The products of the reaction between 6-amine-1,3-dimethyl uracil and bis-chalcones induce cytotoxicity with massive vacuolation in HeLa cervical cancer cell line

As a part of our research in the chemistry of chalcones we have prepared four pyrimidine monoadducts of bis-chalcones through the reaction with 6-amino-1,3-dimethyl uracil. These compounds displayed cytotoxicity with a massive vacuolation in different human cell lines in vitro. Compound 6 was the most cytotoxic inducer of vacuoles, this compound induced G1 phase cell cycle arrest, and their cytotoxicity went without morphological and biochemical evidence of apoptotic cell death in HeLa cells. In addition, our results showed that this vacuole formation does not require de novo protein synthesis and the content vacuolar is acidic. Compound 6 induce necrotic cell death with excessive vacuolation, similar to a process of autophagy. Spautin-1 an inhibitor of autophagy, decreased the transformation of microtubule-associated protein 1 light chain 3 (LC3B-I) to LC3B-II and the vacuolation induced by compound 6 in HeLa cells, both autophagy processes. These compounds could be of pivotal importance in the study of non-apoptotic cell death with vacuole formation and could be useful in research into new autophagy inhibitors agents.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► These pyrimidine monoadducts of bis-chalcones were obtained by Michael addition. ► The compound 6 induces vacuolation, G1 arrest and necrosis in HeLa cells, in vitro. ► The compound 6-induced cytotoxicity is independent of vacuolation process. ► The compound 6-induced vacuolation was inhibited by Spautin-1 an autophagy inhibitor. ► These monoadducts may help in the search for novel inhibitors of autophagy.