Molecules 26 07368 v2 Compressed
Molecules 26 07368 v2 Compressed
Molecules 26 07368 v2 Compressed
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1. Introduction
Cancer is a disease that has become a significant public health and socio-economic
concern worldwide. Hence, it seems urgent to develop strategies for the prevention and
treatment of cancer [1]. Various types of cancers display resistance to chemo, radio, and
hormonal therapies. Owing to these limitations, there is a dire need to develop effec-
tive, readily available, and safe anticancer therapies. Consequently, researchers are now
more focused on exploring natural plant components as potential anticancer agents [2].
Plants produce numerous distinct natural products—secondary metabolites—such as ter-
penoids, phenolics, and alkaloids. In matrices of higher plants, phenolics and terpenoids
are more abundantly present than alkaloids [3]. Among alkaloids, isoquinoline alkaloids
are known as natural plant products that have demonstrated a considerable impact in
drug discovery. Isoquinoline alkaloids are predominantly present in diverse plant families
such as Berberidaceace, Cactaceae, Rutaceae, Fumariaceae, Papaveraceace, Magnoliaeace,
Menispermaceae, Amaryllidaceae, and Ranunculaceae. These alkaloids have remarkable bi-
ological and pharmacological properties such as antifungal, anti-inflammatory, antioxidant,
anticancer, antihypercholesterolemic, antidiabetic, and antimicrobial [4–6].
Berberine (BBR) is a benzyl tetra isoquinoline alkaloid (2,3-methylenedioxy-9,10-dimethoxy
protoberberine chloride, C20 H18 NO4 + ) (Figure 1) with a molar mass of 336.36122 g/mol. It
is a well-known phytochemical compound extracted from the roots of various plants such
as Berberis vulgaris, B. aristotle, B. aquifolium, Hydrastus canadensis, Pellodendron chenins, and
Coptis rhizomes [7,8]. It is a crystal yellow-colored isoquinoline alkaloid traditionally used
in Chinese and Ayurvedic medicine. Recently, scientists have reported that Berberine pos-
sesses broad-spectrum therapeutic potential due to its action against various ailments such
Molecules 2021, 26, x FOR PEER REVIEW 4 of 22
as diabetes, hypertension, depression, obesity, inflammation, and cancer [9–13]. Berberine
sulfate and hydrochloride have also been considered efficient herbal treatments. Scientists
have reported intestinal tract helps
berberine asconvert berberine todrug
a promising its easily absorbable form,
candidate dihydroberberine,
in treating cancer [14] and various
which displays a 5-fold higher intestinal absorption rate compared with its parent mole-
diseases such culeas[36].
diabetes, Alzheimer’s.
Following administration of BBRItinisrats
a and
hydrophilic compound
humans, the presence of the BBRhaving low bioavail-
ability whenmetabolitesadministratedM1, M2, M3, and M4 therefore,
orally; was detected invarious
bile, urine, nanotechnology-based
and feces, as well as BBR strategies are
sulfate and glucuronide conjugates [37]. The pharmacokinetic profile of BBR and its me-
in practice totabolites,elevate berberine
which bioavailability.
was extensively studied both in animal Furthermore,
models [38] and coadministration
in humans [39], with certain
drugs resultsdemonstrated
in increased analogies between the two models, mainly regarding the low oral bioavail-
absorption of berberine. Additionally, for decades it has served
ability of BBR, thus requiring relatively high dosages for clinical practice (0.5–1 g/month).
as a chemical Chenmarker in assessing
et al. studied the quality
the BBR pharmacokinetic profileofin various
rabbits after prescriptions
intravenous admin- in clinical use [15].
istration of 2 mg/kg BBR sulfate, obtaining the following kinetic parameters; t
Therefore, this review
1.18 min, t
1/2(β)
summarizes the pharmacokinetic profile
1/2(α)
of: berberine
: 5.28 ± 1.00 h, total plasma clearance (CL): 5.46 ± 1.62 L/h, elimination rate
2.32 ±
and presents
an in-depth constant overview10 of ±its
(K ): 1.75 1.17anticancer
−1 h , and an areaperspectives.
under the concentration-time curve (AUC): 0.84
± 0.27 μg h/mL [40].
