<p>Combination of Inositol Hexaphosphate and Inositol Inhibits Liver Metastasis of Colorectal Cancer in Mice Through the Wnt/β-Catenin Pathway</p>

Abstract

Introduction: Colorectal cancer, one of the most common tumors, is mainly fatal because of the occurrence of liver metastasis. Inositol hexaphosphate (IP6) and inositol (INS) were found, both, in vitro and in vivo to play an anti-tumor effect, whereas the combination of IP6 and INS was more effective than IP6 or INS alone. Materials and Methods: The inhibitory effects of IP6, INS and the combination of IP6 +INS on tumor progression and liver metastasis of colorectal cancer were investigated in an orthotopic transplantation model of colorectal cancer. The tumor-bearing mice were selected by in vivo bioluminescence imaging and were treated with IP6, INS, and IP6 combined with INS, respectively. All mice were sacrificed after 6 weeks of treatment. The cancer development and metastasis were compared among the groups. The expression of genes related to the Wnt/β-catenin in the model was analyzed. Results: The results demonstrated that liver metastasis was inhibited after treatment with IP6, INS, and IP6+INS. Compared to that of the M_G, survival period was extended, and tumor weight was lowered in IP6_G, INS_G, and IP6+INS_G. Besides, the liver metastatic area of mice in IP6+INS_G was relatively smaller than that in M_G, IP6_G, or INS_G. The results of RNA-seq analysis showed that the expressions of Wnt10b, Tcf7, and c-Myc were significantly downregulated in IP6+INS_G compared to that in M_G (P<0.05). Results of real-time PCR and Western blot showed that mRNA and protein expressions of β-catenin, Wnt10b, Tcf7, and c-Myc were significantly lower in IP6+INS_G compared to that in M_G (P<0.05). Discussion: IP6+INS was more effective in inhibiting liver metastasis of colorectal cancer than IP6 or INS alone. The better inhibition effect may be accomplished through regulating the mutation of Wnt/β-catenin signaling pathway by inhibiting Wnt10b, Tcf7, β-catenin, and c-Myc from abnormally high expression.

The role of WNT10B in physiology and disease: A 10-year update

“…Inositol hexaphosphate (IP6) and its molecular skeleton, inositol (INS), are natural compounds found in grains and legumes and have antitumor effects independently and in combination with each other. Liu et al (2020e) evaluated gene expression changes in CRC liver metastasis in vivo in response to treatment with IP6, INS, or a combination of both (IP6 + INS) using the mouse CT26 colorectal cell line, orthotopically. They revealed through RNA-sequencing, RT-qPCR, and western blotting that the combinatorial treatment of IP6 + INS caused a decrease in the expression of WNT10B, TCF7, and c-MYC.…”

Regulation of Wnt Signaling Pathways at the Plasma Membrane and Their Misregulation in Cancer

“…LiCl treatment also inhibits CRC cell proliferation via concomitant induction of the non-canonical ligand Wnt9 and suppression of β-catenin expression ( Ali et al, 2016 ). Combination of inositol hexaphosphate and inositol can also reduce Wnt/β-catenin signaling via downregulating Wnt10b and β-catenin and suppress liver metastasis of CRC ( Liu et al, 2020 ). Different microRNAs have been shown to affect CRC tumorigenesis as well.…”

Inositol Hexaphosphate (IP6) and Colon Cancer: From Concepts and First Experiments to Clinical Application

“…However, not only that the combination of IP6 and Ins was significantly better in different cancers than was either one alone, but it also consistently reduced all the tumor parameters. This initial hypothesis that Ins potentiates the anticancer effect of IP6, has been recently confirmed by a series of studies conducted by Dr. Song Yang and his group investigating colon cancer and its metastasis to the liver [ 64 , 65 , 66 ] showing that when combining IP6 and Ins the survival was improved, while the tumor mass and liver metastasis were decreased. These findings are of a special importance because metastasis is a primary cause of death in colon cancer patients, with a liver as the most common site [ 64 , 65 , 66 ].…”

“…First, they show again, that the IP6 + Ins was more effective in inhibiting the liver metastasis of colon cancer than each compound administered individually. Additionally, regulation of mutation of Wnt/β-catenin signaling pathway by inhibiting Wnt10b, Tcf7, β-catenin, and c-Myc from abnormally high expression is critical to increase efficacy [ 65 ].…”