Addition of the anti-inflammatory Salsalate to standard-of-care therapies of radiotherapy and Lenvatinib for the treatment of hepatocellular carcinoma

Abstract

Radiotherapy (RT) is an effective treatment for hepatocellular carcinoma (HCC), overshadowed by causing radiation-induced liver disease (RILD), which reduces its therapeutic ratio. Therefore, RT is relegated to a second-line or adjuvant treatment for HCC. Salsalate (SAL) is a non-steroidal anti-inflammatory drug (NSAID) used to treat rheumatoid arthritis, but there is evidence that it can also attenuate RT damage. Previous work from our group found that salsalate possesses anti-cancer efficacy and sensitizes prostate and lung cancer to RT. Ongoing studies also showed the anti-cancer activity of salicylate in HCC cell lines worked well with Lenvatinib. Therefore, salsalate could mitigate RILD and improve HCC sensitivity to RT, with Lenvatinib combination explored to further increase the anti-tumor efficacy. To begin, normal female C57BL/6 mice were pre-treated with salsalate incorporated into the normal chow diet and received whole liver RT. Salsalate pre-treated mice exhibited a survival advantage, so another cohort of mice received similar treatments for tissue analysis to understand the mechanisms behind the survival advantage. For the anti-cancer effects of salicylate, in vitro experimentation on human liver cancer cell lines revealed that salicylate inhibited the proliferation and colony formation, with enhanced inhibition in most cell lines combined with RT. In vitro findings on the anti-tumor efficacy of salicylate alone and in combination with RT were reproduced in vivo with Hep3B xenografts. In Hep3B cells, incorporating Lenvatinib to salicylate and RT generated even greater anti-cancer activity. Very early investigation into the mechanisms of action suggests that the mTOR, MAPK, and Hif-1α pathways, as well as cell cycle markers may be modulated. Overall, these findings suggest that salsalate may be able to mitigate RILD and help improve the efficacy of RT and Lenvatinib in HCC. Additional studies are required to consolidate these findings and generate a solid basis to investigate this concept in clinical studies.