The mTOR inhibitor RAD001 augments radiation-induced growth inhibition in a hepatocellular carcinoma cell line by increasing autophagy.
Treatment of hepatocellular carcinoma (HCC) is a major concern for physicians as its response to chemotherapy and radiotherapy remains generally poor, due, in part, to intrinsic resistance to either form of treatment. We previously reported that an irradiation with fast neutrons, which are high-linear energy transfer (LET) particles, massively induced autophagic cell death in the human HCC SK-Hep1 cell line. In the present study, we tested the capacity of the mammalian target of rapamycin (mTOR) inhibitor RAD001 to augment the cytotoxicity of low and high-LET radiation in these cells. As mTOR is a key component in a series of pathways involved in tumor growth and development, it represents a potential molecular target for cancer treatment. Results indicate that RAD001, at clinically relevant nanomolar concentrations, enhances the efficacy of both high- and low-LET radiation in SK-Hep1 cells, and that the induction of autophagy may account for this effect. However, fast neutrons were found to be more efficient at reducing tumor cell growth than low-LET radiation.
EA 3430, University of Strasbourg, Centre Paul Strauss, Strasbourg, France.
Anaïs
A
Altmeyer
Elodie
E
Josset
Jean-Marc
JM
Denis
John
J
Gueulette
Jakobus
J
Slabbert
Didier
D
Mutter
Georges
G
Noël
Pierre
P
Bischoff
D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects*; D000068338:Everolimus; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D018499:Linear Energy Transfer; D008113:Liver Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D009502:Neutrons; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D006131:Growth Inhibitors; D011838:Radiation-Sensitizing Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus