Berberine sensitizes rapamycin-mediated human hepatoma cell death in vitro

Abstract

Rapamycin is clinically used as an immunosuppressant. Increasing evidence suggests that rapamycin has an important inhibitory role in the development and progression of different types of cancer and that it is a promising candidate for cancer chemotherapy. Berberine is an isoquinoline alkaloid isolated from medicinal plant species, which has been used in traditional Chinese medicine with no significant side effects. Recent research has demonstrated that berberine has anticancer activity against various types of cancer, mediated through the suppression of mammalian target of rapamycin (mTOR). The present study aimed to investigate the in vitro synergistic anticancer effect of combined treatment of rapamycin at various concentrations (0, 10, 50, 100 and 200 nM) and berberine (62.5 µM) in SMMC7721 and HepG2 hepatocellular carcinoma (HCC) cell lines, and the potential underlying molecular mechanism. The combined use of rapamycin and berberine was found to have a synergistic cytotoxic effect, with berberine observed to maintain the cyotoxic effect of rapamycin on HCC cells at a lower rapamycin concentration. Moreover, the cells treated with the combination of the two agents exhibited significantly decreased protein levels of phosphorylated (p)‑p70S6 kinase 1 (Thr389), the downstream effector of mTOR, compared with the cells treated with rapamycin or berberine alone. Furthermore, overexpression of cluster of differentiation (CD) 147, a transmembrance glycoprotein associated with the anticancer effects of berberine, was found to upregulate p‑mTOR expression and inhibit cell death in SMMC7721 cells co‑treated with rapamycin and berberine. In conclusion, the findings of the present study suggest that the combined use of rapamycin and berberine may improve HCC therapy through synergistically inhibiting the mTOR signaling pathway, which is at least in part, mediated through CD147.

p53, Bcl-2 and cox-2 are involved in berberine hydrochloride-induced apoptosis of HeLa229 cells

“…Berberine is an isoquinoline alkaloid derived from the Chinese herb Huang Lian (4), which is commonly used for the treatment of gastrointestinal complaints, diarrhea and other conditions. Previous studies have suggested that berberine exerts significant anticancer activities against various cancer cell types, including human breast cancer (1,5), lung cancer (6), colon cancer (7), uterine leiomyoma (8), multiple myeloma (9), osteosarcoma (10), prostate cancer (11,12), cervical cancer (13,14), nasopharyngeal carcinoma (15,16), hepatocellular carcinoma (17)(18)(19), gastric carcinoma (20) and murine melanoma (21).…”

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

“…Other effects include dissipated ∆Ψ m and upregulation of intracellular ROS levels but the main outcome was improvement in efficacy through drug combination with berberine, which was considered as a synergistic interaction. When nanomolar concentrations of rapamycin (8, Figure 2) was combined with berberine (62.5 µM), a synergistic cytotoxic effect was observed in SMMC7721 and HepG2 hepatocellular carcinoma cell lines [91]. This was coupled with a greater degree of decrease in protein levels of phosphorylated (p)-p70S6 kinase 1 (Thr389), the downstream effector of mammalian target of rapamycin (mTOR), compared with each compound alone.…”

Synergistic Anticancer Activities of Natural Substances in Human Hepatocellular Carcinoma

“…Guo et al [ 79 ] hypothesized that the combination of rapamycin and berberine may increase the efficacy of chemotherapy for HCC by synergistically suppressing the mTOR signaling pathway. They found that the combined use of rapamycin and berberine had a synergistic cytotoxic effect.…”