salicylates and Glioma

A major concern in targeted drug therapy is that the inhibition of receptors and signaling molecules in tumor cells may also affect similar components in the tumor microenvironment or in the immune system, with undefined consequences for inhibition of tumor growth. One example is given by the Ras inhibitor salirasib (Farnesythiosalycilic acid, FTS), which in addition to its antitumor activity in mice and humans also exhibits anti-inflammatory activity. Here we show three major effects through which Ras inhibition by FTS provides a favorable antitumor environment in immune-competent mice with subcutaneous or intracranial tumors. First, FTS exhibited antitumor activity in intracranial immune-competent tumor-bearing mice and increased their survival relative to tumor-bearing immune-compromised mice. Second, FTS induced an increase in regulatory T cells in mouse splenocytes, in which Foxp3+ T cells did not interfere with the tumor growth inhibitory effects of FTS. Third, FTS induced an increase in antitumor cytotoxic T-cell reactivity in glioma cells by downregulating their own expression of Foxp3. This downregulation induced a TGF-β-associated mechanism in glioma cells altering the tumor microenvironment and causing reduced resistance of the tumor to the immune system. These results are important as they might explain some of the major beneficial effects of Ras inhibitors. They may provide an experimental framework for examination of the impact of other anticancer drugs on cancer and the immune system.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Farnesol; Forkhead Transcription Factors; Glioma; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Molecular Targeted Therapy; Oncogene Protein v-akt; Proto-Oncogene Proteins p21(ras); ras Proteins; RNA, Messenger; Salicylates; T-Lymphocytes, Cytotoxic; Transforming Growth Factor beta

The effect of non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (commonly known as aspirin), salicylic acid, piroxicam and indomethacin on the growth of rat glioma cells (RG 2) in vitro and aspirin in vivo was studied. The in vitro studies reveal that aspirin and salicylic acid strongly inhibit growth of rat glioma (RG 2) cells in concentrations used in medicine for treatment of rheumatic diseases. On the other hand, indomethacin and piroxicam had no effect, indicating that the inhibitory effect on tumor growth is not due to the inhibition of prostaglandin synthesis. The synthesis of ATP was markedly reduced (34% of control) in the presence of drugs, whereas protein synthesis measured as 3H-leucine incorporation was slightly more inhibited (73% of control) than cell growth. Aspirin administered to Fischer 344 rats inhibited growth of RG 2 cells inoculated into the caudate nucleus in vivo, both when administered the day before inoculation of tumor cells and when tumors had formed, i.e. 5 days post inoculation.

Topics: Adenosine Triphosphate; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Brain Neoplasms; Cell Division; Female; Glioma; Hydrogen-Ion Concentration; Indomethacin; Male; Neoplasm Proteins; Neoplasm Transplantation; Piroxicam; Rats; Rats, Inbred F344; Salicylates; Tumor Cells, Cultured