Apoptosis

Overview

Apoptosis is a form of programmed cell death that enables multicellular organisms to control cell proliferation and avoid the propagation of damaged cells that could become malignant.1


  • It is a highly controlled process for eliminating unneeded or damaged cells in response to developmental cues, cellular stress, or injury.1
  • In adult tissues, homeostasis is regulated and maintained by a balance between cell proliferation and apoptosis.1
  • Apoptosis is also instrumental in safeguarding the integrity of the genome in response to severe DNA damage.2,3

Targeting Multiple Apoptosis Proteins

Apoptosis diagram

Oncogenic Expression

  • A complex network of intrinsic and extrinsic signaling pathways regulates apoptosis and determines whether a cell lives or dies.4
  • Two main apoptotic pathways1,2:
    • Extrinsic pathway: triggered through death receptors, such as the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor.
    • Intrinsic pathway: mediated by BCL-2 family members; also referred to as the mitochondrial pathway.
    • Both pathways converge to activate caspases, resulting in apoptosis.
  • In most cancer cells, dysregulation of these pathways allows the cell to evade apoptosis.1,4
  • Dysregulated apoptotic pathways promote tumor development and metastasis, and confer resistance to conventional anticancer agents.1,4

Therapeutic Potential

  • The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy.3,5
  • Pharmacological research in this area focuses on approaches to restore the cancer cell's ability to die, including:
    • BCL-2 inhibition, which triggers the intrinsic pathway of apoptosis in certain cancers5
    • PARP inhibition, which inhibits salvage pathways for DNA repair3
    • TRAIL receptor activation, which triggers the extrinsic pathway of apoptosis in certain cancers5
  1. Cory S, Huang DCS, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590-8607.
  2. Anders CK, Winer EP, Ford JM, et al. PARP inhibition: "targeted" therapy for triple negative breast cancer. Clin Cancer Res. 2010;16(19):4702-4710.
  3. Plummer ER, Calvert H. Targeting poly (ADP-Ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res. 2007;13(21):6252-6256.
  4. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
  5. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3:279-296.

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