DEVELOPMENT OF A INTESTINAL MINI-ORGAN PLATFORM FOR TESTING FIRST-LINE PHARMACEUTICALS COMBINED WITH WNT/β-CATENIN PATHWAY INHIBITOR CHEMICAL COMPOUNDS

INTRODUCTION AND OBJECTIVE: The Wnt/β-catenin signaling pathway plays a central role in regulating the levels of the β-catenin protein and is associated with events such as the establishment of embryonic axes, controlling cell proliferation, adhesion, and differentiation, as well as stem-cells maintaining in adult tissues. However, uncontrolled activation of the pathway results in many cancers such as colorectal cancer (CRC). The chemotherapy drug 5-Fluorouracil (5-FU) is widely used in CRC treatments but has limited activity in many cases, and this resistance and tumor recurrence may be associated with many factors such as intra-tumor heterogeneity, tumor microenvironment (TME), and the existence of cancer stem cells (CSCs), which is impossible to solve with the standard approaches currently available in clinical practice. In this sense, we sought to develop a platform of three-dimensional cell structures such as oncospheres and organoids, to test the effects of the combination of the chemotherapy drug 5-FU with Wnt/β-catenin inhibitor such as the chalcone lonchocarpin. MATERIAL AND METHODS: We used the CRC cell lines HCT116 and DLD-1, which harbor a mutation in β-catenin and APC, respectively, to develop a three-dimensional cell culture by oncospheres through a hanging drop. To analyze the effects of 5-FU and lonchocarpin in 3D cell culture, the oncospheres were treated with 10µM 5-FU and 20 µM lonchocarpin alone or combined 1:1 for 48 hours. The control group corresponds to the volume corresponding to the vehicle of each drug, DMSO, and saline. RESULTS AND CONCLUSION: We observed that the combined treatment with 5-FU and lonchocarpin altered the CRC spherical morphology and decreased the size of the spheres compared to the control group. However, the combined treatment of 5-FU and lonchocarpin was more efficient compared to either 5-FU or lonchocarpin alone. Our data support that the inhibition of the Wnt/β-catenin signaling pathway can enhance 5-FU effects in 3D cancer models.
Keywords: Wnt signaling; 5-FU; colorectal cancer
Supported by: CNPq and FAPERJ