BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models

• Published in: Cell death & disease Vol. 11; no. 9; p. 769
• Main Authors: Vervloessem, Tamara, Sasi, Binu K., Xerxa, Elena, Karamanou, Spyridoula, Kale, Justin, La Rovere, Rita M., Chakraborty, Supriya, Sneyers, Flore, Vogler, Meike, Economou, Anastassios, Laurenti, Luca, Andrews, David W., Efremov, Dimitar G., Bultynck, Geert
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.09.2020
• Subjects: 13/1; 13/2; 13/95; 14/34; 631/154/556; 631/67/1059/602; 692/308/575; 692/699/1541/1990/283/1895; 692/699/67/1990/291; 82/29; 82/80; 82/83; 96/31; 96/63; 96/95; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Immunology; Life Sciences
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02944-6

Several cancer cell types, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) upregulate antiapoptotic Bcl-2 to cope with oncogenic stress. BH3 mimetics targeting Bcl-2’s hydrophobic cleft have been developed, including venetoclax as a promising anticancer precision medicine for treating CLL patients. Recently, BDA-366 was identified as a small molecule BH4-domain antagonist that could kill lung cancer and multiple myeloma cells. BDA-366 was proposed to switch Bcl-2 from an antiapoptotic into a proapoptotic protein, thereby activating Bax and inducing apoptosis. Here, we scrutinized the therapeutic potential and mechanism of action of BDA-366 in CLL and DLBCL. Although BDA-366 displayed selective toxicity against both cell types, the BDA-366-induced cell death did not correlate with Bcl-2-protein levels and also occurred in the absence of Bcl-2. Moreover, although BDA-366 provoked Bax activation, it did neither directly activate Bax nor switch Bcl-2 into a Bax-activating protein in in vitro Bax/liposome assays. Instead, in primary CLL cells and DLBCL cell lines, BDA-366 inhibited the activity of the PI3K/AKT pathway, resulted in Bcl-2 dephosphorylation and reduced Mcl-1-protein levels without affecting the levels of Bcl-2 or Bcl-xL. Hence, our work challenges the current view that BDA-366 is a BH4-domain antagonist of Bcl-2 that turns Bcl-2 into a pro-apoptotic protein. Rather, our results indicate that other mechanisms beyond switching Bcl-2 conformation underlie BDA-366’s cell-death properties that may implicate Mcl-1 downregulation and/or Bcl-2 dephosphorylation.