Table 1.

Cellular targets of berberine as an anticancer agent.

Cell Type or Animal Model	Cellular Target	Main Endpoint Outcome	Reference
P-53-null leukemic (Jurkat and U937) cell lines	Decreased the mRNA expression of MDM2; enhance MDM2 self-ubiquitination; induce autophagy which could be inhibited by inhibitors 3-methyladenine.	Induction of autophagy in p53-null leukemic cells.	Liu et al. [23]
Human colorectal (SW480) cancer cells	Induce apoptosis; inhibit cell surface expression of GRP78; modulate the expression of apoptosis regulators (Bax, Bcl-2 and c-Myc); effect reversed by overexpression of GRP78.	Inhibition of proliferation and cell migration.	Gong et al. [24]
Breast cancer(MCF-7 and MDA-MB-231) cells	Induce cytotoxicity and G1 phase arrest; upregulate p21/cip1 and p27/kip1 and their nuclear localization by increasing their post-translational stability; effects mediated via inhibition of Akt.	Induction of cell death.	Tak et al. [25]
HeLa cells	Downregulate NF-κB (30 µM) and affect various pathways (HIF1A/NFE2L2/AP-1) at 100 µM.	Inhibition of cell growth.	Belanova et al. [26]
Glioblastoma (U87 and U251) cells in vitro and their xenografts in mice	Induce cytotoxicity and inhibit endothelial cell (HUVEC) migration; antitumour effect (survival rate and tumour size) in vivo; inhibit the phosphorylation of VEGFR2 and ERK.	Inhibition of angiogenesis.	Jin et al. [27]
Glioblastoma U343 and pancreatic carcinoma MIA PaCa-2 cells vs. Human dermal fibroblasts as non-cancerous cells	Decrease citrate synthase and caspase-3 activity and autophagy; induce cell cycle arrest at G2 and senescence without autophagy in U343 cells; induce G1 arrest, senescence and autophagy in MIA PaCa-2 cells.	Induction of cell-dependent cell cycle arrest and autophagy.	Agnarelli et al. [28]
Endometrial cancer (AN3 CA and HEC-1-A) cells in vitro; HEC-1-A xenograft in nude mice.	Suppress COX-2 (protein) PGE2 levels; effect dependent on upregulation of miR-101 via AP-1 modulation.	Inhibition of cell growth, migration, invasion and metastasis both in vitro and in vivo.	Wang and Zhang [29]
Cholangiocarcinoma (KKU-213 and -214) cell lines	Induce G1 phase arrest; reduce cyclin D1, and cyclin E; reduce the expression and activation of STAT3 and NF-κB; suppress ERK 1/2.	Cell cycle arrest and growth inhibition.	Puthdee et al. [30]
Preventive effect against DMBA-induced breast cancer in female rats.	Suppress lipid peroxidation (MDA level), pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), antioxidants (SOD and CAT, GSH and vitamin C) and NF-κB.	Inhibition of ductal carcinoma and invasiveness.	Karnam et al. [31]
Cervical cancer HeLa cells	Inhibit cell proliferation (IC50 of 18 μM), tubulin and microtubule assembly; induce G2/M arrest; bind to tubulin at a single site with a Kd of 11 μM; inhibit the assembly of tubulin into microtubules and disrupt microtubules polymerization in the presence of glutamate and paclitaxel; form a stable complex with tubulin and bind at a novel site 24 Å from the colchicine site on the β-tubulin.	Inhibition of cancer cell proliferation by targeting mitotic microtubules.	Raghav et al. [32]
Human Saos-2 and MG-63 osteosarcoma cells	Reduce the expression of caspase-1 and IL-1β.	Improvement of inflammatory microenvironment in addition to cytotoxicity.	Jin et al. [33]
MCF-7 breast cancer cells	Suppress chemokine receptors (mRNA) expression (at 10–80 μg/mL)	Suppression of cell migration in wound healing assay.	Ahmadiankia et al. 2016 [34]
FaDu head and neck squamous cell carcinoma cells	Upregulate apoptotic ligands (FasL and TRAIL); activate caspase-8, -7 and -3, PARP; upregulate pro-apoptotic factors, (Bax, Bad, Apaf-1, and the active form of caspase-9); downregulate anti-apoptotic factors (Bcl-2 and Bcl-xL); increase the expression of p53; downregulate VEGF, MMP-2 and MMP-9; suppress the phosphorylation (p) of ERK1/2 and p38.	Induction of apoptosis and inhibition of cell migration.	Seo et al. [35]
In vitro NIH-3T3 and C3H/10T1/2 mouse embryo fibroblast cells, HEK-293T human epithelial kidney cells, and LS174T colon cancer cells; allografting medulloblastoma into nude mice	Inhibit the hedgehog pathway and associated Smoothened; inhibits medulloblastoma cells (isolated from medulloblastoma in patch+/−; p53−/− mice) growth in hedgehog dependent manor.	Inhibition of cancer cell growth both in vitro and in vivo.	Wang et al. [36]
