Harnessing Postbiotics to Boost Chemotherapy: N-Acetylcysteine and Tetrahydro β-Carboline Carboxylic Acid as Potentiators in Pancreatic and Colorectal Cancer

Pancreatic cancer (PC) and colorectal cancer (CRC) are among the most lethal malignancies, with growing evidence pointing to the gut microbiota role in their progression. This study explores the anticancer potential of two microbiota-derived postbiotics, N-acetylcysteine (NAC) and tetrahydro β-carboline carboxylic acid (THC), in targeting some hallmark traits of PC and CRC, both as standalone agents and in combination with standard chemotherapeutics (gemcitabine for PC and 5-fluorouracil (5-FU) for CRC). Here, we found that NAC selectively reduced the viability of PC cells BxPC-3 without triggering apoptosis, while effectively inducing apoptosis in PC cells Panc-1 and in CRC cell lines. THC exhibited stronger anticancer activity, inhibiting proliferation and promoting apoptosis in all tested PC and CRC cells, even at lower concentrations. Combination treatments yielded promising synergistic effects. NAC enhanced the cytotoxicity of gemcitabine in Panc-1 cell through increased apoptosis. NAC when combined with 5-FU also increase apoptosis of CRC cells. THC further potentiated gemcitabine impact on Panc-1 cells by increasing apoptosis and by inducing cell cycle changes in BxPC-3. In CRC model, THC co-treatment with 5-FU reduced cell viability and increased apoptosis in all cells. These findings underscore the therapeutic potential of integrating microbiota-derived postbiotics with conventional chemotherapy, offering a novel avenue to improve outcomes in PC and CRC treatment.