Berberine

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Preclinical evidence for improving treatment outcomes

All the evidence of berberine’s effects on treatment outcomes so far is preclinical. The strongest evidence to date shows improved survival in animals treated with berberine, which has been reported only in lung cancer and multiple myeloma.   

Cancer as a whole

• Anticancer activity among several types of cancer cells treated with berberine¹Gu S, Song X et al. Berberine inhibits cancer cells growth by suppressing fatty acid synthesis and biogenesis of extracellular vesicles. Life Sciences. 2020;257:118122; Youn MJ, So HS et al. Berberine, a natural product, combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cells. Biological & Pharmaceutical Bulletin. 2008 May;31(5):789-95; Jantová S, Cipák L, Cernáková M, Kost’álová D. Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells. Journal of Pharmacy and Pharmacology. 2003 Aug;55(8):1143-9.
• Greater sensitization to doxorubicin of several types of cancer cells treated with berberine²Ji C, Yang B et al. Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition. Oncogene. 2010 Dec 16;29(50):6557-68. 
• Less metastasis of solid tumors in cells treated with 8-Oxo-epiberberine (OPB), a natural alkaloid extracted from the roots of Coptis chinensis Franch³Liu X, Zhang Y et al. Natural alkaloid 8-oxo-epiberberine inhibited TGF-β1-triggred epithelial-mesenchymal transition by interfering Smad3. Toxicology and Applied Pharmacology. 2020;404:115179.

Bladder cancer

• Berberine enhanced the cytotoxicity of gemcitabine in bladder cancer cells⁴Gao X, Liu J et al. Berberine enhances gemcitabine‑induced cytotoxicity in bladder cancer by downregulating Rad51 expression through inactivating the PI3K/Akt pathway. Oncology Reports. 2022;47(2):33.
• Anticancer effects in bladder cancer cells treated with berberine⁵Xia Y, Chen S et al. Berberine suppresses bladder cancer cell proliferation by inhibiting JAK1-STAT3 signaling via upregulation of miR-17-5p. Biochemical Pharmacology. 2021;188:114575.

Brain and nervous system cancers

Brain cancer:

• Anticancer activity among glioma cells and mice with glioma treated with berberine⁶Sun Y, Huang H et al. Berberine inhibits glioma cell migration and invasion by suppressing TGF-β1/COL11A1 pathway. Biochemical and Biophysical Research Communications. 2022;625:38-45.
• Berberine inhibited proliferation and induced apoptosis in human glioma cells⁷Jin Y, Zhang J, Pan Y, Shen W. Berberine suppressed the progression of human glioma cells by inhibiting the TGF-β1/SMAD2/3 signaling pathway. Integrative Cancer Therapies. 2022;21:15347354221130303; Palma TV, Lenz LS et al. Berberine induces apoptosis in glioblastoma multiforme U87MG cells via oxidative stress and independent of AMPK activity. Molecular Biology Reports. 2020;47(6):4393-4400.
• Anticancer activity among glioblastoma cells treated with berberine⁸Agnarelli A, Natali M et al. Cell-specific pattern of berberine pleiotropic effects on different human cell lines. Scientific Reports. 2018 Jul 13;8(1):10599; Wang J, Qi Q et al. Berberine induces autophagy in glioblastoma by targeting the AMPK/mTOR/ULK1-pathway. Oncotarget. 2016 Oct 11;7(41):66944-66958; Eom KS, Hong JM et al. Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway. Biological & Pharmacological Bulletin. 2008 Apr;31(4):558-62.
• Neuroprotective effects on glioma cells treated with berberine⁹Yu X, Wang S et al. Berberine induces CYP2J2 expression in human U251 glioma cells via regulation of peroxisome proliferator-activated receptor alpha. Pharmacology. 2020;105(5-6):360-368.

Neuroblastoma:

• Anticancer effects on neuroblastoma cells treated with berberine¹⁰Choi MS, Yuk DY et al. Berberine inhibits human neuroblastoma cell growth through induction of p53-dependent apoptosis. Anticancer Research. 2008 Nov-Dec;28(6A):3777-84.

