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

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. 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. 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. 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. [Display omitted] •A selective AMPK activator was identified among naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives•The new drug actives AMPK in breast cancer cells but not in their non-cancer counterpart•As a consequence of AMPK activation, the new drug downregulates unfolded protein response pathway•AMPK activation and UPR downregulation selectively increases cancer cells death and autophagy