Induction of G₂/M Arrest by Berberine via Activation of PI3K/Akt and p38 in Human Chondrosarcoma Cell Line

Abstract

Berberine is a clinically important natural isoquinoline alkaloid found in many medicinal herbs. Berberine has been shown to have many pharmacological effects including antimicrobial, antitumor, and anti-inflammatory activities. However, the effects and mechanism of action of berberine have not been studied in chondrosarcoma. Therefore, the effects of berberine on proliferation in a human chondrosarcoma cell line (HTB-94) were investigated. Berberine inhibited cell proliferation in a concentration-dependent manner. We also determined that inhibition of cell proliferation by berberine occurred via G2/M phase arrest in HTB-94 cells. Berberine induced cell cycle arrest at the G2/M phase by upregulation of p53 and p21 expression and suppressed cyclin B1, cyclin-dependent kinase 1 (cdc2), cdc25c, and phosphorylated retinoblastoma tumor-suppressor protein (pRb) expression. In addition, berberine stimulated phosphorylation of protein kinase B (Akt) and p38 kinase. Inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt with LY294002 (LY) and p38 kinase with SB203580 (SB), respectively, decreased berberine-induced p53 and p21 expression and restored cell proliferation and expression of cyclin B1, cdc2, cdc25c, and pRb cell cycle progression proteins. These results suggest that berberine-induced inhibition of cell proliferation by cell cycle arrest at the G2/M phases was regulated through PI3K/Akt and p38 kinase pathways in HTB-94 chondrosarcoma cells.

3′-hydroxy-3,4,5,4′-tetramethoxystilbene, the metabolite of resveratrol analogue DMU-212, inhibits ovarian cancer cell growth in vitro and in a mice xenograft model

“…In the A-2780 cell line, DMU-214 was shown to decrease the cyclin B1 mRNA level, paralleled to the block in cell cycle progression in the G2/M phase leading to p53-dependent apoptosis. Our results correspond to other authors’ findings showing that cell cycle arrest in the G2/M phase was associated with the inhibition of cyclin B12829. Although we did not find any changes in cyclin B1 expression in SKOV-3, cell cycle arrest in the G2/M phase was observed.…”

Berberine Impairs the Survival of Triple Negative Breast Cancer Cells: Cellular and Molecular Analyses

“…In our results, we found that cyclin B1 protein was also expressed at lower levels after berberine treatment in BT-20 and HCC70 causing G2/M phase arrest in HCC70. Previous findings report that berberine inhibited the expression of cyclin B1 to induce G2/M phase arrest in numerous cancer types [23,24].…”

<p>The Anti-Cancer Mechanisms of Berberine: A Review</p>

“…23 In HBT-94 chondrosarcoma cells, BBR upregulated the expression of p53 and p21 by modulating activation of the PI3K/Akt and p38 signaling pathways, which resulted in G2/M phase arrest. 24 In MDA-MB-231 breast cancer cells, BBR arrested cells in S phase, which contributed to high sensitivity of cancer cells to chemotherapy. 25 BBR has also been shown to influence cell cycle through regulation of Rb.…”