ABSTRACT
The present in vitro study aimed to assess the effects of combining the mTOR inhibitor RAD001 and temozolomide (TMZ) together with irradiation by either low-linear energy transfer (LET) radiation (γ-rays) or high-LET radiation (fast neutrons) on the growth and cell survival of the human glioblastoma cell line U-87. We observed a strong decrease in cell proliferation along with a concomitant increase in cell death as a function of the radiation dose. As expected, high-LET radiation was more effective and induced more sustained damage to DNA than low-LET radiation. While RAD001 in association with TMZ induced autophagic cell death, additional combination with either type of radiation did not further increase its occurrence. On the contrary, apoptosis remained at a low level in all experimental groups.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Glioblastoma/drug therapy , Glioblastoma/radiotherapy , Apoptosis/drug effects , Apoptosis/radiation effects , Brain Neoplasms/pathology , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Cell Survival/drug effects , Cell Survival/radiation effects , DNA Damage/drug effects , DNA Damage/radiation effects , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Dose-Response Relationship, Radiation , Everolimus , Gamma Rays , Glioblastoma/pathology , Histones/metabolism , Humans , Linear Energy Transfer , Sirolimus/administration & dosage , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , TemozolomideABSTRACT
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.