Enhanced Radiosensitization in Non-Small Cell Lung Cancer via Induction of Apoptosis and Autophagy

Researchers at Vanderbilt University have published a study investigating the effectiveness of combining Bcl-2 and mammalian target of rapamycin (mTOR) inhibitors to enhance radiation therapy in non-small cell lung cancer. The study found that the combination of ABT-737 and rapamycin significantly increased the sensitivity of cancer cells to radiation, inducing apoptosis and autophagy in vitro and in a mouse xenograft model.

Key Takeaways:

• The combination of ABT-737 and rapamycin enhanced radiosensitivity of H460 cells in vitro by 2.47-fold (p=0.002) in clonogenic assay.
• In vivo, the combination therapy resulted in a 100% increase in caspase-3 activity (apoptosis) and a 6-fold decrease in p62 protein level (indicative of autophagic flux) compared to radiation alone.
• Cell proliferation (Ki-67 staining) was reduced by 77% (p=0.001) and vascular density (von Willebrand factor staining) by 67.5% (p=0.09) compared to radiation alone.
• Combination therapy significantly decreased tubule formation in human umbilical vein endothelial cells.
• The researchers conclude that further investigations are warranted to assess the clinical potential of this strategy in lung cancer patients.

Statistics:

• Dose enhancement ratio: 2.47 (p=0.002)
• Increase in caspase-3 activity: 100%
• Decrease in p62 protein level: 6-fold
• Reduction in cell proliferation: 77% (p=0.001)
• Reduction in vascular density: 67.5% (p=0.09)
• Decrease in tubule formation: significant (data not exact)

Sources:

• Combined Bcl-2/mammalian target of rapamycin inhibition leads to enhanced radiosensitization via induction of apoptosis and autophagy in non-small cell lung tumor xenograft model. Clinical Cancer Research, 2009;15(19):6096-105.
• Vanderbilt University, Vanderbilt-Ingram Cancer Center, Dept. of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-5671 USA.