Novel natural therapeutic approaches for colorectal cancer prevention and treatment

Abstract

Colorectal cancer (CRC) is one of the most death-leading cancer in the world. The numbers are projected to continuously increase for the coming decades despite early-on colonoscopy screening schemes are implemented in many countries. Often, by the time CRC patients got diagnosed, they have already reached later stages of the cancer due to the asymptomatic nature of CRC. Typically, surgical procedures and chemotherapy are the standard treatment for CRC. Nonetheless, the efficacy of fluorouracil (5-FU), the backbone of CRC chemotherapy, exerts only 10% of response rate while inducing toxic side effects. Therefore, the need for developing an efficacious treatment is pressing in order to save lives.

Natural compounds and probiotics are two vastly studied alternative treatment options for CRC. We identified the natural compounds theabrownin (TB), zearalenone (ZEA), and a novel probiotic mixture from our group, Prohep, to be tested for their potential in alleviating CRC tumorigenesis. TB exerts the health benefits in tumor prevention and gut microbiota modulation. However, whether TB induce anti-CRC effects in vivo is not known. ZEA presented apoptotic and cell-death properties when exposed to a higher dose. From preliminary data of our group, ZEA induced cytotoxic effects to CRC cells but not to normal colon cells, showing there is a potential which ZEA could combat CRC. We further suggested that TB and ZEA could be employed as a novel natural compound mixture, Thearalenone, to improve 5-FU efficacy working as adjuvant CRC treatment. Prohep is a novel probiotic mixture developed by our group with alleviative effects over hepatocellular carcinoma (HCC) and metabolic syndromes. Most of the microbial components of Prohep demonstrated anti-CRC properties. The potential of Prohep to be utilized as 5-FU adjuvant agents was tested as well.

Using the azoxymethane/dextran sodium sulphate (AOM/DSS) mice model, TB significantly reduced tumor count through suppressing PI3K/Akt/mTOR pathway and elevating short-chain fatty acids (SCFAs) producing bacteria Prevotellaceae and Alloprevotella. Also, ZEA significantly inhibited the progression of CRC through suppressing Ras/Raf/ERK/cyclin D1 pathway, increasing the abundance of SCFAs producing bacteria unidentified Ruminococcaceae, Parabacteroidies and Blautia, and the fecal acetate levels. Furthermore, Thearalenone improved survival and inhibited CRC tumorigenesis by reducing pro-inflammatory cytokines, suppressing oncogenic PI3K/AKT and IL-6/STAT3 pathways, elevating beneficial bacteria including Desulfovibrionaceae bacterium LT0009 and Candidatus Borkfalkia ceftriaxoniphilla and increasing fecal acetate and propionate concentration. In addition, Prohep was also found to improve survival and alleviate CRC tumorigenesis through downregulating pro-inflammatory TNF-α, suppressing proliferative p-STAT3, promoting apoptotic p53, enriching abundance of Desulfovibrio porci and Candidatus Borkfalkia ceftriaxoniphila, and promoting fecal acetate concentration. Surprisingly, both Thearalenone and Prohep exerted stronger inhibitory effects on CRC over 5-FU and their combination with 5-FU.

To sum up, our studies revealed that TB, ZEA, Thearalenone and Prohep attenuated CRC in the AOM/DSS mice model through the regulation of oncogenic signaling pathway and the modulation of gut microbial profile including both the microbiota and their derived metabolites especially SCFAs. Our studies provided insights on the potential of developing novel alternative treatments for CRC using natural compounds mixture and probiotic mixture in the future.