Cyclovirobuxine inhibits the progression of clear cell renal cell carcinoma by suppressing the IGFBP3-AKT/STAT3/MAPK-Snail signalling pathway

Abstract

Of all pathological types of renal cell cancer (RCC), clear cell renal cell carcinoma (ccRCC) has the highest incidence. Cyclovirobuxine (CVB), a triterpenoid alkaloid isolated from Buxus microphylla, exhibits antitumour activity against gastric cancer and breast cancer; however, the mechanism by which CVB inhibits ccRCC remains unclear. The aim of our study was to explore the antitumour effects of CVB on ccRCC and to elucidate its exact mechanism. Cell viability, proliferation, cell cycle distribution, apoptosis, wound healing and invasion were evaluated. Furthermore, Western blotting, immunofluorescence staining, immunohistochemical staining, and bioinformatics analyses were utilized to comprehensively probe the molecular mechanisms. The in vivo curative effect of CVB was explored using a 786-O xenograft model established in nude mice. CVB reduced cell viability, proliferation, angiogenesis, the epithelial-mesenchymal transition (EMT), migration and invasion. In addition, CVB induced cell cycle arrest in S phase and promoted apoptosis. The expression of the EMT-related transcription factor Snail was significantly downregulated by CVB via the inhibition of the AKT, STAT3 and MAPK pathways. We revealed that insulin-like growth factor binding protein 3 (IGFBP3) was the true therapeutic target of CVB. CVB exerted anti-ccRCC effects by blocking the IGFBP3-AKT/STAT3/MAPK-Snail pathway. Targeted inhibition of IGFBP3 with CVB treatment may become a promising therapeutic regimen for ccRCC.

Accumulation of TOX high mobility group box family member 3 promotes the oncogenesis and development of hepatocellular carcinoma through the MAPK signaling pathway

“…Liu et al. showed that IGFBP3 can directly regulate the key molecules of the AKT, EMT, and MAPK signaling pathways, thereby influencing the oncogenesis and development of renal carcinoma 29 . Therefore, according to previous studies, pathway enrichment analysis, WB assays, and IHC staining in this study, it is plausible to suggest that TOX3 up‐regulates IGFBP3 expression level by binding to the CRE site in the promoter of the downstream gene IGFBP3.…”

Cyclovirobuxine D, a cardiovascular drug from traditional Chinese medicine, alleviates inflammatory and neuropathic pain mainly via inhibition of voltage-gated Cav3.2 channels

“…Our study shows that CVB-D effectively and long-lastingly relieves PTX-induced thermal hypersensitivity ( Figure 8 ). This finding, in conjunction with recent reports of CVB-D’s promising in vitro and in vivo antiproliferative activities ( Wu et al, 2015 ; Jiang et al, 2020 ; Zhang et al, 2020 ; Zhou et al, 2020 ; Liu et al, 2021 ; Zeng et al, 2021 ), also raises the potential of an application of CVB-D in cancer treatment and chemotherapy: a combination of CVB-D and PTX may offer a promising opportunity to concurrently enhance the anticancer effect of PTX and reduce its unwanted neuropathic symptoms.…”

Therapeutic Potential of Natural Products in the Treatment of Renal Cell Carcinoma: A Review

“…Furthermore, exposure to cyclovirobuxine significantly decreased levels of p-AKT, p-STAT3, p-JNK, p-P38 and p-ERK. Mechanistic analyses suggested that cyclovirobuxine inhibits RCC cells by blocking the insulin-like growth factor binding protein 3(IGFBP3)-Akt/STAT3/MAPK-Snail pathway [ 32 ]. Ratnayake et al extracted two unique bioactive sesquiterpenes from Tanzanian Phyllanthus engleri , namely englerin A and B [ 48 ].…”