Anti-neoplastic and demethylating activity of a newly synthetized flavanone-derived compound in Renal Cell Carcinoma
Ângela Marques-Magalhães1, Inês Graça2, Vera Miranda-Gonçalves2
1Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto 4200-072, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal.
Abstract:
Renal Cell Carcinoma (RCC) is on the top 10 of the most incident cancers worldwide, being a third of patients diagnosed with advanced disease, for which no curative therapies are currently available. Thus, new effective therapeutic strategies are urgently needed. Herein, we tested the antineoplastic effect of newly synthesized 3-nitroflavanones (MLo1302) on RCC cell lines. 786-O, Caki2, and ACHN cell lines were cultured and treated with newly synthesized 3-nitroflavanones. IC50 values were calculated based on the effect on cell viability assessed by MTT assay, after 72 h of exposure. MLo1302 displayed antineoplastic properties in RCC cell lines through marked reduction of cell viability, increased apoptosis and DNA damage, and morphometric alterations indicating a less aggressive phenotype. MLo1302 induced a significant reduction of global DNA methylation and DNMT mRNA levels, increasing global DNA hydroxymethylation and TET expression. Moreover, MLo1302 decreased DNMT3A activity in RCC cell lines, demethylated and re-expressed hypermethylated genes in CAM-generated tumors. A marked in vivo decrease in tumor growth and angiogenesis was also disclosed. MLo1302 disclosed antineoplastic and demethylating activity in RCC cell lines, constituting a potential therapeutic agent for RCC patients.
Insights
Newly synthesized 3-nitroflavanones (MLo1302) show significant antineoplastic effects against renal cell carcinoma (RCC) by reducing cell viability and promoting DNA demethylation. This compound represents a promising therapeutic agent for advanced kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Renal Cell Carcinoma (RCC) is a leading global cancer, with a significant proportion diagnosed at advanced stages.
- Current therapies for advanced RCC are limited, necessitating the development of novel treatment strategies.
Purpose of the Study:
- To evaluate the antineoplastic effects of newly synthesized 3-nitroflavanones (MLo1302) on human RCC cell lines.
- To investigate the molecular mechanisms underlying the anti-cancer activity of MLo1302, including its impact on DNA methylation.
Main Methods:
- RCC cell lines (786-O, Caki2, ACHN) were treated with MLo1302.
- Cell viability was assessed using MTT assays to determine IC50 values.
- Apoptosis, DNA damage, global DNA methylation/hydroxymethylation, DNMT and TET expression, and DNMT3A activity were analyzed.
- In vivo studies assessed tumor growth and angiogenesis in CAM-generated tumors.
Main Results:
- MLo1302 significantly reduced RCC cell viability, induced apoptosis, DNA damage, and altered cell morphology.
- MLo1302 decreased global DNA methylation and DNMT mRNA levels while increasing DNA hydroxymethylation and TET expression.
- The compound inhibited DNMT3A activity, demethylated and re-expressed hypermethylated genes, and reduced tumor growth and angiogenesis in vivo.
Conclusions:
- MLo1302 exhibits potent antineoplastic and demethylating activities in renal cell carcinoma.
- These findings suggest that MLo1302 is a potential therapeutic agent for patients with advanced RCC.
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