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.
Department of Chemistry and Biochemistry, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, USA.
Jennifer
J
Nguyen
Department of Chemistry and Biochemistry, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, USA.
Luxi
L
Chen
Department of Chemistry and Biochemistry, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, USA.
Dhiraj
D
Kumar
Department of Chemistry and Biochemistry, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, USA. Electronic address: jiyong.lee@utdallas.edu.
Jiyong
J
Lee
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D013329:Structure-Activity Relationship; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
C494772:BAK1 protein, human; C494826:BAX protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
Anticancer therapeutics; Apoptosis-defective cells; Autophagic cell death; Autophagonizer