1. Selective AMPK activator leads to unfolded protein response downregulation and induces breast cancer cell death and autophagy
- Author
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Amanda Rodrigues Pinto Costa, Fernanda da C. S. Boechat, Anna C. Cunha, Mauro Sola-Penna, Ricardo Imbroisi Filho, Patricia Zancan, Angélica Lauria Nascimento Mello, Vinícius R. Campos, Fernanda S. Sagrillo, Alan Gonçalves de Souza, and Maria Cecília B. V. de Souza
- Subjects
0301 basic medicine ,Enzyme Activators ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,AMP-Activated Protein Kinases ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Autophagy ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cell Proliferation ,Activator (genetics) ,Chemistry ,AMPK ,General Medicine ,Metabolism ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Mechanism of action ,Cancer cell ,Unfolded protein response ,Cancer research ,Unfolded Protein Response ,Female ,medicine.symptom ,Signal Transduction - Abstract
Aims AMPK plays a critical role regulating cell metabolism, growth and survival. Interfering with this enzyme activity has been extensively studied as putative mechanism for cancer therapy. The present work aims to identify a specific AMPK activator for cancer cells among a series of novel heterocyclic compounds. Materials and methods A series of novel hybrid heterocyclic compounds, namely naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives, were synthesized via Michael reaction and their structures confirmed by spectral data: infrared; 1H and 13C NMR spectroscopy (COSY, HSQC, HMBC); and high-resolution mass spectrometry (HRMS). The novel compounds were screened and tested for antitumoral activity and have part of their mechanism of action scrutinized. Key findings Here, we identified a selective AMPK activator among the new hybrid heterocyclic compounds. This new compound presents selective cytotoxicity on breast cancer cells but not on non-cancer counterparts. We identified that by specifically activating AMPK in cancer cells, the drug downregulates unfolded protein response pathway, as well as inhibits mTOR signaling. Significance These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.
- Published
- 2020