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Published on: April 22, 2019
Bortezomib sensitizes human head and neck carcinoma cells SQ20B to radiation
Charles N Weber1, George J Cerniglia, Amit Maity
1Department of Radiation Oncology, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
Abstract:
The proteasome inhibitor bortezomib was tested in a cell screen as a single agent with good efficacy in multiple hematologic and solid cancer cell lines. Phase II/III studies have supported the use of bortezomib in hematologic malignancies. In solid tumors, however, the results have been poor. There is data that bortezomib can induce PTEN expression resulting in down-regulation of PI3K-Akt signaling. We and others have shown that down-regulation of Akt results in radiation sensitization. We therefore evaluated the use of bortezomib in the head and neck cancer cell line SQ20B as a radiation sensitizer. SQ20B have a constitutively active mutation in EGFR resulting in a robust Akt response. We found that 10 nM of bortezomib decreased Akt signaling to almost undetectable. This same concentration decreased the surviving fraction after 2 Gy (SF2) from 0.77 to 0.45. Given that radiation is usually given at 2 Gy increments daily for 30 or more treatments, the exponential difference in log kill could be as high as 7 logs. The dose of bortezomib is also 2 logs less as a sensitizer than that required for single agent efficacy. Further studies should be done to explore this model in vivo.
Insights
Bortezomib, a proteasome inhibitor, significantly enhances radiation therapy effectiveness in head and neck cancer cells. This combination therapy shows promise for improving cancer treatment outcomes by sensitizing tumors to radiation.
Area of Science:
- Oncology
- Cancer Biology
- Radiation Oncology
Background:
- Bortezomib (Velcade) is an effective proteasome inhibitor for hematologic cancers but shows limited efficacy in solid tumors.
- Bortezomib can induce PTEN expression, leading to the downregulation of the PI3K-Akt signaling pathway.
- Downregulation of Akt signaling has been shown to enhance radiosensitivity.
Purpose of the Study:
- To investigate the efficacy of bortezomib as a radiation sensitizer in head and neck cancer.
- To evaluate the effect of bortezomib on Akt signaling in the SQ20B head and neck cancer cell line.
Main Methods:
- Utilized the head and neck cancer cell line SQ20B, which harbors a constitutively active EGFR mutation leading to robust Akt signaling.
- Administered bortezomib at a concentration of 10 nM to assess its impact on Akt signaling and radiation sensitivity.
- Measured the surviving fraction after 2 Gy (SF2) radiation to quantify radiosensitization.
Main Results:
- 10 nM bortezomib reduced Akt signaling in SQ20B cells to near-undetectable levels.
- The same concentration of bortezomib decreased the surviving fraction after 2 Gy (SF2) from 0.77 to 0.45.
- This radiosensitization could translate to a significant increase in log kill (up to 7 logs) in clinical radiation regimens.
Conclusions:
- Bortezomib acts as a potent radiation sensitizer in head and neck cancer cells with activated Akt signaling.
- The effective sensitizing dose of bortezomib is significantly lower than that required for single-agent efficacy.
- Further in vivo studies are warranted to explore the therapeutic potential of this combination approach.
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