4. Anticancer Perspectives
4.1. Breast Cancer
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype. Berberine
was cytotoxic against all treated TNBC cell lines such as MDA-MB-231, MDA-MB-468,
HCC1937, HCC70, HCC38, BT-20, HCC1143, and BT-549. Among all these experimented
cell lines, the most sensitive ones were HCC70 (IC50 = 0.19 µM), BT-20 (IC50 = 0.23 µM), and
MDA-MB-468 (IC50 = 0.48 µM) [45]. Using flow cytometry techniques, BBR at 0.5 and 1 µM
for 120 and 144 h not only induced cell cycle arrest at first growth (G1) and second-growth
(G2)/medium phases, but it also triggered significant apoptosis [45]. Interestingly, although
BBR was cytotoxic to TNBC cells, it did not affect the viability of normal human breast
cells (MCF10) cultured in a 3D Matrigel model 15. These results suggest that berberine
may be a suitable potential candidate for the development of a TNBC drug. Berberine
addition at a dose of 1 µM to MDA-MB-468 cells induced a significant increase in the G1
phase population with a decrease in the S and G2/M phases [46].
BBR reduced the expression of the proliferating cell nuclear antigen (PCNA) protein
and cyclin D1 in MDA-MB-468 cell cultures to block their progression into the G1 phase
of the cell cycle. Likewise, application of BBR to MDA-MB-468 cells at a dose of 6 and
12 µM for 48 h caused a cell cycle arrest in the first growth (G1) phase with a decrease
Molecules 2021, 26, 7368 5 of 19
in the expression of cyclin D1 depending on the dose [46]. Zhao and Zhang recently
investigated the role of berberine regarding the behavior of the MDA-MB-231 malignant
breast tumor cell line. Namely, BBR reduced cell migration ability, provoked inhibition
of phosphorylation, decreased overexpression of the tumor necrosis factor α (TNF-α)
and Interleukin 6 (IL-6), and induced suppression of the nuclear factor kappa light chain
enhancer of activated β cells (NF-Kβ) [47].
On the other hand, autophagy is a conservative mechanism for maintaining cellular
homeostasis by clearing misfolded proteins and damaged organelles [48]. In cancer therapy,
autophagy is seen as a double-edged sword because it can prevent early tumorigenesis
and protect cancer cells later in life [49]. Thus, the combination of autophagy inhibitors
and chemotherapy is expected as a promising cancer treatment strategy, and multiple
autophagy inhibitors are already in the preclinical stage [50].
In MCF-7 breast cancer cells and the doxorubicin-resistant (ADR) cells MCF-7 (MCF-7/
ADR), BBR was recently identified as an autophagy suppressor, inhibiting the formation of
autophagosomes in MCF-7/ADR cells [51]. Berberine treatment blocked the accumulation
of the LC3II protein, which is associated with autophagy, leading to accumulation of the
signaling adaptor p62 protein, decreasing cell proliferation, and reversing doxorubicin re-
sistance [52]. Mechanically, BBR inhibits autophagy by modulating the PTEN/Akt/mTOR
signaling pathway. It also regulates the mitogen-activated protein kinase and the Wing-
less/Integrated (Wnt)/β-catenin signaling pathways in breast cancer cells [53] while sup-
pressing chemotherapy resistance through autophagy regulation [46,54]. BBR as a potent
anticancer agent significantly reduces cell viability, inhibits colony formation, cell migration,
and decreases the secretion of proinflammatory cytokines (IL-1α, IL-6, TNF-α, IL-1β) [55].
BBR also increases the release of Lactic Acid Dehydrogenase (LDH) in the MDA epithelial
human breast cancer cell line (MDA-cells) and downregulates the purinoceptor 7 (P2 × 7)
associated with speck apoptosis, procaspase-1, and caspase-1 p20, domain recruitment
(ASC), IL-1β proteins, interleukin-18 (IL-18), the mRNA expression of caspase-1 and ASC
in the NOD-, and LRR- and the pyrin domain-containing protein 3 (NLRP3) inflammasome
cascade [55]. Proposed mechanisms regarding the breast anticancer properties of berberine
are presented in Table 2.
expression of PDCD4 proteins in the HCT116 cell line. Overexpression of miR-21 reduces
the anticancer effects of BBR on cell viability, apoptosis rate, and caspase-3 activity of the
HCT116 cell line [60,61]. Table 2 provides an overview of berberine action against various
colon cancer cell lines and the proposed anticancer mechanisms.
that BBR inhibits the proliferation of pancreatic cancer cells via the regulation of citrate
metabolism and, therefore, citrate metabolism may be considered a promising target
in drug development for the treatment of pancreatic cancers. Similarly, according to
another study carried out in the pancreatic cancer cells PANC-1, treatment of gemcitabine
(a standard drug) and BBR resulted in the reduction of side-population cells to 6.8 and
5.7%, respectively. Further, in BBR and gemcitabine-treated PANC-1 and MIA-PaCa-2 cells,
all the examined stem cell-associated genes (NOTCH1, NANOG, POU5F1, and SOX2) were
suppressed, except NOTCH1. Hence, the authors believed that the stem cell-associated
genes (NANOG, POU5F1, and SOX2) may serve as promising markers and that BBR can be
considered a potent anticancer agent for the treatment of pancreatic cancers [73].
STAT3 activation [92], which resulted in growth inhibition and apoptosis in NPC cells.
IL-6 was found to be secreted by tumor-associated fibroblasts, and conditioned media
from fibroblasts activated STAT3 in NPC cells [92]. BBR or antibodies to IL-6 and IL-6R
may also inhibit STAT3 activation by regulatory media of tumor-associated fibroblasts [93].
Treatment with BBR impaired the development of the human esophageal squamous cell
carcinoma cell line KYSE-70 and the esophageal adenocarcinoma line SKGT4 in a dose-
and time-dependent manner. The inhibitory function of BBR was more sensitive in KYSE-
70 cells than in SKGT4 cells. The number of cells in the G2/M process (25.94%/5.01%)
was higher in KYSE-70 cells treated with 50 µmol/L BBR for 48 h than in the control
(9.77%/1.28%). At 12 and 24 h after treatment, flow cytometric analysis indicated that BBR
significantly increases the KYSE-70 apoptosis population relative to control cells (0.83%
vs. 43.78%, 12 h) [94]. The apoptosis effect of BBR was higher at 24 h compared to 12 h
(81.86% vs. 43.78% p%, p < 0.01). BBR blocked the phosphorylation of rapamycin and
Akt, the mammalian targets of P70-S6-Kinase, and increased AMP-activated protein kinase
phosphorylation in a prolonged fashion, according to Western blotting [94] (Table 2).
BBR can inhibit miR-21 transcription in multiple myeloma by downregulating IL-6 through
STAT3 downregulation. Apoptosis, G2 step cell cycle arrest, and colony suppression were
also caused by BBR and seed-targeting anti-miR-21 oligonucleotides in multiple myeloma
cell lines (Table 2). Short interfering RNA depletion of PDCD4 could preserve BBR-induced
cytotoxicity in multiple myeloma cells [102]. The anticancer mechanisms of berberine
Molecules 2021, 26, x FOR PEER REVIEW 11 of 22are
presented in Figure 2.
in U251 and U87 cells [107]. Furthermore, BBR has the potential to reverse the mechanism
of epithelial–mesenchymal metastasis, which is a sign of tumor invasion [107].
BBR inhibits tumor development by regulating the differentiation and the role of stem
cells and inducing cell death in neuroblastoma cells. Around the same time, inhibiting
the adrenergic signal slows neuroblastoma development and increases cell differentiation.
Calvani et al. [108] have summarized the potential benefits of BBR in inhibiting tumor
growth and development in different types of cancer, especially neuroblastoma [108], BBR
(6.25–200 µmol/L, 6–48 h) impaired cell viability and proliferation of U87 and U251 human
glioblastoma cell lines in BALB/c nude mice (IC50 of 42 and 32 µmol/L, respectively). BBR
(50 µmol/L) prevented HUVEC cell migration in the transwell assay by 67.50 ± 8.14%
and the Matrigel assay by 73.00 ± 1.12% [109]. In the ectopic xenograft form, BBR
(50 mg/kg) greatly decreased tumor weight (401.2 71.5 mg vs. 860.7 117.1 mg in the vehicle
group) [109]. The hemoglobin content was greatly decreased by BBR (28.81 ± 3.64 µg/mg
vs. 40.84 ± 5.15 µg/mg in the vehicle group, p < 0.001). BBR (50 mg/kg) greatly in-
creased the survival rate of mice in a stereotactic xenograft model. BBR inhibited VEGFR2
and ERK phosphorylation [109] (Table 2).
Table 2. Summarized data of berberine effects against various cancers and their proposed mechanisms.
Cancer
Experimental Model (s) Dose Proposed Mechanism (s) References
Type
MDA-MB-231,
MDA-MB-468, HCC1937, Induction of G1 and -G2/M phase cell cycle arrest,
0.2, 0.5 and 1.0 µM [45]
HCC70, HCC38, BT-20, Stimulation of apoptosis in cancer cells
HCC1143 and BT-549
Cell cycle arrest at G1 phase,
MDA-MB-468 6 and 12 µM [46]
Decrease in cyclin D1 expression
Reduction of cell migration,
MDA-MB-231 25 µM/L Phosphorylation inhibition, [47]
Breast
Decrease of TNF-α and IL-6 overexpression
Cancer
MCF-7/ADR 100 µM Inhibition of the formation of autophagosomes [51]
Blocking the accumulation of the LC3II protein,
MCF-7/ADR 100 µM Decrease of cell proliferation, [52]
Reversion of doxorubicin resistance
Reduction of cell viability,
Inhibition of colony formation, cell migration, and
MDA-MB-231 2.5–100 µg/mL [55]
decrease of the secretion of the proinflammatory
cytokines (IL-1α, IL-6, TNF-α, IL-1β)
Upregulation of LncRNA CASC2, Suppression of
HT29, HCT116 0–100 µM [56]
Colon Bcl-2 gene
cancer Induction of apoptosis,
HCT116 1, 10 or 100 µM [60]
Promotion of caspase-3 activity
PANC-1, MiaPaCa-2 0.3–6 µM Inhibition of DNA synthesisCell cycle arrest at G1 [62]
Cell cycle arrest at G1,
PANC-1, MiaPaCa-2 15 µM and 10 µM [68]
Induction of apoptosis
AsPC-1, BxPC-3,
MIA-PaCa-2 and 100, 1000 and 10,000 nM Suppression of the proliferation of cancer cells [69]
PANC-28).
Pancreatic
cancer BxPC-3 10–200 µM Mediation of caspase-independent cell death [70]
PANC-1, MiaPaCa-2, Induction of apoptosis,
5 µM [71]
AsPC-1 Inhibition of PARP and Rad51 expression
Damage of the mitochondria of pancreatic cancer cells,
PANC-1 2.5, 3.75, 5 and 10 µM [72]
Targeting citrate metabolism
PANC-1, MiaPaCa-2 10 µM, 15 µM Downregulation of NANOG, POU5F1, and SOX2 [73]
SNU-5 75 µM Inhibition of MMP-1, -2 and -9 gene expression [75]
AGS 0–50 µM Suppression of survivin and STAT3 expression [76]
SGC7901, MKN45, Downregulation of the expression of Bcl-xL and
15–90 µM [77]
BGC823 cyclin-D1 proteins
Gastric Cell cycle arrest,
cancer SGC7901, AGS 10–80 µM Attenuation of tumor invasion via the down-regulation [78]
of C-myc, cyclin-D1, and MMP-3 expressions
BGC-823, SGC-7901 1–1000 µM Inhibition of PI3K/AKT/mTOR signaling [79]
BGC-823, SGC-7901 10 µM Modulation of the miR-203/Bcl-w apoptotic axis [80]
MGC 803 0–60 µM Modulation of MAPK-signaling pathways [82]
Molecules 2021, 26, 7368 13 of 19
Table 2. Cont.
Cancer Type Experimental Model (s) Dose Proposed Mechanism (s) References
HepG2 0, 50 and 100 µM Inhibition of cyclin D1 expression [83]
Suppression of glutamine uptake, Inhibition
Hep3B, BEL-7404 50–125 µM [84]
of SLC1A5
Liver cancer
Induction of G1 phase cell cycle arrest in
HepG2, Huh-7 30–120 µM [85]
cancer cells
Modulation of the expression of multiple
SNU-182, Hep3B, HepG2 10–100 µM [86]
tumorigenesis-related gene proteins
Induction of apoptosis,
KB 0, 0.1 and 1 µg/mL [91]
Enhancement of caspase-3 and -7 activities
Oral cancer
C666-1, HONE1, & HK1 0–50 µM Inhibition of STAT3 activation [92]
HONE1 0–300 µM Inhibition of STAT3 activation [93]
Inhibition of the caspase-1/IL-1 inflammatory
Saos-2, MG-63 0–100 µM [95]
Bone Cancer signaling axis
MG-63 0–80 µM Induction of apoptosis in cancer cells [96]
Glioblastoma
U251, U87 100 µM Induction of autophagy [103]
cancer
Inhibition of inflammatory cytokine
U251, U87 50 µM, 100 µM [107]
caspase-1 activation
Inhibition of MMP1, MMP13, uPA, and
Skin cancer A375.S2 0–2 µM [110]
Ras expressions
Inhibition of cancer cell proliferation,
A431 0–100 µg/mL [111]
Induction of apoptosis
Down-regulation of p-PI3K, p-AKT expressions,
B16 5–160 µM [112]
Up-regulation of RARβ and RARγ expressions
LNCaP, DU-145 20–400 µM Inhibition of VEGF and HIF-1α expressions [118]
LNCaP, 22Rv1, Decrease of cellular testosterone synthesis in a
Prostate cancer 12.5–50 µM/L [119]
PC3M, PC3 dose-dependent manner
LNCaP, 22Rv1, PC3 0–100 µM Suppression of androgen receptor signaling [120]
metastatic [49]. The inhibitory activity of BBR resulted in a substantial reduction in the
expression of a panel of mesenchymal genes that control developmental EMT. High BMP7,
NODAL, and Snail gene expression in metastatic prostate cancer tissues is associated with
shorter survival in patients with prostate cancers and offers potential therapeutic targets
among the EMT-related genes downregulated by BBR [49] (Table 2).
5. Conclusions
Cancer is a large category of disease that severely affects people’s health. Thus, there is
a vital need for cancer prevention and treatment advancement. Surgery, radiotherapy, and
chemotherapy are the most often used approaches to cancer care. People may also abandon
anticancer treatments due to their ineffectiveness and adverse side effects, resulting in
the illness progression and reduced overall survival rate. Resistance to anticancer drugs
may be conferred by target alteration, drug-efflux pumps, increased cellular tolerance to
apoptosis, increased DNA harm tolerance to therapy, reparability, and enhanced neoplastic
proliferation. Resistance may be due to improvements in the stroma and tumor climate
as well as cancer microenvironments. Cancer cells utilize a number of these pathways,
complicating clinical strategies for each patient. Recent advancements in cancer care, such
as selective and immunotherapy, also provided substantial benefits.
However, during the last decade, several clinical studies and lab analyses have been
conducted to investigate the efficacy of BBR in curing cancer. Additionally, BBR was found
to control pro and anticancer miRNAs and lncRNA levels and has been shown to improve
the effectiveness of chemotherapy and radiation therapy. However, BBR’s direct cytotoxic
impact is not considered very powerful. It acts at concentrations sometimes greater than
100 µM for certain cancer cell lines. Nevertheless, the cytotoxic action of BBR is moderate
as it ranges from 10 to 100 µM. BBR’s slow absorption, efflux from intestinal cells by
P-gc, and comprehensive metabolism by intestinal and hepatic cells render difficult its use
in vivo. Consequently, progresses must be made on developing both the pharmacokinetic
profile and the anticancer efficacy of BBR in the future. As BBR shows promising efficacy
concerning anticancer potential, it may be a potential candidate in innovative anticancer
drug discovery.
Author Contributions: Conceptualization, A.R. and M.I.; methodology, A.R., M.I., Z.A.S., T.A.-I. and
T.B.E.; software, A.R. and M.I.; validation, A.R., M.I., Z.A.S., T.A.-I. and T.B.E.; formal analysis, S.M.,
Z.K., F.A.A., A.S.M.A., I.K., M.M.R., P.J. and T.A.G.; investigation, A.R. and M.I.; resources, S.M., Z.K.,
F.A.A., A.S.M.A., I.K., M.M.R., P.J. and T.A.G.; data curation, A.R., M.I., Z.A.S., T.A.-I. and T.B.E.;
writing—original draft preparation, A.R., M.I., T.B.E., A.A.K. and S.M.; writing—review and editing,
S.M., Z.K., F.A.A., A.S.M.A., I.K., M.M.R., P.J. and T.A.G.; visualization, A.R. and M.I.; supervision,
A.R. and P.J.; project administration, A.R. and P.J.; funding acquisition, A.R. and P.J. All authors have
read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Molecules 2021, 26, 7368 15 of 19
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