Tiliroside suppresses triple-negative breast cancer as a multifunctional CAXII inhibitor

Abstract

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. In this preclinical study, we examines Tiliroside (TS, C30H26O13), as one of the major compounds of Tribulus terrestris L. which has been used as an alternative therapy in clinic practice of breast cancer treatment, for its therapeutic use in TNBC. The association between CAXII expression level and survival probability of TNBC patients, and the difference of CAXII expression level between TNBC and normal samples were evaluated by using publicly accessible databases. To determine the anticancer efficacy of TS on TNBC cells, cell proliferation, wound healing, cell invasion, and 3D spheroid formation assays were performed and excellent anticancer activities of TS were displayed. Mouse models further demonstrated that TS significantly reduced the tumor burden and improved survival rate. The properties of TS as a novel CAXII inhibitor have also been evaluated by CAXII activity assay, pHi, pHe and lactate level assay. Further RT-PCR and Caspase-3 activity analyses also revealed the positive regulating effects of TS on E2F1,3/Caspase-3 axis in TNBC cells cultured in 2D or 3D systems. The findings indicate that TS suppresses TNBC progression as a potential novel CAXII inhibitor in preclinical experiments, which warrants further investigation on its therapeutic implications.

CAXII inhibitors: Potential sensitizers for immune checkpoint inhibitors in HCC treatment

“…In addition, CAXIIis have also been found to increase the apoptosis of macrophages, reduce the ratio of macrophages in total CD45+ cells, and increase the ratio of CD8+ T cells in total tumor lymphocytes ( 47 ). Such a result is partly consistent with our previous study in which targeting CAXII can effectively inhibit the development of liver cancer and triple-negative breast cancer cells ( 32 , 49 ). What is noteworthy is that even though CAXII was mainly concentrated on tumor-infiltrating macrophages in the majority of tumor samples, it has also been found that CAXII might be important for the survival and function of M2-subtype macrophages in the tissues of HCC ( 47 ).…”

“…Evidence has displayed that TS can inhibit the proliferation, colony formation, migration, three-dimensional (3D) organoid formation, and invasive abilities by regulating apoptosis and stemness in HCC cells while having low toxicity to normal cells ( 32 ). The study also found that TS can regulate the tumor microenvironment by modulating the levels of pHi, pHe, and lactate, therefore inhibiting the development of triple-negative breast cells, and act as a multifunctional CAXIIi ( Figure 1 ) ( 49 ).…”

Tiliroside Combined with Anti-MUC1 Monoclonal Antibody as Promising Anti-Cancer Strategy in AGS Cancer Cells

“…Tiliroside is an example of a flavonoid with potential for anti-cancer therapy [12][13][14][15][16]. Among others, it revealed its anti-cancer properties by acting as a CAXII inhibitor in liver cancer [12] and by reducing the E2F/caspase-3 axis in breast cancer cell carcinoma [13].…”

“…Tiliroside is an example of a flavonoid with potential for anti-cancer therapy [12][13][14][15][16]. Among others, it revealed its anti-cancer properties by acting as a CAXII inhibitor in liver cancer [12] and by reducing the E2F/caspase-3 axis in breast cancer cell carcinoma [13]. Recently we have demonstrated the anti-tumor potential of tiliroside in AGS gastric cancer cells by affecting MUC1 and some specific glycoforms involved in cancer development [28].…”

“…The representative of such compounds is tiliroside, glycosidic dietary flavonoid (kaempferol 3-Oβ-D-(6 -E-p-coumaroyl)-glucopyranoside) (Figure 1) [9]. Many pharmacological properties have been reported for tiliroside, including anti-diabetic, anti-inflammatory, anti-microbial, anti-oxidant, anti-viral, as well as anti-cancer [10][11][12][13][14][15][16]. The regulation of MAPK/JNK/p38 axis, NF-κB signaling pathway, and apoptosis induction have been reported in leukemia cells as proposed mechanisms of tiliroside action [17].…”