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

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. T...

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Bibliographic Details
Published in:Radiotherapy and oncology Vol. 103; no. 3; pp. 388 - 393
Main Authors: Anbalagan, Selvakumar, Pires, Isabel M., Blick, Christopher, Hill, Mark A., Ferguson, David J.P., Chan, Denise A., Hammond, Ester M.
Format: Journal Article
Language:English
Published: Ireland Elsevier Ireland Ltd 01.06.2012
Subjects:
Antineoplastic Agents - pharmacology
Autophagy
Autophagy - drug effects
Carcinoma, Renal Cell - genetics
Carcinoma, Renal Cell - physiopathology
Carcinoma, Renal Cell - radiotherapy
Cell Cycle - drug effects
Cell Cycle - radiation effects
Cell Hypoxia
Cell Line, Tumor
Cell Survival - drug effects
Cell Survival - radiation effects
Hematology, Oncology and Palliative Medicine
Humans
Hypoxia
Kidney Neoplasms - genetics
Kidney Neoplasms - physiopathology
Kidney Neoplasms - radiotherapy
Mutation
Pyridines - pharmacology
Radiation
Radiation Dosage
Radiation Tolerance - physiology
Radiosensitivity
Sirolimus - analogs & derivatives
Sirolimus - pharmacology
Thiazoles - pharmacology
Tumor Stem Cell Assay
VHL
Von Hippel-Lindau Tumor Suppressor Protein - genetics
Hypoxia
Radiosensitivity
VHL
Autophagy
Radiation
ISSN:0167-8140, 1879-0887, 1879-0887
Online Access:Get full text
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Summary: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. 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. 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. 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.
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ISSN:0167-8140
1879-0887
1879-0887
DOI:10.1016/j.radonc.2012.04.001