Berberine Induces Cell Cycle Arrest in Cholangiocarcinoma Cell Lines <i>via</i> Inhibition of NF-κB and STAT3 Pathways

Abstract

Berberine is a natural compound found in several herbs. Anticancer activity of berberine was reported in several cancers, however, little is known regarding the effects of berberine against cholangiocarcinoma (CCA). In this study, the growth inhibitory effects of berberine on CCA cell lines and its molecular mechanisms were explored. Cell growth and cell cycle distribution were examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. The expression levels of cell cycle regulatory proteins were determined by Western blot analysis. Berberine significantly inhibited growth of CCA cell lines in a dose and time dependent fashion. The inhibition was largely attributed to cell cycle arrest at the G1 phase through the reduction of cyclin D1, and cyclin E. Moreover, berberine could reduce the expression and activation of signal transducers and activator of transcription 3 (STAT3) and probably nuclear factor-kappaB (NF-κB) via suppression of extracellular signal-regulated kinase (ERK) 1/2 action. These results highlight the potential of berberine to be a multi-target agent for CCA treatment.

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

“…BBR inhibited the NF-κB and the STAT3 pathways in cholangiocarcinoma. This induced cell cycle arrest at the G 1 phase which suppressed cancer cell growth (Puthdee et al, 2017). Reduced CYCLIN D1 and CYCLIN E levels and increased levels of activated STAT3 and ERK1/2 were observed.…”

The role of tumour microenvironment: a new vision for cholangiocarcinoma

“…revealed that the inhibition of NF‐κB signalling pathway impedes CCA metastasis and migration via suppressing the transcription of its target genes that express intercellular cell adhesion molecules in CCA cell lines . What's more, a growing number of substances have been found to inhibit CCA by blocking NF‐κB signalling pathway like Magnolol, Berberine, Caffeic acid phenethyl ester, and beta‐eudesmo . The above evidence indirectly demonstrates the importance of NF‐κB signalling pathway in the development of CCA.…”

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

“…In the latter case, the role of poly (ADP-ribose) polymerase (PARP) activation in the mitochondrial-dependent caspase activation and cell death has been shown [35,39,40,63]. The cell cycle arrest that vary depending on cell-type is initiated by targeting key checkpoint kinase targets leading to a reduction of, for example, cyclin D1 and cyclin E for G1 phase arrest [30] or cyclin D1, cyclin E, Cdk2, and Cdk4 for G0/G1 phase arrest [59]. In this regard, upregulation of cyclin-dependent kinase inhibitors (P21 and p27) by increasing their posttranslational stability through inhibition of their degradation is a further mechanism of action for berberine [25,50,52,53].…”

“…Yu et al [64] Melanoma B16 cells and U937 cells B16 cells (IC 100 < 1 µg/mL) much more sensitive than U937 cells (IC 100 < 100 µg/mL) U937 cells; apoptotic cell death in U937 and necrosis in NB16 cells Cytotoxic to cancer cells Letasiová et al [65] The mitogen-activated protein kinase pathway which has profound effect on cell growth regulation is involved in mediating the anticancer effect of berberine. Accordingly, suppression of extracellular signal-regulated kinase (ERK) 1/2 action was shown in cholangiocarcinoma cell lines [30]; the phosphorylation of ERK1/2 and p38 was suppressed in FaDu head and neck squamous cell carcinoma cells [35], or in human non-small-cell lung cancer (NSCLC) cells [49]. Activation of p38 MAPK and c-Jun N-terminal kinase (JNK) while suppressing Janus kinase-2 (JAK2) was noted in breast cancer cells [45].…”