What triggers apoptosis (programmed cell death)?

From the Guidelines

Apoptosis is triggered through multiple pathways, including intrinsic apoptosis, extrinsic apoptosis, and other forms of regulated cell death, as outlined in the 2012 recommendations of the nomenclature committee on cell death 1. These pathways can be initiated by various stimuli, including:

• Intrinsic stress conditions, such as DNA damage, oxidative stress, and endoplasmic reticulum stress, which can lead to mitochondrial outer membrane permeabilization and activation of caspases 1
• Extrinsic stress signals, such as the binding of death ligands to death receptors, which can activate caspase-8 and initiate the caspase cascade 1
• Detachment from the extracellular matrix, also known as anoikis, which can trigger caspase-dependent intrinsic apoptosis 1
• Other forms of regulated cell death, such as autophagic cell death, necroptosis, and pyroptosis, which can be triggered by various stimuli, including infection, inflammation, and cellular stress 1 The understanding of these pathways is crucial for developing therapies for diseases characterized by excessive or insufficient apoptosis, such as cancer and neurodegenerative disorders. Some of the key triggers of apoptosis include:
• DNA damage and oxidative stress, which can activate the intrinsic pathway 1
• Death ligands, such as FASL and TNF, which can activate the extrinsic pathway 1
• Detachment from the extracellular matrix, which can trigger anoikis 1
• Infection and inflammation, which can trigger necroptosis and pyroptosis 1 The most recent and highest quality study on the topic, published in 2012, provides a comprehensive overview of the different pathways and triggers of apoptosis, and highlights the importance of understanding these mechanisms for the development of effective therapies 1.

From the FDA Drug Label

Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both

• The ways in which apoptosis is triggered by doxorubicin include:
  • Nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin
  • Interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes
  • Free radical formation, including the hydroxyl free radical OH•, generated by enzymatic electron reduction of doxorubicin
  • Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar, yielding aglycones accompanied by free radical formation 2

From the Research

Apoptosis Triggering Mechanisms

Apoptosis can be triggered through various mechanisms, including:

• Intrinsic pathway: leads to increased permeability of the outer mitochondrial membrane and the release of apoptogenic factors like cytochrome c, which is regulated by the Bcl-2 family of proteins 3, 4
• Extrinsic pathway: initiated by the binding of death ligands such as TNF-α and Fas to their respective receptors on the cell surface 3, 5, 4
• Cell-extrinsic pathway: triggered by extracellular ligands through cognate death receptors at the surface of target cells 5
• Cell-intrinsic pathway: consisting of Bcl-2 family proteins and initiated by internal sensors for severe cell distress 5, 4

Signaling Pathways

The signaling pathways involved in apoptosis triggering include:

• Death receptor signaling: kept tightly in check and plays critical homeostatic roles during embryonic development and throughout life 5
• Caspase activation: a family of proteases responsible for the final cell demise in the so-called execution phase of apoptosis 5, 4
• Bcl-2 family proteins: regulate the intrinsic pathway and the release of apoptogenic factors like cytochrome c 3, 4
• TNF receptor gene superfamily: involved in the extrinsic pathway and the initiation of apoptosis 6

Gene Families Involved

Various gene families are involved in the process of apoptosis, including:

• Caspases: a family of proteases responsible for the final cell demise in the so-called execution phase of apoptosis 6
• Inhibitor of apoptosis proteins: regulate the activity of caspases and the execution of apoptosis 6
• Bcl-2 family of genes: regulate the intrinsic pathway and the release of apoptogenic factors like cytochrome c 6
• Tumor necrosis factor (TNF) receptor gene superfamily: involved in the extrinsic pathway and the initiation of apoptosis 6
• p53 gene: involved in the regulation of apoptosis and the maintenance of genomic stability 6