Neuroepithelial cancer:

• Smaller tumor volume among animals with neuroepithelial cancer treated with berberine in a meta-analysis of 2 preclinical studies¹¹Xu J, Long Y et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):589. 

Breast cancer

• Smaller tumor volume and weight among animals with breast cancer treated with berberine in a meta-analysis of 5 preclinical studies¹²Xu J, Long Y et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):589. 
• Anticancer activity among breast carcinoma cells treated with berberine¹³Dian L, Xu Z et al. Berberine alkaloids inhibit the proliferation and metastasis of breast carcinoma cells involving Wnt/β-catenin signaling and EMT. Phytochemistry. 2022;200:113217; Ziasarabi P, Sahebkar A, Ghasemi F. Evaluation of the effects of nanomicellar curcumin, berberine, and their combination with 5-fluorouracil on breast cancer cells. Advances in Experimental Medicine and Biology. 2021;1328:21-35.
• Anticancer activity among triple-negative breast cancer cells treated with berberine¹⁴Qi M, Liu X et al. Berberine Inhibits MDA-MB-231 cells as an agonist of G protein-coupled estrogen receptor 1. International Journal of Molecular Sciences. 2021;22(21):11466; Sakaguchi M, Kitaguchi D et al. Berberine-induced nucleolar stress response in a human breast cancer cell line. Biochemistry and Biophysical Research Communications. 2020;528(1):227-233; Yao M, Fan X et al. Berberine inhibits NLRP3 Inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell. BMC Complementary and Alternative Medicine. 2019 Aug 14;19(1):216.

Colorectal cancer

• Smaller tumor volume but not tumor weight among animals with colorectal cancer treated with berberine in a meta-analysis of 5 preclinical studies¹⁵Xu J, Long Y et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):589. 
• Berberine suppressed cell growth in colorectal cancer cells and inhibited tumorigenesis in animals treated with berberine¹⁶Li SY, Shi CJ, Fu WM, Zhang JF. Berberine inhibits tumour growth in vivo and in vitro through suppressing the lincROR-Wnt/β-catenin regulatory axis in colorectal cancer. Journal of Pharmacy and Pharmacology. 2023;75(1):129-138.
• Berberine inhibited the survival, invasion, and migration of colorectal cancer cells in cell and animal studies¹⁷Ni L, Sun P et al. Berberine inhibited the formation of metastasis by intervening the secondary homing of colorectal cancer cells in the blood circulation to the lung and liver through HEY2. Phytomedicine. 2022;104:154303; Liu Y, Fang X et al. Berberine suppresses the migration and invasion of colon cancer cells by inhibition of lipogenesis through modulation of promyelocytic leukemia zinc finger-mediated sterol-regulatory element binding proteins cleavage-activating protein ubiquitination. Journal of Pharmacy and Pharmacology. 2022;74(9):1353-1363; Gong C, Hu X et al. Berberine inhibits proliferation and migration of colorectal cancer cells by downregulation of GRP78. Anticancer Drugs. 2020;31(2):141-149; Liu X, Ji Q et al. Berberine inhibits invasion and metastasis of colorectal cancer cells via COX-2/PGE2 mediated JAK2/STAT3 signaling pathway. PLoS One. 2015 May 8;10(5):e0123478.
