Synergistic Effect of Linebacker-1 With Radiation Therapy in a Mouse Lung Cancer Model

Myricetin is a small-molecular-weight U.S. Food and Drug Administration-recognized dietary supplement showing efficient anticancer effects. The recent development of myricetin derivative Linebacker-1 (LB1), which changes a hydroxyl group on the B ring to a chlorine atom, exhibits DNA-binding ability by interacting with the minor grooves of DNA and may also act as an antitumor drug. This study demonstrates the anticancer effect and radiosensitization of LB1 in a lung cancer model.

In vitro studies were performed in human A549 (American Type Culture Collection [ATCC]) and HT29 (ATCC), and in murine Lewis lung carcinoma (LLC1) (ATCC) cancer cell lines. A syngeneic murine model of lung adenocarcinoma was generated subcutaneously in 1 flank of wild (+/+) C57/BL6 background mice using the LLC1 cell line. Image guided radiation therapy (IGRT) targeting the tumor was administered with a small animal radiation research platform.

Our in vitro study observations demonstrate that LB1 induces an antineoplastic effect in human lung A549 (P < .001) and colon HT29 (P < .001) adenocarcinoma cell lines. In the murine lung cancer model, we further demonstrate that a single dose of 8 Gy IGRT substantially enhances treatment response by reducing tumor volume (P < .01) and increasing survival percent and duration (P < .001). In addition, adding LB1 with a checkpoint inhibitor (antibody to programmed death-1 [anti-PD1]) or with IGRT+ anti-PD1 further increases the survival percentage (P < .05, P < .05, respectively), with no significant change in mouse body weight or body score.

LB1 demonstrates enhancement of the antitumor effect of radiation in a lung cancer model, whereas anti-PD1 treatment further enhances the effect. The results provide impetus for further studies, including in vivo studies in orthotopic lung cancer models, to provide robust preclinical data for potential future application of LB1 as a radiosensitizer in the clinic.