A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy

The identification of new therapeutic strategies against osteosarcoma (OS), the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. OS originates from the transformation of mesenchymal stem cells (MSCs) and/or osteoblast progenitors, and the loss of differentiation is a common biological OS feature which strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel non-nucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking OS cells in G1 or G2/M phases and induced osteoblastic differentiation through the specific re-expression of genes regulating this physiological process. While 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 (DXR) and cisplatin (CDDP), two major chemotherapeutic agents used to treat OS. Specifically, MC3343 increased stable DXR bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this non-nucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for OS patients who respond poorly to pre-adjuvant chemotherapy.

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