologna, Italy.
Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, Rome, Italy.
Mol Cancer Ther. 2018 Sep;17(9):1881-1892. doi: 10.1158/1535-7163.MCT-17-0818. Epub 2018 Jun 29.
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 G or G-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 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. .
寻找新的治疗策略来对抗骨肉瘤（最常见的原发性骨肿瘤）仍然是提高对常规化疗耐药患者治疗效果的首要目标。骨肉瘤起源于间充质干细胞（MSC）和/或成骨祖细胞的转化，分化丢失是骨肉瘤的一个常见生物学特征，这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可能具有治疗益处。在这里，我们证明了新型非核苷类 DNMT 抑制剂（DNMTi）MC3343 通过阻断骨肉瘤细胞在 G 期或 G1-M 期而影响肿瘤增殖，并通过特异性重新表达调节这一生理过程的基因诱导成骨细胞分化。尽管 MC3343 与 5-氮杂胞苷（一种传统的 FDA 批准的 DNA 甲基化核苷抑制剂）具有相似的抗增殖作用，但它对细胞分化的影响是不同的。当 MC3343 用于患者来源的异种移植（PDX）时，诱导成熟成骨细胞表型并伴有持续的细胞抑制反应也得到了证实。此外，MC3343 与阿霉素和顺铂（CDDP）两种用于治疗骨肉瘤的主要化疗药物表现出协同作用。具体来说，MC3343 增加了稳定的阿霉素与 DNA 的结合，联合治疗导致持续的 DNA 损伤和增加的细胞死亡。总的来说，这种非核苷类 DNMTi 是一种有效的新型药物，因此可能成为对新辅助化疗反应不佳的骨肉瘤患者的一种潜在治疗选择。
