ChemInform Abstract: Novel Non‐Cross Resistant Diaminoanthraquinones as Potential Chemotherapeutic Agents.

Jiang, Jia; Johnson, Michael G.; Defauw, Jean; Beine, T. M.; Ballas, Lawrence M.; Janzen, William P.; Loomis, Carson R.; Seldin, Jan; Cofield, Divann J.; Adams, Lauren; Cianciolo, Giuseppe; Degen, Diana E.; Hoff, Daniel D. Von

doi:10.1002/chin.199321141

Cited by 1 publication

(1 citation statement)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, inhibition of signaling pathways that regulate Mcl-1 expression and Bcl-2 phosphorylation may account for the Bcl-2 conformation-independent mechanisms of apoptosis that were observed in our study. Along these lines, it is also worth noting that BDA-366 was originally designed as an inhibitor of PKC 45 and different isoforms of this enzyme have been implicated in regulating Mcl-1 expression and Bcl-2 phosphorylation 35,40,43 . Moreover, since AKT phosphorylation of Bax at residue S184 has been reported to enable Bax to bind and sequester proapoptotic BH3 proteins and prevent Bax from inserting into the mitochondria, part of the activity of BDA-366 may be derived from blocking these antiapoptotic effects 46 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract