Abstract B020: Quercetin sensitizes PDAC cells to radiation therapy in vitro and in vivo
Authors: Mueller Adam C. , Gandhi Vishwa , Laufer Talya 
Published: January 2025

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most treatment resistant cancers, accounting for 7% of total cancer deaths worldwide. One of the major challenges in treating PDAC with radiotherapy (RT) effectively is its proximity to sensitive GI organs. One strategy to increase the efficacy of RT is combination with radiosensitizing drugs targeting tumor physiology, to selectively increase the sensitivity of tumor cell killing by RT, without increasing toxicity to normal tissues. With this aim, we investigated quercetin, a nutraceutical flavonoid compound. Previously, Quercetin has been reported as having antioxidant, anti-inflammatory, and cancer preventative effects. On a cellular level, it can inhibit ATP-citrate lyase (ACLY), a key enzyme of de novo lipogenesis. Inhibition of lipogenesis has been found to promote cancer cell death via ferroptosis, and de novo lipid synthesis is necessary for cancer cell division during G2/M phase, both of which could alter sensitivity to RT. We hypothesized that as inhibitor of lipogenesis, quercetin might radiosensitize PDAC cells to RT. Thus, we investigated whether quercetin could radiosensitize mouse (PK5L1940) and human (AsPC-1, PANC-1 and BXPC-3) PDAC cells in vitro and in vivo. To understand the effect of quercetin on radiation response of various PDAC lines, we performed clonogenic survival assays. We pre-treated PDAC cells for 24 hrs. with quercetin (25 µM), then exposed to increasing doses RT (0 Gy, 2 Gy, 4Gy, 6 Gy and 8 Gy), and incubated for 7 days to determine clonogenic survival. Quercetin (25 µM) treatment sensitized the PDAC cells lines with dose modification factor (DMF) at D50 (Dose required to kill 50% of cell population) of 0.53, 0.07,0.45 and 0.58 in PK5L1940, AsPC-1, PANC-1 and BXPC-3, respectively. We further validated these in vitro results in vivo. We implanted flank tumors with PK5L1940 cells in C57BL/6 mice and treated with vehicle (DMSO,10%: PEG300,40%: Tween 80,5%: Saline, 45%), quercetin (100 mg/kg of body weight for 7 days), 16Gy RT + Vehicle, or 16Gy RT + quercetin. Tumor measurements were taken twice a week using vernier calipers and mice were euthanized when the average tumor volume of RT treated mice was reached 2000 mm3. Quercetin and RT individually did not significantly reduce the tumor volume or delay time to tumor endpoint. The combination of quercetin and RT however significantly reduced tumor size at all time points, and on the day of experiment termination, the average tumor volume of the combination group was 1127 mm3 compared to all 3 other groups whose average volume surpassed 2000 mm3. We performed PI FACS analysis of PK5L1940 cells treated with quercetin and found a significant G2/M delay compared to untreated cells. These data support quercetin radiosensitizing PDAC in vitro and in vivo, perhaps by causing a cell cycle arrest in the sensitive G2/M phase of the cell cycle through inhibition of de novo lipid synthesis.
Citation Format: Adam C. Mueller, Vishwa Gandhi, Talya Laufer. Quercetin sensitizes PDAC cells to radiation therapy in vitro and in vivo. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B020.