Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy

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• 作者：Selvakumar Anbalagan^a ; Isabel M. Pires^a ; Christopher Blick^b ; Mark A. Hill^a ; David J.P. Ferguson^c ; Denise A. Chan^d ; Ester M. Hammond^a ; ^{Ester.Hammond@oncology.ox.ac.uk}
• 关键词：Autophagy ; Radiation ; VHL ; Radiosensitivity ; Hypoxia
• 刊名：Radiotherapy and Oncology
• 出版年：2012
• 期刊代码：231_01678140
• 类别：med
• 出版时间：June, 2012
• 卷：103
• 期：3
• 页码：388-393
• 文件大小：600 K

摘要

Background and purpose

For patients diagnosed with advanced renal cell carcinoma (RCC), there are few therapeutic options. Radiation therapy is predominantly used to treat metastasis and has not proven effective in the adjuvant setting for renal cancer. Furthermore, RCC is resistant to standard cytotoxic chemotherapies. Targeted anti-angiogenics are the standard of care for RCC but are not curative. Newer agents, such as mTOR inhibitors and others that induce autophagy, have shown great promise for treating RCC. Here, we investigate the potential use of the small molecule STF-62247 to modulate radiation.

Materials and methods

Using RCC cell lines, we evaluate sensitivity to radiation in addition to agents that induce autophagic cell death by clonogenic survival assays. Furthermore, these were also tested under physiological oxygen levels.

Results

STF-62247 specifically induces autophagic cell death in cells that have lost VHL, an essential mutation in the development of RCC. Treatment with STF-62247 did not alter cell cycle progression but when combined with radiation increased cell killing under oxic and hypoxic/physiological conditions.

Conclusions

This study highlights the possibility of combining targeted therapeutics such as STF-62247 or temsirolimus with radiation to reduce the reliance on partial or full nephrectomy and improve patient prognosis.