Selective AMPK activator leads to unfolded protein response downregulation and induces breast cancer cell death and autophagy

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 highresolution 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.

Automated summary

The study identified a selective AMPK activator among novel hybrid heterocyclic compounds, which showed selective cytotoxicity on breast cancer cells but not on non-cancer cells. By specifically activating AMPK in cancer cells, the compound downregulated unfolded protein response pathway and inhibited mTOR signaling, leading to autophagy activation and ultimately cancer cell death. These findings support the potential anticancer activity of this novel compound as a strong modulator of metabolism.