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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy
Maria Cristina Manara1, Sergio Valente2, Camilla Cristalli1
1Laboratory of Experimental Oncology, IRCCS - Istituto Ortopedico Rizzoli, Bologna, Italy.
Abstract:
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.
Insights
A novel nonnucleoside DNA methyltransferase inhibitor (DNMTi), MC3343, effectively treats osteosarcoma by blocking cancer cell proliferation and inducing osteoblastic differentiation. It also synergizes with chemotherapy, offering a new therapeutic option for resistant osteosarcoma patients.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- Osteosarcoma, a primary bone cancer, often resists conventional chemotherapy, necessitating novel therapeutic strategies.
- Loss of cell differentiation is a hallmark of osteosarcoma, correlating with tumor aggressiveness.
- Epigenetic reprogramming, specifically restoring differentiation, presents a promising therapeutic avenue.
Purpose of the Study:
- To investigate the therapeutic potential of a novel nonnucleoside DNA methyltransferase inhibitor (DNMTi), MC3343, against osteosarcoma.
- To evaluate MC3343's effects on osteosarcoma cell proliferation, differentiation, and its synergy with standard chemotherapies.
- To assess MC3343's efficacy in a patient-derived xenograft (PDX) model of osteosarcoma.
Main Methods:
- Treatment of osteosarcoma cells and a patient-derived xenograft (PDX) model with MC3343.
- Analysis of cell cycle progression (G1 and G2-M phases) and gene reexpression.
- Assessment of osteoblastic differentiation and phenotype induction.
- Evaluation of synergistic effects with doxorubicin and cisplatin (CDDP).
Main Results:
- MC3343 inhibited osteosarcoma cell proliferation by cell cycle arrest and induced osteoblastic differentiation via gene reexpression.
- MC3343 demonstrated efficacy *in vivo* in a PDX model, inducing a mature osteoblast phenotype and cytostatic response.
- MC3343 exhibited synergistic effects with doxorubicin and cisplatin, enhancing DNA damage and cell death.
Conclusions:
- The novel nonnucleoside DNMTi MC3343 is a potential therapeutic agent for osteosarcoma, effectively inhibiting proliferation and inducing differentiation.
- MC3343's ability to restore osteoblastic differentiation and synergize with chemotherapy offers a promising strategy for chemoresistant osteosarcoma.
- MC3343 represents a viable new therapeutic option for patients with osteosarcoma refractory to standard chemotherapy.
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