• Anticancer activity among colorectal cancer cells¹⁸Samad MA, Saiman MZ, Abdul Majid N, Karsani SA, Yaacob JS. Berberine inhibits telomerase activity and induces cell cycle arrest and telomere erosion in colorectal cancer cell line, HCT 116. Molecules. 2021;26(2):376; Shen ZQ, Wang J, Tan WF, Huang TM. Berberine inhibits colorectal tumor growth by suppressing SHH secretion. Acta Pharmacologica Sinica. 2021;42(7):1190-1194; Zhang Y, Liu X et al. Berberine inhibits proliferation and induces G0/G1 phase arrest in colorectal cancer cells by downregulating IGF2BP3. Life Sciences. 2020;260:118413; or colon cancer cells¹⁹Nie Q, Peng WW et al. β-catenin correlates with the progression of colon cancers and berberine inhibits the proliferation of colon cancer cells by regulating the β-catenin signaling pathway. Gene. 2022;818:146207; Li G, Zhang C et al. Berberine regulates the Notch1/PTEN/PI3K/AKT/mTOR pathway and acts synergistically with 17-AAG and SAHA in SW480 colon cancer cells. Pharmaceutical Biology. 2021;59(1):21-30; Liu Y, Hua W et al. Berberine suppresses colon cancer cell proliferation by inhibiting the SCAP/SREBP-1 signaling pathway-mediated lipogenesis. Biochemical Pharmacology. 2020 Apr;174:113776; Wang L, Cao H et al. Berberine inhibits proliferation and down-regulates epidermal growth factor receptor through activation of Cbl in colon tumor cells. PLoS One. 2013;8(2):e56666; Chidambara Murthy KN, Jayaprakasha GK, Patil BS. The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells. European Journal of Pharmacology. 2012 Aug 5;688(1-3):14-21; Wang L, Liu L et al. Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor. PLoS One. 2012;7(5):e36418; Fukuda K, Hibiya Y et al. Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells. Journal of Ethnopharmacology. 1999 Aug;66(2):227-33. treated with berberine
• Less migration in colorectal cancer cells treated with berberine²⁰Park JJ, Seo SM et al. Berberine inhibits human colon cancer cell migration via AMP-activated protein kinase-mediated downregulation of integrin β1 signaling. Biochemical and Biophysical Research Communications. 2012 Oct 5;426(4):461-7.
• Enhanced anticancer effects from irinotecan in colon cancer cells treated with berberine²¹Yu M, Tong X et al. Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NF‑κB. Molecular Medicine Reports. 2014 Jan;9(1):249-54.
• Anticancer effects on colon cancer cells treated with demethyleneberberine, a natural berberine analogue²²Wang Z, Wang L et al. Demethyleneberberine promotes apoptosis and suppresses TGF-β/Smads induced EMT in the colon cancer cells HCT-116. Cell Biochemistry and Function. 2021;39(6):763-770.

Gastrointestinal cancer

Colorectal cancer and pancreatic cancer are listed separately.

Gallbladder cancer:

• Berberine inhibited growth of cholangiocarcinoma cells in a dose-dependent manner²³Obchoei S, Detarya M et al. Low dose berberine suppresses cholangiocarcinoma cell progression as a multi-kinase inhibitor. Asian Pacific Journal of Cancer Prevention. 2022;23(10):3379-3386. 

Liver cancer:

• Smaller tumor volume among animals with liver cancer treated with berberine in a meta-analysis of 4 preclinical studies²⁴Xu J, Long Y et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):589. 
• Greater tumor response to sorafenib among mice with hepatocellular carcinoma treated with berberine²⁵Cheng CS, Tan HY et al. Berberine suppresses metastasis and recurrence of hepatocellular carcinoma by targeting circulating tumour cells: abridged secondary publication. Hong Kong Medical Journal. 2022;28 Suppl 6(6):10-11.
• Anticancer activity in mice with non-alcoholic steatohepatitis-derived hepatocellular carcinoma treated with berberine²⁶Luo Y, Tian G et al. Berberine prevents non-alcoholic steatohepatitis-derived hepatocellular carcinoma by inhibiting inflammation and angiogenesis in mice. American Journal of Translational Research. 2019 May 15;11(5):2668-2682.
• Anticancer activity in liver cancer cells treated with berberine²⁷Du H, Gu J et al. Berberine suppresses EMT in liver and gastric carcinoma cells through combination with TGFβR regulating TGF-β/Smad pathway. Oxidative Medicine and Cellular Longevity. 2021;2021:2337818; Vishnoi K, Ke R et al. Berberine represses β-catenin translation involving 4E-BPs in hepatocellular carcinoma cells. Molecular Pharmacology. 2021;99(1):1-16; Shukla S, Rizvi F, Raisuddin S, Kakkar P. FoxO proteins’ nuclear retention and BH3-only protein Bim induction evoke mitochondrial dysfunction-mediated apoptosis in berberine-treated HepG2 cells. Free Radical Biology & Medicine. 2014 Nov;76:185-99; Wang N, Zhu M et al. Berberine-induced tumor suppressor p53 up-regulation gets involved in the regulatory network of MIR-23a in hepatocellular carcinoma. Biochimica et Biophysica Acta. 2014 Sep;1839(9):849-57; Yang X, Huang N. Berberine induces selective apoptosis through the AMPK‑mediated mitochondrial/caspase pathway in hepatocellular carcinoma. Molecular Medicine Reports. 2013 Aug;8(2):505-10; Hou Q, Tang X et al. Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147. Cancer Science. 2011 Jul;102(7):1287-92; Wang N, Feng Y et al. Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism. Journal of Cellular Biochemistry. 2010 Dec 15;111(6):1426-36; Tai CJ, Jassey A et al. Targeting autophagy augments BBR-mediated cell death in human hepatoma cells harboring hepatitis C virus RNA. Cells. 2020;9(4):908. 
• Less hepatoma cell invasion in cells treated with berberine²⁸Liu B, Wang G et al. Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes. PLoS One. 2011;6(6):e21416.
• Greater sensitization to radiotherapy (x-rays)²⁹Ramesh G, Das S, Bola Sadashiva SR. Berberine, a natural alkaloid sensitizes human hepatocarcinoma to ionizing radiation by blocking autophagy and cell cycle arrest resulting in senescence. Journal of Pharmacy and Pharmacology. 2020;72(12):1893-1908. or gamma radiation³⁰Hur JM, Hyun MS, Lim SY, Lee WY, Kim D. The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. Journal of Cellular Biochemistry. 2009 Aug 1;107(5):955-64. in hepatoma cells treated with berberine

Stomach cancer:

• Smaller tumor weight and a very weak trend toward smaller volume among animals with gastric cancer treated with berberine in a meta-analysis of 2 preclinical studies³¹Xu J, Long Y et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):589.
• Berberine inhibits gastric cancer development and progression in cells and mice.³²Xu M, Ren L et al. Berberine inhibits gastric cancer development and progression by regulating the JAK2/STAT3 pathway and downregulating IL-6. Life Sciences. 2022;290:120266.
• Anticancer activity in gastric cancer cells treated with berberine³³Du H, Gu J et al. Berberine suppresses EMT in liver and gastric carcinoma cells through combination with TGFβR regulating TGF-β/Smad pathway. Oxidative Medicine and Cellular Longevity. 2021;2021:2337818; Zhang Q, Wang X et al. Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways. Biomedical Pharmacotherapy. 2020;128:110245.

Gynecological cancer

Ovarian cancer is listed separately.

Cervical cancer:

• Berberine inhibited cervical cancer cell viability, migration, and invasion³⁴Liu L, Sun L, Zheng J, Cui L. Berberine modulates Keratin 17 to inhibit cervical cancer cell viability and metastasis. Journal of Receptor and Signal Transductor Research. 2021;41(6):521-531.
• Less resistance to radiotherapy in cervical cancer cells treated with berberine³⁵Zeng X, Wan L et al. Effect of low dose of berberine on the radioresistance of cervical cancer cells via a PI3K/HIF-1 pathway under nutrient-deprived conditions. International Journal of Radiation Biology. 2020;96(8):1060-1067.

Endometrial cancer:

• Smaller tumor volume among animals with endometrial carcinoma treated with berberine in a meta-analysis of 2 preclinical studies³⁶Xu J, Long Y et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):589. 
• Berberine inhibited the proliferation and metastasis of endometrial cancer cells and promoted apoptosis³⁷Liang H, Liu Y, Fu L, Li L, Gong N. Berberine inhibits the development of endometrial cancer through circ_ZNF608/miR-377-3p/COX2 axis. Autoimmunity. 2022;55(7):485-495.

Head, neck, and oral cancer

• Smaller tumor volume among animals with nasopharyngeal carcinoma treated with berberine in a meta-analysis of 3 preclinical studies³⁸Xu J, Long Y et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):589. 
• Smaller tumor volume among animals with tongue squamous carcinoma treated with berberine in a preclinical study³⁹Ho YT, Yang JS et al. Berberine inhibits human tongue squamous carcinoma cancer tumor growth in a murine xenograft model. Phytomedicine. 2009 Sep;16(9):887-90. 
• Anticancer activity in nasopharyngeal cells treated with berberine hydrochloride⁴⁰Li CH, Wu DF et al. Berberine hydrochloride impact on physiological processes and modulation of twist levels in nasopharyngeal carcinoma CNE-1 cells. Asian Pacific Journal of Cancer Prevention. 2014;15(4):1851-7. 
• Less metastasis of nasopharyngeal carcinoma in cells treated with berberine⁴¹Tang F, Wang D et al. Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting Rho kinase-mediated Ezrin phosphorylation at threonine 567. Journal of Biological Chemistry. 2009 Oct 2;284(40):27456-66. 
• Anticancer activity in KB oral cancer cells treated with berberine⁴²Kim JS, Oh D et al. Berberine induces FasL-related apoptosis through p38 activation in KB human oral cancer cells. Oncology Reports. 2015 Apr;33(4):1775-82; Kuo CL, Chi CW, Liu TY. Modulation of apoptosis by berberine through inhibition of cyclooxygenase-2 and Mcl-1 expression in oral cancer cells. In Vivo. 2005 Jan-Feb;19(1):247-52. 

Leukemia

• Anticancer activity in chronic lymphocytic leukemia cells treated with berberine⁴³Abdollahi M, Mohammadlou M et al. Anti-tumor effect of berberine on chronic lymphocytic leukemia cells. Medical Oncology. 2022;39(12):217; Ravera S, Ghiotto F et al. Berberine affects mitochondrial activity and cell growth of leukemic cells from chronic lymphocytic leukemia patients. Scientific Reports. 2020;10(1):16519; Mohammadlou M, Abdollahi M et al. Apoptotic effect of berberine via Bcl-2, ROR1, and mir-21 in patients with B-chronic lymphocytic leukemia. Phytotherapy Research. 2021;35(4):2025-2033. 
• Anticancer activity in acute lymphocytic leukemia cells treated with berberine⁴⁴Liu J, Liu P et al. Berberine induces autophagic cell death in acute lymphoblastic leukemia by inactivating AKT/mTORC1 signaling. Drug Design, Development and Therapy. 2020;14:1813-1823; Liu J, Chen Z et al. Berberine promotes XIAP-mediated cells apoptosis by upregulation of miR-24-3p in acute lymphoblastic leukemia. Aging (Albany NY). 2020;12(4):3298-3311.
• Anticancer activity in P-53-null leukemic cells treated with berberine⁴⁵Liu J, Zhu Z et al. MDM2 inhibition-mediated autophagy contributes to the pro-apoptotic effect of berberine in p53-null leukemic cells. Life Sciences. 2020;242:117228.
• Anticancer activity in Jurkat leukemic cells treated with berberine⁴⁶Hu S, Chen CW et al. Inhibitory effect of berberine on interleukin-2 secretion from PHA-treated lymphocytic Jurkat cells. International Immunopharmacology. 2019 Jan;66:267-273. 
• Anticancer activity in promyelocytic leukemia cells treated with berberine⁴⁷Okubo S, Uto T et al. Berberine induces apoptotic cell death via activation of caspase-3 and -8 in HL-60 human leukemia cells: nuclear localization and structure-activity relationships. American Journal of Chinese Medicine. 2017;45(7):1497-1511; Lin CC, Kao ST, Chen GW, Ho HC, Chung JG. Apoptosis of human leukemia HL-60 cells and murine leukemia WEHI-3 cells induced by berberine through the activation of caspase-3. Anticancer Research. 2006 Jan-Feb;26(1A):227-42; Lin CC, Lin SY et al. Down-regulation of cyclin B1 and up-regulation of Wee1 by berberine promotes entry of leukemia cells into the G2/M-phase of the cell cycle. Anticancer Research. 2006 Mar-Apr;26(2A):1097-104.

Lung cancer

• Anticancer activity and prolonged survival of non-small cell lung cancer tumor-bearing mice treated with berberine⁴⁸Ni L, Li Z et al. Berberine inhibits non-small cell lung cancer cell growth through repressing DNA repair and replication rather than through apoptosis. Clinical and Experimental Pharmacology and Physiology. 2022;49(1):134-144.
• Smaller tumor volume and weight among animals with lung cancer treated with berberine in a meta-analysis of 8 preclinical studies⁴⁹Xu J, Long Y et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):589. 
• Anticancer activity in non-small cell lung cancer cells treated with berberine⁵⁰Kumar R, Awasthi M, Sharma A, Padwad Y, Sharma R. Berberine induces dose-dependent quiescence and apoptosis in A549 cancer cells by modulating cell cyclins and inflammation independent of mTOR pathway. Life Sciences. 2020;244:117346; Chen J, Huang X et al. Berberine chloride suppresses non-small cell lung cancer by deregulating Sin3A/TOP2B pathway in vitro and in vivo. Cancer Chemotherapy and Pharmacology. 2020;86(1):151-161. 
• Less acquired resistance to osimertinib therapy among mice with non-small cell lung cancer xenografts treated with berberine⁵¹Chen Z, Vallega KA et al. The natural product berberine synergizes with osimertinib preferentially against MET-amplified osimertinib-resistant lung cancer via direct MET inhibition. Pharmacological Research. 2022;175:105998.
• Less icotinib resistance in non-small cell lung cancer cells and mice treated with berberine⁵²Chen P, Dai CH et al. Synergistic inhibitory effect of berberine and icotinib on non-small cell lung cancer cells via inducing autophagic cell death and apoptosis. Apoptosis. 2021;26(11-12):639-656.
• Enhanced effects of doxorubicin against lung adenocarcinoma cells treated with extracts of Mahonia aquifolium, whose main constituents are berberine and protoberberine alkaloids⁵³Damjanović A, Kolundžija B et al. Mahonia aquifolium extracts promote doxorubicin effects against lung adenocarcinoma cells in vitro. Molecules. 2020;25(22):5233. 
• Enhanced anticancer effects from radiation in non-small-cell lung cancer cells treated with berberine⁵⁴Peng PL, Kuo WH, Tseng HC, Chou FP. Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: the contribution of autophagic cell death. International Journal of Radiation Oncology, Biology, Physics. 2008 Feb 1;70(2):529-42.
• Enhanced effects of paclitaxel (Taxol), fluorouracil (5-FU), and camptothecin against human non-small cell lung cancer cell growth⁵⁵He C, Rong R et al. Effects of Coptis extract combined with chemotherapeutic agents on ROS production, multidrug resistance, and cell growth in A549 human lung cancer cells. Chinese Medicine. 2012 Apr 30;7(1):11. 

Lymphoma

• Anticancer activity in diffuse large B-cell lymphoma cells treated with berberine⁵⁶Ren S, Cai Y et al. Berberine exerts anti-tumor activity in diffuse large B-cell lymphoma by modulating c-myc/CD47 axis. Biochemical Pharmacology. 2021;188:114576.

Melanoma

• Anticancer activity in melanoma cells treated with berberine⁵⁷Palma TV, Bianchin NB et al. Berberine increases the expression of cytokines and proteins linked to apoptosis in human melanoma cells. Molecular Biology Reports. 2022;49(3):2037-2046; Lee Y, Liu L, Yi Y. Inhibitory effect of berberine from Coptidis rhizoma on melanin synthesis of murine malignant melanoma. Pharmazie. 2018;73(5):300-303.
• Differing effects depending on the dose in  melanoma cells treated with berberine⁵⁸Serafim TL, Oliveira PJ et al. Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line. Cancer Chemotherapy and Pharmacology. 2008 May;61(6):1007-18.

Mesothelioma

• Anticancer activity in malignant pleural mesothelioma cells treated with berberine⁵⁹Yao Z, Wan Y et al. Berberine induces mitochondrial‑mediated apoptosis and protective autophagy in human malignant pleural mesothelioma NCI‑H2452 cells. Oncology Reports. 2018 Dec;40(6):3603-3610. 

Multiple myeloma

• Anticancer activity and longer survival of mice bearing multiple myeloma xenografts treated with berberine⁶⁰Gu C, Yin Z et al. Identification of berberine as a novel drug for the treatment of multiple myeloma via targeting UHRF1. BMC Biology. 2020;18(1):33.
• Anticancer activity in multiple myeloma cells treated with berberine⁶¹Hu HY, Li KP et al. Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells. Acta Pharmacological Sinica. 2013 Jan;34(1):157-66. 
• Less cell proliferation and synergism with bortezomib in multiple myeloma cells treated with berberine⁶²Li C, Su R et al. Discovery of the oncogenic MDM2, a direct binding target of berberine and a potential therapeutic, in multiple myeloma. Functional & Integrative Genomics. 2022;22(5):1031-1041. 

Ovarian cancer

• Less chemotherapy-exacerbated ovarian cancer metastasis in cells treated with berberine⁶³Zhao Y, Yang X et al. Berberine inhibits chemotherapy-exacerbated ovarian cancer stem cell-like characteristics and metastasis through GLI1. European Journal of Pharmacology. 2021;895:173887.
• Anticancer activity in ovarian cancer cells treated with berberine, whether with or without cisplatin⁶⁴Liu L, Fan J et al. Berberine in combination with cisplatin induces necroptosis and apoptosis in ovarian cancer cells. Biological Research. 2019 Jul 18;52(1):37. 
• Less proliferation, migration and invasion of ovarian cancer cells treated with berberine⁶⁵Li J, Zhang S, Wu L, Pei M, Jiang Y. Berberine inhibited metastasis through miR-145/MMP16 axis in vitro. Journal of Ovarian Research. 2021;14(1):4.
• Less motility and invasiveness of ovarian cancer cells treated with berberine⁶⁶Chuang TC, Wu K et al. Dual down-regulation of EGFR and ErbB2 by berberine contributes to suppression of migration and invasion of human ovarian cancer cells. Environmental Toxicology. 2021;36(5):737-747.

Pancreatic cancer

• Anticancer activity in pancreatic cancer cells treated with berberine⁶⁷Liu J, Luo X, Guo R, Jing W, Lu H. Cell metabolomics reveals berberine-inhibited pancreatic cancer cell viability and metastasis by regulating citrate metabolism. Journal of Proteome Research. 2020;19(9):3825-3836; Agnarelli A, Natali M et al. Cell-specific pattern of berberine pleiotropic effects on different human cell lines. Scientific Reports. 2018 Jul 13;8(1):10599.

Prostate cancer

• Anticancer effects in prostate cancer cells treated with berberine⁶⁸Huang ZH, Zheng HF et al. Berberine targets epidermal growth factor receptor signaling to suppress prostate cancer proliferation in vitro. Molecular Medicine Reports. 2015;11(3):2125-2128; Choi MS, Oh JH et al. Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells. International Journal of Oncology. 2009 May;34(5):1221-30; Mantena SK, Sharma SD, Katiyar SK. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Molecular Cancer Therapeutics. 2006 Feb;5(2):296-308.

Sarcoma

• Smaller tumor weight among animals with sarcoma treated with berberine in a preclinical study⁶⁹Zhang L, Li J et al. Synthesis and cytotoxicity evaluation of 13-n-alkyl berberine and palmatine analogues as anticancer agents. Molecules. 2012 Sep 25;17(10):11294-302. 
• Anticancer effects in osteosarcoma cells treated with berberine, whether alone or with cisplatin⁷⁰Gao X, Zhang C et al. Berberine and cisplatin exhibit synergistic anticancer effects on osteosarcoma MG-63 cells by inhibiting the MAPK pathway. Molecules. 2021;26(6):1666; Mishra R, Nathani S, Varshney R, Sircar D, Roy P. Berberine reverses epithelial-mesenchymal transition and modulates histone methylation in osteosarcoma cells. Molecular Biology Reports. 2020;47(11):8499-8511; Liu Z, Liu Q et al. Berberine induces p53-dependent cell cycle arrest and apoptosis of human osteosarcoma cells by inflicting DNA damage. Mutation Research. 2009 Mar 9;662(1-2):75-83.
• Enhanced radiosensitivity of osteosarcoma cells treated with berberine⁷¹Wang D, Zhang KF, Du G, Wang J, Zhao J. Berberine enhances the radiosensitivity of osteosarcoma by targeting Rad51 and epithelial-mesenchymal transition. Journal of Cancer Research and Therapeutics. 2020;16(2):215-221.

