Therapeutic potential of a peptide targeting BCL-2 cell guardians in cancer

Distinct BimBH3 (BimSAHB) Stapled Peptides for Structural and Cellular Studies

“…Although on the basis of these results the authors concluded that “BimSAHB is not inherently cell-permeable”, we had performed cellular uptake analyses on the treated MEFs and found that BIM SAHB A (aa 146–166) was indeed taken up by the cells, but the fibroblasts manifested relative resistance compared to the observed effects on a series of hematologic cancer cell lines, highlighting a potential therapeutic window for BIM SAHB A (aa 146–166) treatment . In agreement with our conclusions, senior WEHI investigator Dr. Jerry Adams wrote in his complimentary preview of our 2012 JCI article, “Notably, at low μM levels the BIM SAHB killed the cultured tumor cells but not nontransformed fibroblasts, and the cell death had all the hallmarks of apoptosis.”…”

“…6 In agreement with our conclusions, senior WEHI investigator Dr. Jerry Adams wrote in his complimentary preview of our 2012 JCI article, "Notably, at low μM levels the BIM SAHB killed the cultured tumor cells but not nontransformed fibroblasts, and the cell death had all the hallmarks of apoptosis." 15 To probe the sequence dependence of BIM SAHB A (aa 146−166) on direct activation of BAX in genetically defined cells, we previously reconstituted Bax −/− Bak −/− MEFs with wild-type BAX and then treated with BIM SAHB A (aa 146− 166) in an initial serum-free, detached-cell setting, which enabled us to detect a sequence-specific difference in apoptosis induction that linked the cellular activity of BIM SAHB A (aa 146−166) to direct BAX interaction. 5 These cellular findings correlated with our structural, biochemical, and in vitro functional results.…”

“…To achieve a complex stable enough for short-term NMR acquisitions, we screened a series of BIM SAHBs of differential length and sequence composition, ultimately identifying a BIM SAHB A construct that, while still triggering BAX, exhibited sufficiently weak binding activity to monitor the complex [ref 5]." 13 In our subsequent 2011 review of the BAX activation pathway, we again wrote, "Initial NMR analyses of 15 N-BAX upon BIM SAHB titration highlighted the catch-22 of trying to study the structure of, literally, a moving target. Because ligand binding triggered rapid BAX oligomerization, precluding structural analysis, the composition of BIM SAHB was adjusted to weaken its binding activity in an effort to slow down the activation process.…”

“…In the Introduction of our 2010 Molecular Cell study that delineated the series of allosteric conformational changes induced upon BIM SAHB A (aa 145−164) engagement of the novel BAX trigger site, we noted, "Among the SAHBs tested for BAX-binding activity, BIM SAHB displayed the strongest binding affinity (EC 50 , 24 nM) 10 and was subsequently employed in nuclear magnetic resonance (NMR) spectroscopy studies designed to localize the BH3-binding site on BAX. However, chemical shift perturbation mapping of 15 N-BAX upon BIM SAHB titration was precluded by the potency of BIM SAHB in binding and triggering BAX oligomerization in solution. To achieve a complex stable enough for short-term NMR acquisitions, we screened a series of BIM SAHBs of differential length and sequence composition, ultimately identifying a BIM SAHB A construct that, while still triggering BAX, exhibited sufficiently weak binding activity to monitor the complex [ref 5]."…”

Silk fibroin peptide suppresses proliferation and induces apoptosis and cell cycle arrest in human lung cancer cells

“…The results revealed that SFP can influence the DNA synthesis of lung cancer cells. Cell apoptosis or programmed cell death is the primary mechanism by which chemotherapeutic drugs inhibit the growth of cancer cells [34]. Apoptosis is mediated by two signaling pathways: the intrinsic pathway, which involves the activation of mitochondria and several caspases, and the extrinsic pathway, which involves the activation of death receptors [35].…”