Bufalin-Mediated Regulation of Cell Signaling Pathways in Different Cancers: Spotlight on JAK/STAT, Wnt/β-Catenin, mTOR, TRAIL/TRAIL-R, and Non-Coding RNAs

Abstract

The renaissance of research into natural products has unequivocally and paradigmatically shifted our knowledge about the significant role of natural products in cancer chemoprevention. Bufalin is a pharmacologically active molecule isolated from the skin of the toad Bufo gargarizans or Bufo melanostictus. Bufalin has characteristically unique properties to regulate multiple molecular targets and can be used to harness multi-targeted therapeutic regimes against different cancers. There is burgeoning evidence related to functional roles of signaling cascades in carcinogenesis and metastasis. Bufalin has been reported to regulate pleiotropically a myriad of signal transduction cascades in various cancers. Importantly, bufalin mechanistically regulated JAK/STAT, Wnt/β-Catenin, mTOR, TRAIL/TRAIL-R, EGFR, and c-MET pathways. Furthermore, bufalin-mediated modulation of non-coding RNAs in different cancers has also started to gain tremendous momentum. Similarly, bufalin-mediated targeting of tumor microenvironments and tumor macrophages is an area of exciting research and we have only started to scratch the surface of the complicated nature of molecular oncology. Cell culture studies and animal models provide proof-of-concept for the impetus role of bufalin in the inhibition of carcinogenesis and metastasis. Bufalin-related clinical studies are insufficient and interdisciplinary researchers require detailed analysis of the existing knowledge gaps.

ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy

“…In addition, our Western blotting and phosphoprotein assays revealed the inhibitory effect of bufalin on Src activity, leading to the disruption of signal transduction. Indeed, bufalin has been reported to regulate pleiotropically a myriad of signal transduction cascades in various cancers [59]. The involvement of the ATP1A1-Cav1-Src complex in the inhibitory activity of cardiotonic steroids on signaling pathways has been demonstrated in various cancer types [9,16,[48][49][50][51], and now we have established its signi cance in melanoma.…”

ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy

“…In addition, our Western blotting and phosphoprotein assays revealed the inhibitory effect of bufalin on Src activity, leading to the disruption of signal transduction. Indeed, bufalin has been reported to regulate pleiotropically a myriad of signal transduction cascades in various cancers [ 59 ]. The involvement of the ATP1A1-Cav1-Src complex in the inhibitory activity of cardiotonic steroids on signaling pathways has been demonstrated in various cancer types [ 9 , 16 , 48 – 51 ], and now we have established its significance in melanoma.…”

Global trends in bufalin application research for cancer from 2003 to 2022: A bibliometric and visualised analysis

“…It plays a crucial role in inhibiting cell migration and invasion, reversing multi-drug resistance, inducing apoptosis, and inhibiting blood vessel production [ 12 ]. Its mechanism involves multiple signal pathways, such as PI3K-AKT, HEDGENHOG, MAPK, JNK, WNT/Β-CATENIN, TGF-β/SMAD, integrated vegetarian signalling pathway, and NF-κB signalling pathway [ 13 , 14 ]. While there have been numerous reports on its anti-tumour mechanisms, not all of the mechanisms of action have been clearly and credibly proven.…”