Achyrocline B (3,5 dihydroxy-6,7,8-trimethoxyflavone) synergizes with 5-fluorouracil allowing for dose reduction and reduced off-target toxicity in the treatment of colonic and pancreatic cancers

Abstract

Surgically unresectable colorectal and pancreatic carcinomas have a high rate of mortality as current therapeutic options are limited. One common chemotherapeutic used to broadly treat both cancers is 5-flurouracil (5-Fu); however, treatment serves only to slow progression of the disease and comes with many side effects due to 5-Fu’s intrinsic toxicity. Thus, strategies to decrease the dose of 5-Fu utilized therapeutically as well as reduce 5-Fu’s off-target toxicity are paramount. Using cell models of colorectal and pancreatic cancers, we show that cotreatment with Achyrocline B (3,5 dihydroxy-6,7,8-trimethoxyflavone, AcB), a natural flavone from Achyrocline bogotensis, allows for four-fold reduction in 5-Fu dosage without loss of efficacy. We further show that the action of AcB is due to continued cell cycle progression despite 5-Fu pressure to synchronize at the G1/S threshold. In addition to AcB’s effect on cancer cells, we found that AcB can directly reduce toxicity of 5-Fu in cells mimicking non-cancerous tissues. These in vitro results are then supported by xenograft modeling. AcB was shown to increase apoptosis in tumors leading to degeneration of the outer tumoral boundary. Furthermore, in 5-Fu treated animals it was found that AcB provided protection to the intestinal tract as indicated by preserved histological and immunohistochemical features. These results show promise for a new adjuvant therapy for colorectal and pancreatic carcinomas that not only reduces tumor progression, but more importantly has the potential to improve patient quality of life.

Keywords

• Colon cancer
• Pancreatic cancer
• Flavone
• Cell Cycle, Chemotherapy, Fluorouracil