Synergistic effect of Linebacker-1 (LB1) with radiotherapy in a mouse lung cancer model

<h2>ABSTRACT</h2><h3>Purpose</h3> Myricetin is a small molecular weight FDA-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 anti-tumor drug. This study demonstrates the anticancer effect and radio-sensitization of LB1 in a lung cancer model. <h3>Methods</h3> In vitro studies were performed in human A549 (ATCC) and HT29 (ATCC) and in murine LLC1 (ATCC) cancer cell lines. A syngeneic murine model of lung adenocarcinoma was generated subcutaneously in one flank of wild (+/+) C57/BL6 background mice using the LLC1 cell line. Image-guided radiotherapy (IGRT) targeting the tumor was administered with a small animal radiation research platform (SARRP). <h3>Results</h3> Our in vitro study observations demonstrate that LB1 induces an antineoplastic effect in human lung A549 (p<0.001) and colon HT29 (p<0.001) 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<0.01) and increasing survival percent and duration (p<0.001). Additionally, adding LB1 with a checkpoint inhibitor (anti-PD1) or with IGRT+ anti-PD1 further increases the survival percentage (p<0.05, p<0.05, respectively), with no significant change in mouse body weight or body score. <h3>Conclusion</h3> LB1 demonstrates enhancement of the anti-tumor effect of radiation in a lung cancer model, while antiPD1 treatment further enhances the effect. The results provide impetus for further studies, including in vivo studies in orthotopic lung cancer models, to provide robust pre-clinical data for potential future application of LB1 as a radio-sensitizer in the clinic.