Apoptosis: Inducers and Inhibitors

Chemical modulators able to initiate or prevent programmed cell death are crucial tools to investigate the complex components of molecular pathways. As illustrated in the table below, apoptosis inducers are grouped based on their mechanism of action and include several examples of classic chemotherapeutic agents that interfere with DNA synthesis. Novel compounds such as AZD 5585 dihydrochloride and MSC 2032964A allow for more selective targeting and activation of apoptotic pathways.

Common Inducers of Apoptosis

* Effective doses are dependent on the cellular context and should be determined empirically.
**Commonly used modulators. Apoptosis modulators available at Tocris: www.tocris.com/cell-biology/apoptosis

Blocking the progression of apoptosis frequently involves either a cell-permeable, broad-spectrum caspase or caspase-specific inhibitor. For instance, if measuring cytochrome c release from mitochondria, pan caspase inhibitors will prevent the downstream activation of the caspase cascade. While caspase-mediated cell death is blocked, cell survival may not be long term. Similarly, cells treated with caspase inhibitors and death receptor ligands (e.g. TNF-α) are diverted to other cell death pathways (i.e. necroptosis).

Caspase Inhibitors

How to Determine an Effective Drug Concentration

The suitable drug concentration required to initiate or inhibit an apoptotic response in the majority of targeted cells can be determined by performing a dose titration experiment. For a good starting point, consult the literature to identify potential working concentrations. It is also important to understand the relationship between concentration and exposure times. If inducing apoptosis at a low dose, or with a mild stimulus, then a longer treatment time may be necessary.

Why are Experimental Controls Important?

All experiments measuring apoptosis should include both positive and negative controls. During data analysis, negative and positive controls are key to identify and separate healthy and apoptotic populations in experimental samples. Negative controls are also used to assess the health of vehicle-treated cells and serve as baseline measurements crucial for determining the magnitude of the apoptotic response. If cells lacking treatment with apoptosis inducers or treated with caspase inhibitors already show significant signs of cell death, then the activity and effect of the drug will be difficult to establish.

Explore Apoptosis Signaling Cascade