Berberine combined with 2-deoxy-d-glucose synergistically enhances cancer cell proliferation inhibition via energy depletion and unfolded protein response disruption

• Published in: Biochimica et biophysica acta 2013-11, Vol.1830 (11), p.5175-5183
• Main Authors: Fan, Li-xia, Liu, Chang-mei, Gao, An-hui, Zhou, Yu-bo, Li, Jia
• Format: Article
• Language: English
• Subjects: 2-Deoxy-d-glucose; Adenosine Triphosphate - metabolism; AMP-Activated Protein Kinases - metabolism; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Berberine; Berberine - pharmacology; Cancer metabolism; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Deoxyglucose - pharmacology; Drug Screening Assays, Antitumor; Drug Synergism; Energy Metabolism - drug effects; GRP78; HCT116 Cells; Heat-Shock Proteins - metabolism; HEK293 Cells; Humans; Signal Transduction - drug effects; Unfolded Protein Response - drug effects; UPR
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.07.010

Targeting multiple aspects of cellular metabolism, such as both aerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), has the potential to improve cancer therapeutics. Berberine (BBR), a widely used traditional Chinese medicine, exerts its antitumor effects by inhibiting OXPHOS. 2-Deoxy-d-glucose (2-DG) targets aerobic glycolysis and demonstrates potential anticancer effects in the clinic. We hypothesized that BBR in combination with 2-DG would be more efficient than either agent alone against cancer cell growth. The effects of BBR and 2-DG on cancer cell growth were evaluated using the Sulforhodamine B (SRB) method. Cell death was detected with the PI uptake assay, and Western blot, Q-PCR and luciferase reporter assays were used for signaling pathway detection. An adenovirus system was used for gene overexpression. BBR combined with 2-DG synergistically enhanced the growth inhibition of cancer cells in vitro. Further mechanistic studies showed that the combination drastically enhanced ATP depletion and strongly disrupted the unfolded protein response (UPR). Overexpressing GRP78 partially prevented the cancer cell inhibition induced by both compounds. Here, we report for the first time that BBR and 2-DG have a synergistic effect on cancer cell growth inhibition related to ATP energy depletion and disruption of UPR. Our results propose the potential use of BBR and 2-DG in combination as an anticancer treatment, reinforcing the hypothesis that targeting both aerobic glycolysis and OXPHOS provides more effective cancer therapy and highlighting the important role of UPR in the process. [Display omitted] •BBR combined with 2-DG synergistically enhanced cancer cell growth inhibition.•ATP was depleted drastically and unfolded protein response was disrupted strongly.•Overexpressing GRP78 partially prevented cancer cell growth inhibition.•AMPK activation was not involved in UPR disruption and cell growth inhibition.