Hepatocellular carcinoma (H22, HepG2 and Bel-7404) cells; H22 transplanted tumour model in mice	Reduce cell viability and induce apoptosis; suppress tumour growth in vivo; reduce cytosolic PLA2 and COX-2 protein levels; elevate the content ratio of arachidonic acid to PGE2.	Induction of apoptosis and tumour growth inhibition both in vitro and in vivo.	Li et al. [37]
T47D and MCF7 cell lines.	Induce cytotoxicity (IC50 of 25 µM in both cell lines compared to doxorubicin as 250 nM and 500 nM in T47D and MCF-7 respectively); induce G2/M arrest in the T47D cells, but G0/G1 arrest in the MCF-7 cells; doxorubicin induced G2/M arrest in both cell lines.	Induction of cell cycle arrest and cytotoxicity.	Barzegar et al. [38]
BGC-823 gastric cancer cells; xenograft in nude mice injected with human gastric cancer cells	Increase the expression level of cleaved PARP and caspase-3; impair Δψm; inhibit the Akt/mTOR/p70S6/S6 pathway; inhibit Akt activation.	Induction of apoptosis in vitro and tumour growth inhibition in vivo.	Yi et al. [39]
KB oral cancer cells	Increase the expression of the death receptor ligand, FasL; activate pro-apoptotic factors (caspase-8, -9 and -3 and PARP, Bax, Bad and Apaf-1); suppress anti-apoptotic factors (Bcl-2 and Bcl-xL); pan-caspase inhibitor (VAD-FMK) inhibit the activation of caspase-3 and PARP by berberine.	Induce apoptosis through both extrinsic death receptor- and intrinsic mitochondrial-dependent signalling pathways.	Kim et al. [40]
Prostate cancer (LNCaP, DU-145, and PC-3) cells	Suppress a panel of mesenchymal genes (high BMP7, NODAL and Snail) expression that regulate the developmental epithelial-to-mesenchymal transition.	Inhibition of migration and invasiveness of highly metastatic cancer cells.	Liu et al. [41]
Human ovarian (SKOV3) cancer cells	Downregulate anti-apoptotic genes (BCL-2 and survivin); up-regulate pro-apoptotic gene (Bax).	Inhibition of cell proliferation and induction of apoptosis.	Jin et al. [42]
Pancreatic cancer (PANC-1 and MIA-PaCa2) cell lines	Induce G1-phase arrest through mechanisms related to ROS production and caspase 3/7 activation.	Induction of cell cycle arrest and apoptosis.	Park et al. [43]
Human prostate (LnCaP and PC-3) cancer cell lines	Induce G1 phase arrest; inhibit the expression of PSA and the activation of EGFR.	Inhibition of cell growth and induction of apoptosis.	Huang et al. [44]
MDA-MB-231 breast cancer cells	Inhibit IL-8 secretion by suppressing PI3K, JAK2, NF-κB and AP-1; downregulate gene expression of MMP-2, EGF, E-cadherin, bFGF and fibronectin; induce G2/M arrest and cell apoptosis in an IL-8-independent manner; activate p38 MAPK and JNK while suppressing JAK2, p85 PI3K, Akt and NF-κB.	Inhibition of cell proliferation and cell invasion induced by IL-8.	Li et al. [45]
MG-63 human osteosarcoma cells	Induce DNA damage and apoptosis.	Induction of apoptosis.	Zhu et al. [46]
Human multiple myeloma cell line U266	Suppress the expression of DNA methyltransferases (DNMT1 and DNMT3B) which triggers hypomethylation of TP53 by changing the DNA methylation level and the alteration of p53 dependent signal pathway.	Induction of apoptosis.	Qing et al. [47]
p53-Null leukaemia cells	Induce apoptotic cell death via inhibition of XIAP protein; inhibit MDM2 expression.	Induction of apoptosis.	Liu et al. [48]
Human non-small-cell lung cancer (NSCLC) cells	Inhibit AP-2α and AP-2β expression and their binding on hTERT promoters; inhibit hTERT expression; suppress NF-κB mobilisation and binding to COX-2 promoter; inhibit COX-2 expression; downregulate HIF-1α and VEGF expression; inhibit Akt and ERK phosphorylation; induce cytochrome-c release from mitochondria; promote caspase and PARP activity; modulate Bax and Bcl-2 expression.	Inhibition of cell proliferation, migration, and colony formation, and induction of apoptosis.	Fu et al. [49]
Human hepatoma Bel7402 cells.	Induce G1 cell cycle arrest; effect enhanced by calmodulin inhibitors; decrease the phosphorylation of calmodulin kinase II; block MEK1 activation and p27 protein degradation.	Cell cycle arrest and inhibition of cell growth	Ma et al. [50]
MDA-MB-231 breast cancer cells	Downregulate MMP2 (activities) and MMP9 (expression); inhibit Akt, NF-κB and AP-1; supress Akt expression via modulating its mRNA expression and protein degradation.	Potential for inhibition of cancer metastasis	Kuo et al. [51]
Thyroid cancer 8505C and TPC1cell lines.	Induce cell cycle arrest at the G0/G1 phase (TPC1 cells); upregulate p-27; induce cell death (IC50 of 10 µM).	Inhibition of growth and induction of apoptosis	Park et al. [52]
Human epithelial ovarian carcinoma (OVCAR-3 and SKOV-3) cell lines	Induce cytotoxicity and G2/M phase (OVCAR-3 cells) and S phase (SKOV-3 cells) arrest; upregulate p27.	Inhibition of cell proliferation	Park et al. [53]
Angiogenesis using B16F-10 melanoma cells and capillary formation in C57BL/6 mice; angiogenesis model of endothelial cells from rat aortic ring	Inhibition in tumour-directed capillary formation and in various proangiogenic factors (VEGF, IL-1β, IL-6, TNF-α, and GM-CSF); increase the serum levels of antitumor factors (IL-2 and TIMP); suppress NF-ĸB, c-Fos, CREB, and ATF-2; inhibit the expression (mRNA) levels of proangiogenic factors (COX-2, iNOS, and HIF).	Inhibition of angiogenesis both in vitro and in vivo; inhibition of endothelial cell motility, migration, tube formation, and vessel sprouting.	Hamsa and Kuttan [54]
Human ductal breast epithelial tumour (T47D) cell line	Decrease COX-2, iNOS and survivin proteins.	Inhibition of cell viability and induction of apoptosis.	Pazhang et al. [55]
Human colon cancer (HCT-8) cell line	Induce cell cycle arrest at S phase; upregulate p-regulated mRNA and/or protein expressions of Fas, FasL, TNF-α and caspase-3; down-regulate pro-caspase-3; decrease Bcl-2 and increase of Bax (mRNA and protein) expressions.	Inhibition of cell growth and induce apoptosis.	Xu et al. [56]
Non-small cell human lung (A549 as a wild-type p53, and H1299 as p53-deficient) cancer cells in vitro and H1299 tumour xenograft growth athymic nude mice.	p53-Dependent cell death; disrupt Δψm, reduce the levels of Bcl-2, Bcl-xl while increasing in Bax, Bak; activate caspase-3.	Inhibition of cell proliferation and induction of apoptotic cell death in vitro and inhibition of tumour growth in vivo.	Katiyar et al. [57]
Human hepatocellular carcinoma (HepG2) cells in vitro and in vivo	Increase the expression level of Fas and P53, cause depolarization of mitochondrial membrane and decrease Δψm; activate caspase-3, -8, and -9.	Reduce cell growth and induce apoptosis; reduce tumour growth rates in mice.	Wang et al. [58]
Human neuroblastoma SK-N-SH and SK-N-MC cells	More cytotoxic to p53-expressing SK-N-SH (IC50 = 37 μM) than p53-deficient SK-N-MC cells (IC50 ≥ 100 μM); induce cell cycle arrest at G0/G1 phase; decrease G0/G1 phase-associated CDK (cyclin D1, cyclin E, Cdk2, and Cdk4) expression; increase apoptotic gene expression and activate caspase-3 in susceptible cells.	Induction of apoptotic cell death in cancer but not in normal cortical neuronal cells.	Choi et al. [59]
Human gastric SNU-5 cancer cells	Downregulate MMP-1 -2, and -9 (no effect on the level of MMP-7); inhibit gene expression for MMP-1, -2 and -9 (no effect on MMP-7); induce ROS production.	Reduction of cell viability.	Lin et al. [60]
Human oral squamous cell carcinoma (HSC-3) cells	Induce mainly G0/G1-phase arrest; increase intracellular levels of ROS and Ca2+; reduce Δψm.	Inhibition of cell growth and induction of apoptosis.	Lin et al. [61]
Human cervical cancer Ca Ski cells	Increase the ratio of p53 and Bax/Bcl-2 proteins; increase the levels of ROS and Ca2+; disrupt Δψm; promote caspase-3 activity; induce the expression of transcription factor GADD153.	Induction of apoptosis	Lin et al. [62]
Human colonic carcinoma SW620 cells	Activate caspases (-3 and -8), cleavage of PARP and the release of cytochrome-c; downregulate the expression of anti-apoptosis factor (c-IAP1, Bcl-2, and Bcl-XL); increase the phosphorylation of JNK and p38 MAPK; induce ROS generation; increase the cellular levels of c-Jun and FasL.	Induction of apoptosis	Hsu et al. [63]
Murine leukaemia WEHI-3 cells in vitro; and in vivo WEHI-3 cancer cells injected in mice	Induce cytotoxicity in cancer cells in vitro; promote differentiation of the B-cells precursors in vivo; reduce Mac-3 and CD11b markers (inhibit differentiation of precursors of macrophages and granulocytes); no effect on the CD14- and CD19-augmented (promotion of B-cells precursors differentiation).	Induction of cytotoxicity in vitro and reduction of spleen weight in cancer bearing animals in vivo.	Yu et al. [64]
Melanoma B16 cells and U937 cells	B16 cells (IC100 < 1 μg/mL) much more sensitive than U937 cells (IC100 < 100 μg/mL) U937 cells; apoptotic cell death in U937 and necrosis in NB16 cells	Cytotoxic to cancer cells	Letasiová et al. [65]