Lidocaine enhances antitumor effects of sorafenib and GW5074 in colorectal cancer cells.

Targeted therapies have broadened the treatment landscape for colorectal cancer (CRC), highlighting the need for rational combination strategies. Although sorafenib and GW5074 show therapeutic promise and lidocaine may sensitise cancer cells to treatment, the mechanisms underlying these combinations remain poorly understood. Here, we systematically evaluated the effects of combining lidocaine with sorafenib and/or GW5074 in CRC cell lines. Combination index analysis showed that sorafenib increased responsiveness to GW5074 by 19.5- and 1.7 × 107-fold in HT29 and SW480 cells, respectively, while lidocaine enhanced this response by 45- and 3 × 107-fold. Ropivacaine, bupivacaine, and levobupivacaine also showed synergistic interactions with GW5074 by 14- and 1.03 × 107-fold, 15.1- and 6.5 × 106-fold, and 33.6- and 3.8 × 107-fold in HT29 and SW480 cells, respectively. Lidocaine and ropivacaine in combination with sorafenib exhibited an antagonistic effect in HT29 cells, others were synergistic effects. These combinations modulated cell-cycle progression, activated cell death pathways, and amplified cellular stress responses in a context-dependent manner.