fraxetin and Colonic-Neoplasms

Fraxetin is a natural compound extracted from Fraxinus spp. and has various functions such as antibacterial, antioxidant, neuroprotective, and antifibrotic effects. Although studies have reported its anticancer properties in lung and breast cancer, little is known about colon cancer, the most frequent type of cancer. Thus, we used two colon cancer cell lines, HT29 and HCT116 cells, to investigate whether fraxetin could inhibit the capabilities acquired during tumor development. In this study, fraxetin suppressed cell viability and induced apoptotic cell death in HT29 and HCT116 cells. Furthermore, fraxetin regulated the expression of proteins involved in apoptosis in HT29 and HCT116 cells. Additionally, fraxetin induced reactive oxygen species levels and calcium influx with loss of mitochondrial membrane potential (ΔΨm) and endoplasmic reticulum stress. Moreover, fraxetin induced G2/M arrest and modulated the intracellular signaling pathway, including AKT, ERK1/2, JNK, and P38. Nevertheless, we found no cause-effect correlation between the antiproliferative action of fraxetin and modulation of the phosphorylation state of signaling proteins. Fraxetin-induced inhibitory effect on colon cancer cell viability was synergistic with 5-fluorouracil (5-FU) or irinotecan even in 5-FU resistant-HCT116 cells. Collectively, our results suggest that fraxetin can be effectively used as a therapeutic agent for targeting colon cancer, although it is necessary to further elucidate the relationship between the hallmark capabilities that fraxetin inhibits and the intracellular regulatory mechanism.

Topics: Cell Death; Colonic Neoplasms; Coumarins; Drug Resistance, Neoplasm; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; Mitochondria

Fraxetin, extracted from the bark of Fraxinus rhynchophylla, has been shown to exhibit antitumour and anti-inflammatory pharmacological properties. However, the mechanism underlying its anticancer activity towards colon adenocarcinoma (COAD) is not well understood. We aimed to determine the antitumour effect of fraxetin on COAD cell lines and elucidate its biochemical and molecular targets.. The cell lines HCT116 and DLD-1 were used to evaluate the in vitro antitumour efficacy of fraxetin. Cytotoxicity and viability were assessed by CCK-8 and plate colony formation assays. Flow cytometry was used to assess apoptosis and cell cycle progression in fraxetin-treated COAD cells. Western blot, RT-qPCR, molecular docking, immunohistochemical, and immunofluorescence analyses were used to gain insights into cellular and molecular mechanisms. Preclinical curative effects were evaluated in nude mouse xenograft models.. Fraxetin significantly inhibited COAD cell proliferation in both dose- and time-dependent manners, specifically by inducing S-phase cell cycle arrest and triggering intrinsic apoptosis. Additionally, the level of p-JAK2 was decreased by fraxetin via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling pathway. Interestingly, in COAD cells, fraxetin directly targeted the Y. Fraxetin inhibits the proliferation of COAD cells by regulating the JAK2/STAT3 signalling pathway, providing evidence that targeting JAK2 with fraxetin may offer a novel potential auxiliary therapy for COAD treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Coumarins; Fraxinus; Humans; Janus Kinase 2; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Phosphorylation; Proliferating Cell Nuclear Antigen; S Phase Cell Cycle Checkpoints; S-Phase Kinase-Associated Proteins; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays