Regulatory effects of berberine on microRNome in Cancer and other conditions

https://doi.org/10.1016/j.critrevonc.2017.05.008Get rights and content

Abstract

Berberine (BBR) is an isoquinoline alkaloid found in different plant families such as Berberidaceae, Ranunculaceae, and Papaveraceae. BBR is well-known for its anti-inflammatory, lipid-modifying, anticancer, anti-diabetic, antibacterial, antiparasitic and fungicide activities. Multiple pharmacological actions of BBR stem from different molecular targets of this phytochemical. MicroRNAs (miRs) are single-stranded, evolutionary conserved, small non-coding RNA molecules with a length of 19–23 nucleotides that are involved in RNA silencing and post-transcriptional regulation of gene expression through binding to the 3′-untranslated region (3′UTR) of target mRNA. MiRs emerged as important regulatory elements in almost all biological processes like cell proliferation, apoptosis, differentiation and organogenesis, and numerous human diseases such as cancer and diabetes. BBR was shown to regulate the expression of miRs in several diseases. Here, we reviewed the target miRs of BBR and the relevance of their modulation for the potential treatment of serious human diseases like multiple myeloma, hepatocellular carcinoma, colorectal cancer, gastric cancer, ovarian cancer and glioblastoma. The role of miR regulation in the putative anti-diabetic effects of BBR is discussed, as well.

Section snippets

Berberine: source and structure

Berberine (BBR) is a phytochemical compound found in different plant families such as Berberidaceae, Ranunculaceae, and Papaveraceae families (Singh and Mahajan, 2013). It is primary isolated from roots, rhizome, and stem bark of barberry (Berberis vulgaris), tree turmeric (Berberis aristata), goldenseal (Hydrastis canadensis), Coptis (Coptis chinensis) and Oregon grape (Berberis aquifolium) (Singh and Mahajan, 2013, Srivastava et al., 2015). Chemically, BBR is an isoquinoline alkaloid

Berberine: bioavailability and pharmacokinetic data

Due to poor water solubility, the BBR intestinal absorption is scarce (Godugu et al., 2014) with an oral bioavailability less than 5% (Pan et al., 2003). However, changing the BBR structure or coadministering BBR with an absorption enhancer can improve the BBR bioavailability (Chen et al., 2011). Dihydroberberine (dhBBR) is one of the absorbable structurally modified compounds of BBR. BBR converts to dhBBR in the intestine via a reduction reaction. Some studies showed that bacterial

Berberine: tolerability and safety

In animal models, orally administered highly purified BBR sulfate has a LD50 (lethal dose for the 50% of treated animals) of 25 mg/kg (Ye et al., 2009). BBR does not have any genotoxic, cytotoxic and mutagenic activity, however it can cause dose-dependent gastrointestinal/abdominal discomfort (till 34.5% events) on the middle-term use (Yina et al., 2008). On the other hand, BBR strongly interacts with macrolides potentially causing dangerous arrhythmias (Caliceti et al., 2015, Ji and Shen, 2011

Berberine: pharmacological effects

Pharmacological effects of BBR were the subject of extensive in vitro, in vivo and clinical researches (Imanshahidi and Hosseinzadeh, 2008). It is a wildly used natural product that showed multiple pharmacological activities in modern and traditional medicine (Li et al., 2014). Plants rich in BBR were largely employed in traditional eastern medicine for their anti-inflammatory, anticancer, anti-diabetic, antibacterial, antiparasitic, anti-diarrheal and fungicide activities (Imanshahidi and

Berberine: molecular targets

Beyond the above-described metabolic effect on PCSK9, several mechanistic investigations have demonstrated that BBR can also inhibit inflammation both in vitro and in vivo (Kuo et al., 2004, Küpeli et al., 2002) and suppress the growth of a wide variety of tumor cells with different mechanisms (Pandey et al., 2008, Sun et al., 2009).

BBR can inhibit transcription of proinflammatory genes such as IL-1β, TNF-α, IL-6 and monocyte chemoattractant protein 1 (MCP-1) (Jeong et al., 2009). On the other

MicroRNA

MicroRNAs (miRs) are single stranded, evolutionary conserved, small non-coding RNA molecules with 19–23 nucleotides. miRs are involved in RNA silencing and post-transcriptional regulation of gene expression by binding to 3′ untranslated region (3′UTR) of target mRNA (Ambros, 2004, Bartel, 2004, Filipowicz et al., 2008). More than 60% of human protein coding genes are regulated by miRs through post-transcriptional operation (Lewis et al., 2005).

