Fraxetin exerts anticancer effect in glioma by suppressing MiR‐21‐3p

Abstract

Fraxetin (FXT) exerts anticancer function in multiple cancers, but its function on glioma was ill‐defined. This article expounded the mechanism by which FXT exerts an anticancer effect in glioma. The effect of gradient concentration of FXT on the viability of glioma cell lines was determined by cell counting kit 8. Effects of FXT on proliferation, apoptosis, and cell cycle in glioma cell lines were determined by colony formation assay, flow cytometry, and Hoechst 33342 staining. Expressions of apoptosis‐related gene, cycle‐related gene, and glioma‐related miRNAs after FXT (25 and 50 μmol/L) treatment were determined by quantitative reverse transcription polymerase chain reaction and western blot as needed. After miR‐21‐3p overexpression, cell viability and apoptosis of glioma cell lines treated with FXT (50 μmol/L) were tested again. Although 1 μmol/L FXT had no significant effect on cell viability, 5, 10, 25, and 50 μmol/L FXT suppressed cell viability in a concentration‐dependent manner. FXT inhibited proliferation, promoted apoptosis, and induced cell cycle arrest in G0/G1 phase in glioma cell lines. These effects may be achieved by elevated expressions of Bax and cleaved caspase‐3 and diminished expressions of Bcl‐2, Bcl‐XL, cyclin E1, cyclin D1, and cyclin‐dependent kinase‐6. FXT attenuated the contents of miR‐21‐3p and miR‐455‐3p, and escalated the contents of miR‐124‐3p and miR‐7‐5p. The regulation of FXT on cell viability, proliferation and apoptosis was reversed by miR‐21‐3p overexpression. FXT suppressed the development of glioma cells by downregulating miR‐21‐3p.

Health benefits of fraxetin: From chemistry to medicine

“…[56,57] At 25-50 µM, fraxetin inhibited cell viability, as well as induced cell-cycle arrest in G0/G1 phase, and apoptosis in human gioblastoma multiform T98G and LN-229 cancer cell lines. [58] The effects are derived from Bax enhancement, caspase-3 cleavage, reductions of B-cell lymphoma 2 (Bcl-2), BclXL, cyclin E1, cyclin D1, and cyclindependent kinase-6, especially miR-21-3p downregulation. [58] In another report, fraxetin (20-60 µM) could inhibit the growth, and induce apoptosis in breast human breast cancer cell line cancer cells via Bcl-2 downregulation, and Fas, FasL, and Bax upregulation.…”

“…[58] The effects are derived from Bax enhancement, caspase-3 cleavage, reductions of B-cell lymphoma 2 (Bcl-2), BclXL, cyclin E1, cyclin D1, and cyclindependent kinase-6, especially miR-21-3p downregulation. [58] In another report, fraxetin (20-60 µM) could inhibit the growth, and induce apoptosis in breast human breast cancer cell line cancer cells via Bcl-2 downregulation, and Fas, FasL, and Bax upregulation. [59] At 5-40 µM, fraxetin was also able to control the growth and promote apoptosis in endometrial RL95-2 cancer cells via metabolic regulation.…”

“…(2-8 µM) or irinotecan (2-8 µM) was associated with the inhibitions of colon HCT116 cancer cells by inducing G2/M phase arrest and excessive ROS generation, disrupting calcium homeostasis via mitochondrial permeabilization and ER stress and PI3K/Akt signaling pathway (Figure 5). [66] In vitro 25-100 µM Apoptosis in HCC827 and H1650 cancer cells via STAT3 signaling inhibition [55] In vitro 20-80 µM Apoptosis in HTC116 and DLD-1 cancer cells via JAK2/STAT3 signaling inhibition [56] In vivo 20 mg/kg, ip Apoptosis in HTC116 cell-bearing mice via JAK2/STAT3 signaling inhibition [56] In vitro 100-200 µM Apoptosis in U521 cancer cells via JAK2/STAT3 signaling inhibition [57] In vivo 30 mg/kg, po Apoptosis in U521 cell-bearing mice via JAK2/STAT3 signaling inhibition [57] In vitro 25-50 µM Apoptosis in T98G and LN-229 cancer cells via miR-21-3p suppression [58] In vitro 20-60 µM Apoptosis in MCF-7 cancer cells via Bcl-2 downregulation, and Fas, FasL and Bax upregulation [59] In vitro 5-40 µM Apoptosis in RL95-2 cancer cells via metabolic regulation [60] In vitro 40-80 µM To inhibit the growth of SKOV3 and SW626 cancer cells via TLR4/STAT3 signaling inhibition [61] In vitro 10-40 µM Apoptosis in J82 cancer cells via Akt inhibition [62] In vivo 20 mg/kg, ip Apoptosis in bladder J82 cells-bearing mice via Akt inhibition [62] In vitro 10-40 µM Apoptosis in DU145 cancer cells via PI3K/Akt signaling inhibition [63] In vitro 20 µM Apoptosis in Huh7 cancer cells through mitochondria dysfunction [64] In vitro 50 µM Apoptosis in Hep3B cancer cells through mitochondria dysfunction [64] In vitro 50-100 µM Apoptosis in PANC-1 and Patu8988 cancer cells via STAT3 signaling inhibition [65] In vitro fraxetin (20-100 µM) and 5-flurouracil (2-8 µM) or irinotecan (2-8 µM)…”

Non-coding RNAs as potential biomarkers in osteosarcoma

“…Fraxetin (FXT), had been reported to be associated with the development of various tumors ( Yao et al, 2022 ). Through examining the expression of FTX in 25 OS and the adjacent tissues, Huang et al (2020) found that FTX were significantly upregulated in OS tissues, and knocking out FTX gene could inhibit the survival rate, invasion, and migration force of OS cells, as well as promote the apoptosis of OS cells.…”

Fraxetin inhibits proliferation and induces apoptosis of bladder cancer through the Akt pathway in vitro and in vivo

“…[ 10,11 ] Modern pharmacological studies have demonstrated the pharmacological properties of fraxetin, such as tumor suppression, inhibiting oxidative stress, immunomodulation effects, neuroprotection, antibacterial, and anti‐inflammatory. [ 12 ] Accumulating studies have confirmed the anticancer effects of fraxetin on various tumors, such as prostate cancer, [ 13 ] colon cancer, [ 14 ] glioma, [ 15 ] pancreatic cancer, [ 5 ] and lung cancer. [ 16 ] However, whether fraxetin exhibited an anticancer effect on bladder cancer remains unclear.…”