Facile synthesis of autophagonizer and evaluation of its activity to induce autophagic cell death in apoptosis-defective cell line

Some Cancer cells are resistant to Apoptosis, rendering them irresponsive towards apoptosis-inducing chemotherapy drugs. Another mode of action to kill these apoptosis-defective cells is essential and Autophagy, a dynamic process that degrades cytoplasmic contents for cellular maintenance, has been considered as one of the alternate routes. A small molecule inducer of Autophagy, autophagonizer was reported to induce cell death through a novel process that is independent of extrinsic Apoptosis and the normal signaling pathways of Autophagy. Here, we describe an efficient synthetic procedure for the autophagonizer. The newly synthesized autophagonizer (DK-1-49) resulted in an accumulation of autophagy-associated LC3-II and enhanced levels of autophagosomes and acidic vacuoles. Furthermore, cell viability was inhibited by autophagic cell death in not only human Cancer cells but also Bax/Bak double-knockout cells. These findings highlight that intrinsic Apoptosis is not also involved in the induction of cellular death by the autophagonizer suggesting the autophagonizer is a promising candidate for Anticancer therapeutics for Cancer cells that are resistant to apoptosis-inducing chemotherapy.

Anticancer therapeutics; Apoptosis-defective cells; Autophagic cell death; Autophagonizer.