MiRs play a key role in almost every biological

Role of miRs in tumorigenesis

Development of high throughput strategies for miR profiling like miR microarrays (Liu et al., 2004), bead-based flow cytometric miR expression profiling (Lu et al., 2005) and quantitative polymerase chain reaction (qPCR) (Chen et al., 2005) makes it easier to study miR pattern changes in different disease (Aravin and Tuschl, 2005, Creighton et al., 2009, Meyer et al., 2010). Recent studies shown that miR expression is different in cancer versus normal cells and also among different tumors, and

Multiple myeloma

BBR decreases both mRNA and protein of IL-6, that is an important factor in the expansion of multiple myeloma (MM) cells (Kim et al., 2008, Lin et al., 2006, Yu et al., 2007). Different miRs including miR-21, miR-155, miR–17  92, mir-99a  125b and miR–106  25 function as OncomiRs in MM (Luo et al., 2014). miR-21 increases cell proliferation, apoptosis and tumor invasiveness via targeting various proteins such as Bcl-2 (Xu et al., 2014). Hu and coworkers evaluated the effect of various

Anti-diabetic effect

As mentioned above, BBR increases AMPK activity and reduces lipid accumulation in diabetic and obese patients (Lee et al., 2006). Aberrant overexpression of miR-21 was detected in diabetic rats and results in insulin resistance in 3T3-L1 adipocytes (He et al., 2007). Zhao et al. indicated that BBR-containing herbs exert antidiabetic effects through modulation of hepatic gene expression via down-regulation of miR29-b. They treated 3 groups of proved Zucker Diabetic fatty [ZDF] rats with an oral

Conclusion

BBR is a natural compound with well-known metabolic effects and a high safety profile. However, BBR also exerts anticancer and anti-inflammatory effects via regulation of different types of miRs. BBR plays anticancer role through regulating the expression of oncomiRs and tumor-suppressive miRs in various cancer cells. This isoquinoline alkaloid induces cytotoxicity and apoptosis through down-regulating different miRs including miR-21, miR–17  92, mir-99a  125b and miR–106  25 that have oncogenic

Conflict of interests

None.

References (121)

  • C.-L. Kuo et al.

    The anti-inflammatory potential of berberine in vitro and in vivo

    Cancer Lett.

    (2004)
  • C.-H. Lee et al.

    Berberine suppresses inflammatory agents-induced interleukin-1β and tumor necrosis factor-α productions via the inhibition of I(B degradation in human lung cells

    Pharmacol. Res.

    (2007)
  • K.H. Lee et al.

    MicroRNA-296-5p (miR-296-5p) functions as a tumor suppressor in prostate cancer by directly targeting Pin1

    Biochim. Biophys. Acta

    (2014)
  • B.P. Lewis et al.

    Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets

    Cell

    (2005)
  • J. Li et al.

    MiR-429 is an independent prognostic factor in colorectal cancer and exerts its anti-apoptotic function by targeting SOX2

    Cancer Lett.

    (2013)
  • Y. Liu et al.

    Oxidative demethylenation and subsequent glucuronidation are the major metabolic pathways of berberine in rats

    J. Pharm. Sci.

    (2009)
  • C.-S. Liu et al.

    Research progress on berberine with a special focus on its oral bioavailability

    Fitoterapia

    (2016)
  • J.Y. Ma et al.

    Excretion of berberine and its metabolites in oral administration in rats

    J. Pharm. Sci.

    (2013)
  • H. Siomi et al.

    Posttranscriptional regulation of microRNA biogenesis in animals

    Mol. Cell

    (2010)
  • Y.H. Su et al.

    Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer

    Biochim. Biophys. Acta − Mol. Cell Res.

    (2015)
  • X. Wang et al.

    Kinetic difference of berberine between hippocampus and plasma in rat after intravenous administration of Coptidis rhizoma extract

    Life Sci.

    (2005)
  • P. Abidi et al.

    Extracellular signal-regulated kinase–dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine

    Arterioscler. Thromb. Vasc. Biol.

    (2005)
  • F. Affuso et al.

    WJC World

    (2010)
  • V. Ambros

    The functions of animal microRNAs

    Nature

    (2004)
  • I.H. Bae et al.

    Bcl-w promotes gastric cancer cell invasion by inducing matrix metalloproteinase-2 expression via phosphoinositide 3-kinase, Akt, and Sp1

    Cancer Res.

    (2006)
  • F. Bullrich et al.

    Characterization of the 13q14 tumor suppressor locus in CLL identification of ALT1, an alternative splice variant of the LEU2 gene

    Cancer Res.

    (2001)
  • C. Caliceti et al.

    Potential benefits of berberine in the management of perimenopausal syndrome

    Oxid. Med. Cell. Longevity

    (2015)
  • C. Caliceti et al.

    Berberine: new insights from pharmacological aspects to clinical evidences in the management of metabolic disorders

    Curr. Med. Chem.

    (2016)
  • G.A. Calin et al.

    Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • J.A. Chan et al.

    MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells

    Cancer Res.

    (2005)
  • E. Chan

    Displacement of bilirubin from albumin by berberine

    Neonatology

    (1993)
  • C. Chen et al.

    Real-time quantification of microRNAs by stem–loop RT–PCR

    Nucleic Acids Res.

    (2005)
  • W. Chen et al.

    Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats

    Aaps Pharmscitech

    (2011)
  • Q. Chen et al.

    Berberine sensitizes human ovarian cancer cells to cisplatin through miR-93/PTEN/Akt signaling pathway

    Cell. Physiol. Biochem.

    (2015)
  • W.C. Cho

    OncomiRs: the discovery and progress of microRNAs in cancers

    Mol. Cancer

    (2007)
  • K.A. Coughlan et al.

    AMPK activation: a therapeutic target for type 2 diabetes?

    Diabetes Metab. Syndrome Obesity: Targets Ther.

    (2014)
  • C.J. Creighton et al.

    Expression profiling of microRNAs by deep sequencing

    Brief. Bioinform.

    (2009)
  • H. Döhner et al.

    Genomic aberrations and survival in chronic lymphocytic leukemia

    New Engl. J. Med.

    (2000)
  • Y. Deng et al.

    Berberine attenuates autophagy in adipocytes by targeting BECN1

    Autophagy

    (2014)
  • Z. Feng et al.

    Tumor suppressor p53 meets microRNAs

    J. Mol. Cell Biol.

    (2011)
  • M. Feng et al.

    Systematic analysis of berberine-induced signaling pathway between miRNA clusters and mRNAs and identification of mir-99a  125b cluster function by seed-targeting inhibitors in multiple myeloma cells

    RNA Biol.

    (2015)
  • R. Feng et al.

    Transforming berberine into its intestine-absorbable form by the gut microbiota

    Sci. Rep.

    (2015)
  • W. Filipowicz et al.

    Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?

    Nat. Rev. Genet.

    (2008)
  • M. Frau et al.

    Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression

    Hepatology

    (2012)
  • R. Garzon et al.

    MicroRNAs in cancer

    Annu. Rev. Med.

    (2009)
  • C. Godugu et al.

    Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid

    PLoS One

    (2014)
  • C. Gu et al.

    Integrative analysis of signaling pathways and diseases associated with the miR-106b/25 cluster and their function study in berb erine-induced multiple myeloma cells

    Funct. Integr. Genomics

    (2016)
  • L.M. Guamán Ortiz et al.

    Berberine, an epiphany against cancer

    Molecules

    (2014)
  • Y. Guo et al.

    Repeated administration of berberine inhibits cytochromes P450 in humans

    Eur. J. Clin. Pharmacol.

    (2012)
  • A. Gurtner et al.

    Dysregulation of microRNA biogenesis in cancer: the impact of mutant p53 on Drosha complex activity

    J. Exp. Clin. Cancer Res.

    (2016)
  • Cited by (84)

    • Alkaloids: Their relevance in cancer treatment

      2023, New Insights into Glioblastoma: Diagnosis, Therapeutics and Theranostics
    • Coptis chinensis and dried ginger herb combination inhibits gastric tumor growth by interfering with glucose metabolism via LDHA and SLC2A1

      2022, Journal of Ethnopharmacology
      Citation Excerpt :

      It decreases the cell viability and proliferation of gastric cancer cells and induces apoptosis (Chen et al., 2015; Hesari et al., 2018). Berberine exhibits an anti-gastric cancer effect via many regulatory pathways including Notch, MAPK, and NF-κB signaling using specific circRNAs (Ayati et al., 2017; Wang et al., 2021). In addition, It was shown to inhibit the growth of human gastric cancer cells by inhibiting MAPK/mTOR/p70S6K axis and inducing inhibitory autophagy by Akt both in vitro and in vivo (Zhang et al., 2020).

    • The protective impact of berberine against doxorubicin-induced nephrotoxicity in rats

      2021, Tissue and Cell
      Citation Excerpt :

      Berberine (BEB), a quaternary amine-iso-quinoline alkaloid, is the main potent component of a Chinese herb “Berberis species”, also known as Coptis rhizome, is traditionally used for treating several disorders (Tillhon et al., 2012; Liu et al., 2019). BEB is characterized by exhibiting anti-inflammatory, anti-oxidative, and anti-apoptotic potentials (Moghaddam et al., 2014; Ayati et al., 2017), that are reflected in its neuroprotective, hepatoprotective and cardioprotective potentials (Liu et al., 2016; Eissa et al., 2018; Fang et al., 2020). The very low concentration of BEB is maintained for 36 h in plasma; moreover, BEB exhibits a good distribution-manner in organs such as liver and kidney (Ahmad et al., 2019).

    View all citing articles on Scopus
    View full text