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

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 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..

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…While the antiproliferative activity of MC3343 45 was comparable with that of azacytidine 1 , its cell differentiating effect was much more evident. MC3343 45 selectively increased the expression of osteoblastogenesis related‐genes (including OCN, ALP and COL1A2) leading to matrix mineralization, an unregistered effect after azacytidine 1 treatment . In addition, MC3343 45 has been tested in combination with two of the major chemotherapeutic drugs selected for osteosarcoma treatment, cisplatin and doxorubicin 36 , promoting doxorubicin‐DNA bond as well as DNA damage and cell death.…”

“…In particular, the doxorubicin 36 /MC3343 45 combination (Combination L, Figure ) inhibited PDX‐OS#1‐C4 cells growth by 65% after 24 hours, compared with 32% growth inhibition obtained with doxorubicin 36 alone. Considering that none of these differentiating effects has been registered with azacytidine 1 , the use of MC3343 45 alone and mostly in combination for osteosarcoma treatment could be very encouraging and should be further explored in the near future …”

“…MC3343 45 selectively increased the expression of osteoblastogenesis related-genes (including OCN, ALP and COL1A2) leading to matrix mineralization, an unregistered effect after azacytidine 1 treatment. 181 In addition, MC3343 45 has been tested in combination with two of the major chemotherapeutic drugs selected for osteosarcoma treatment, cisplatin and doxorubicin 36, promoting doxorubicin-DNA bond as well as DNA damage and cell death. In particular, the doxorubicin 36/MC3343 45 combination (Combination L, Figure 4) inhibited PDX-OS#1-C4 cells growth by 65% after 24 hours, compared with 32% growth inhibition obtained with doxorubicin 36 alone.…”

“…Considering that none of these differentiating effects has been registered with azacytidine 1, the use of MC3343 45 alone and mostly in combination for osteosarcoma treatment could be very encouraging and should be further explored in the near future. 181 Soft tissue sarcomas (STSs) are rare forms of tumor involving different connective tissues originating primarily from mesoderm. Surgery with or without radiation therapy is the first choice for the treatment of localized sarcoma.…”

The Emerging Spectrum of Early Life Exposure-Related Inflammation and Epigenetic Therapy

“…In addition to targeting HDACs and BET proteins, the inhibitors of DNMTs have been widely used in many pre-clinical studies for a variety of diseases [74–79]. The approved anti-DNMT drugs 5-azacitidine (5AC) and 5-aza-2’-deoxyazacytidine (DAC) are in clinical use for the treatment of myelodysplastic syndrome of all types and chronic myelomonocytic leukemia [80].…”