Intrinsic apoptosis (BCL-2 family)
Intrinsic apoptosis is the cell's self-destruct switch. BCL-2 holds it shut; BAX and BAK pull it open. Venetoclax pries BCL-2 off so the switch can fire.
Stress signals induce BH3-only proteins (BIM, PUMA, NOXA, BAD) that either inhibit anti-apoptotic BCL-2, BCL-XL, MCL-1 or directly activate BAX/BAK, which permeabilise the mitochondrial outer membrane, releasing cytochrome c to activate caspase-9 and executioner caspases. Cancers overexpress BCL-2 (t(14;18) in follicular lymphoma; CLL), MCL-1 (myeloma, AML), or BCL-XL (solid tumours, platelets). Venetoclax (BCL-2) transformed CLL and AML; MCL-1 inhibitors have cardiac toxicity; BCL-XL degraders and platelet-sparing PROTACs are in development.
In one picture
A dam (mitochondrial membrane) held by guards (BCL-2, MCL-1) against demolition crews (BAX/BAK). Cancer hires extra guards. Venetoclax fires the BCL-2 guards, and the dam breaks.
Diagram
top- Venetoclax (BCL-2) in CLL, AML, mantle cell lymphoma
- Next-generation BCL-2 inhibitors sonrotoclax, lisaftoclax
- MCL-1 inhibitors (limited by cardiotoxicity)
- BCL-XL PROTACs sparing platelets
- Combinations with hypomethylating agents, BTK inhibitors, menin inhibitors
Pages like this
not linked directly; found by shared links- Key paperVIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy
Shares Venetoclax + hypomethylating agent, VIALE-A, Azacitidine, BCL-2.
- TermTumour lysis syndrome (TLS)
Shares VIALE-A, Sonrotoclax, Venetoclax, Chronic lymphocytic leukaemia.
- CollectionLeukemia & Lymphoma Society (LLS)
Shares Mantle cell lymphoma, Myelodysplastic syndromes / neoplasms (MDS), Follicular lymphoma, Chronic lymphocytic leukaemia.
- IdeaShorter venetoclax courses in unfit AML
Shares VIALE-A, Azacitidine, Venetoclax, Acute myeloid leukaemia.
- CompanyAbbVie (incl. ImmunoGen, Capstan)
Shares Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Mantle cell lymphoma, Follicular lymphoma, Venetoclax.
- TermHypomethylating agents (azacitidine, decitabine)
Shares Azacitidine, Myelodysplastic syndromes / neoplasms (MDS), Venetoclax, Acute myeloid leukaemia.
- TrialCELESTIAL-TNCLL
Shares Sonrotoclax, BCL-2, Venetoclax, Chronic lymphocytic leukaemia.
- ProductDecitabine + cedazuridine (oral)
Shares Venetoclax + hypomethylating agent, Myelodysplastic syndromes / neoplasms (MDS), Venetoclax, Acute myeloid leukaemia.