Since each cancer is a heterogeneous mix of cancer cells at different stages of development, we are faced with trying to treat many different diseased cells all at once. An authentic approach is to build a genomic and proteomic profile of a patient, identify the target oncogenes and prescribe the combination of targeted drugs tailored for that patient. However, there are many practical problems with this personalized medicine approach: (1) cancers often generate treatment-resistant phenotypes, (2) the treatment could be enormously expensive, and (3) most of the targeted drugs have not been developed yet. We propose a different approach: therapies that combine 2-deoxyglucose (2DG) with Bcl-2 antagonists such as ABT-263/737 (ABT). Pro-apoptotic protein Bak is normally sequestered by Mcl-1 and Bcl-xL. Only when Bak is released from both Mcl-1 and Bcl-xL, can it induce apoptosis. 2DG can prime highly glycolytic cells by dissociating Bak-Mcl-1 complex. Cells primed by 2DG are some brain cells and most cancer cells. ABT can bind to Bcl-xL, dissociating Bak-Bcl-xL complex, freeing Bak and inducing apoptosis. Since ABT cannot cross blood-brain barrier, only cells exposed to both agents are highly glycolytic cancer cells located outside the brain. Because ABT directly triggers apoptosis at the step very near the terminal point of apoptosis, 2DG-ABT combination therapies are applicable to many types of cancer at all stages of development, with little side effect.
- Received September 16, 2011.
- Revision received October 26, 2011.
- Accepted October 26, 2011.
- Copyright © 2011, American Association for Cancer Research.