Cellular stresses endured by nearly all cancer cells—limited blood supply, reactive oxygen species, and exposure to chemotoxins—can lead to increases in pro-apoptotic proteins, much like they would in normal cells. When BCL-2 is overexpressed in cancer cells, it may inhibit the pro-apoptotic signals, allowing the cancer cell to survive under stressful conditions. The high levels of pro-apoptotic proteins bound and sequestered by increased BCL-2 may result in what is called a primed state (Figure 4.1). Primed cells are thought to have a high apoptotic potential: in other words, displacement of pro-apoptotic proteins from BCL-2 can result in a large enough increase in free pro-apoptotic proteins to initiate apoptosis.
The primed state provides a strong rationale for conducting research related to the targeting and inhibition of BCL-2.
Ongoing BCL-2 research
Many cancer therapies have been shown, at least in part, to elicit their effects via apoptosis,4,28,29 in which BCL-2 might play a significant role. Some preclinical models suggested that inhibition of BCL-2 can potentiate the effect of conventional chemotoxic agents,30,31 warranting further study in a clinical setting. In preclinical models, overexpression of anti-apoptotic BCL-2 family members renders cancer cells resistant to multiple classes of anticancer drugs, including DNA-damaging and antimicrotubule agents,5 nucleoside analogs,5 glucocorticoids,32 and immunotherapy.33 Further study of the role of BCL-2 in acquired resistance to cancer therapy is required to substantiate these results.