Artemisinins are the most potent and safe antimalarials available. Despite their clinical potential, no human target for the artemisinins is known. The unbiased interrogation of several human cDNA libraries, displayed on bacteriophage T7, revealed a single human target of artesunate; the intrinsically disordered Bcl-2 antagonist of cell death promoter (BAD). We show that artesunate inhibits the phosphorylation of BAD, thereby promoting the formation of the proapoptotic BAD/Bcl-xL complex and the subsequent intrinsic apoptotic cascade involving cytochrome c release, PARP cleavage, caspase activation, and ultimately cell death. This unanticipated role of BAD as a possible drug target of artesunate points to direct clinical exploitation of artemisinins in the Bcl-xL life/death switch and that artesunate's anticancer activity is, at least in part, independent of reactive oxygen species.
Bibliographical noteFunding Information:
*E-mail: email@example.com. *E-mail: firstname.lastname@example.org. ORCID Michael P. Gotsbacher: 0000-0002-7153-1250 Sung Min Cho: 0000-0003-1889-6370 Ho Jeong Kwon: 0000-0002-6919-833X Peter Karuso: 0000-0002-0217-6021 Present Address §M.P.G.: School of Medical Sciences (Pharmacology), The University of Sydney, Sydney, NSW 2006, Australia. Author Contributions ⊥M.P.G. and S.M.C. contributed equally. Funding This work was supported by ARC grant DP130103281 to P.K. and H.J.K. and NRF grants 2015K1A1A2028365, 2015M3A9C4076321, and BK21plus to H.J.K. Notes The authors declare no competing financial interest.
© 2019 American Chemical Society.
All Science Journal Classification (ASJC) codes
- Molecular Medicine