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How to unleash mitochondrial apoptotic blockades to kill cancers?
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Abstract:
Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death.
Insights
Targeting BCL-2 family proteins can restore cancer cell death. Novel agents and assays like BH3 profiling help overcome apoptosis resistance and guide combination therapies.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- Apoptosis, particularly the intrinsic mitochondrial pathway, is crucial for preventing cancer.
- Dysregulation of apoptosis, involving the BCL-2 protein family, is a hallmark of cancer.
- Cancer cells evade death by exploiting defects in apoptotic pathways.
Purpose of the Study:
- To review the role of BCL-2 family proteins in apoptosis and cancer.
- To explore the interplay between BCL-2 proteins and kinase pathways.
- To discuss novel targeted agents and functional assays for overcoming apoptotic resistance.
Main Methods:
- Literature review focusing on BCL-2 family proteins, kinase interactions, and targeted therapies.
- Discussion of functional assays such as BH3 profiling.
- Analysis of strategies to restore cancer cell sensitivity to apoptosis.
Main Results:
- BCL-2 family proteins are key regulators of mitochondrial apoptosis.
- Targeting BCL-2 proteins or related pathways can re-sensitize cancer cells to death.
- BH3 profiling can predict treatment response and inform combination therapy selection.
Conclusions:
- Restoring apoptotic function is a promising strategy in cancer therapy.
- Novel targeted agents offer new avenues to overcome cancer's evasion of cell death.
- Functional assays are essential for personalized cancer treatment approaches.