Quinine-chalcone hybrids as potent inhibitors of P-glycoprotein with apoptotic effects on EBC-1 cells

Abstract

Chincona alkaloids extracted from the bark stem of Cinchona officinalis have been historically used to treat fever and malaria. More recently, cinchona alkaloid derivatives have been attributed to apoptotic effects in the context of cancer. Similarly, chalcones are plant-derived polyphenolic compounds with known anti-fungal, -microbial, -malarial, and -carcinogenic properties. Here, we reveal cytotoxic and antiproliferative characteristics of synthetic quinine-chalcone hybrids in human cancer cell lines. Two derivatives (AD-12 and AD-13) presented IC₅₀ values below 2 µM in the lung squamous cell carcinoma cell line (EBC-1). Our study shows that AD-12 and AD-13 increased intracellular ROS levels and promoted caspase-3/7, and -8 activity in EBC-1 cells. These apoptotic effects were accompanied by short-term inhibition of P-gp efflux activity, while expression levels of P-gp transporters remained stable. Together, our study illustrates the potential of quinine-chalcone hybrids as novel anticancer drug candidates.

Keywords: Antitumor agents; Calcein retention; P-glycoprotein inhibition; Quinine-chalcone hybrids; Resistance.