Dulaglutide as a Demethylating Agent to Improve the Outcome of Breast Cancer

Abstract

Background: Dulaglutide emerged as a promising therapeutic option for diabetes mellitus Type 2 (DM2). Aims: Owing to epigenetic similarities between the pathophysiology of DM2 and breast cancer (BC), we investigated the antitumor effect of dulaglutide. Materials & methods: To investigate the effect of dulaglutide, we analyzed the expression of methylated gene promoter regions in BC (ESR1, CDH1 and ADAM33). Results: Dulaglutide increased the expression of ESR1, CDH1 and ADAM33 up to fourfold in the MDA-MB-231 lineage by demethylating the gene promoter regions. This effect was translated to in vivo antitumoral activity and revealed significant tumor inhibition by combining the half-dose of methotrexate with dulaglutide. Conclusion: This therapy may mitigate the severe side effects commonly associated with chemotherapy.

Tweetable abstract

Dulaglutide can act as an adjuvant in breast cancer therapy and potentially enable dose reduction of chemotherapeutics without efficiency reduction.

Graphical abstract

Keywords::

• antitumor activity
• breast cancer
• demethylation
• dulaglutide
• triple-negative breast cancer

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2023-0332

Author contributions

JM Tatsch – in vitro and in vivo assays. DP Furman – in vitro and manuscript writing. RMB Nobre – in vitro and manuscript writing. KM Wurzer – in vitro and manuscript writing. GF Picheth – study conception and manuscript writing. EAS Ramos – study conception and manuscript writing. A Acco – in vivo studies. G Klassen – study conception.

Financial disclosure

This work was supported by National council for teaching and research (CNPq; grant no. 454153/2014-7), Federal University of Paraná and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES; finance code 001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The experimental procedures were ethically approved by the local Ethics Committee of Animal Experimentation (CEUA/BIO – UFPR; 1082) and were conducted following the guidelines outlined in the ‘Guide for the care and use of laboratory animals’ [32].

Additional information

Funding

This work was supported by National council for teaching and research (CNPq; grant no. 454153/2014-7), Federal University of Paraná and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES; finance code 001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.