Berberine combined with other therapies

Berberine and benzoic acid

• Anticancer activity in hepatocarcinoma cells treated with extracts of Berberis lycium royle, major compounds of which include berberine and benzoic acid⁷²Mustafa K, Mohamed H et al. In vitro anticancer potential of Berberis lycium royle extracts against human hepatocarcinoma (HepG2) cells. Biomedical Research International. 2020;2020:8256809.

Berberine and costunolide

• Anticancer effects in hepatoma cells treated with berberine and costunolide⁷³Si H, Genna B et al. DaHuangWan targets EGF signaling to inhibit the proliferation of hepatoma cells. PLoS One. 2020;15(4):e0231466.

Berberine and curcumin

• Stronger anticancer activity in breast cancer cells treated with berberine and curcumin in addition to 5-fluorouracil compared to 5-fluorouracil alone⁷⁴Ziasarabi P, Sahebkar A, Ghasemi F. Evaluation of the effects of nanomicellar curcumin, berberine, and their combination with 5-fluorouracil on breast cancer cells. Advances in Experimental Medicine and Biology. 2021;1328:21-35. 

Berberine and d-limonene

• Anticancer effects among gastric carcinoma cells treated with berberine and d-limonene⁷⁵Zhang XZ, Wang L, Liu DW, Tang GY, Zhang HY. Synergistic inhibitory effect of berberine and d-limonene on human gastric carcinoma cell line MGC803. Journal of Medicinal Food. 2014 Sep;17(9):955-62.

Berberine and emodin

• Anticancer activity in breast cancer cells treated with berberine and emodin⁷⁶Ponnusamy L, Kothandan G, Manoharan R. Berberine and emodin abrogates breast cancer growth and facilitates apoptosis through inactivation of SIK3-induced mTOR and Akt signaling pathway. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease. 2020;1866(11):165897.

Berberine and evodiamine

• Anticancer activity in melanoma cells treated with berberine chloride and evodiamine ethosomes⁷⁷Lin H, Lin L, Choi Y, Michniak-Kohn B. Development and in-vitro evaluation of co-loaded berberine chloride and evodiamine ethosomes for treatment of melanoma. International Journal of Pharmacology. 2020;581:119278.
• Anticancer activity and fewer side effects in colorectal cancer cells treated with berberine and evodiamine⁷⁸Guan X, Zheng X et al. Combined effects of berberine and evodiamine on colorectal cancer cells and cardiomyocytes in vitro. European Journal of Pharmacology. 2020;875:173031.
• Anticancer activity in hepatocellular carcinoma cells treated with berberine and evodiamine⁷⁹Wang XN, Han X et al. Enhancement of apoptosis of human hepatocellular carcinoma SMMC-7721 cells through synergy of berberine and evodiamine. Phytomedicine. 2008 Dec;15(12):1062-8.

Berberine and exercise

• Slower progression of breast cancer in mice treated with both berberine and exercise⁸⁰Ma W, Zhang Y et al. In-vitro and in-vivo anti-breast cancer activity of synergistic effect of berberine and exercise through promoting the apoptosis and immunomodulatory effects. [published correction appears in International Immunopharmacology. 2020 Aug 19;88:106899]. International Immunopharmacology. 2020;87:106787.

Berberine and galangin

• Smaller tumor volume among animals with esophageal cancer treated with berberine and galangin in a preclinical study⁸¹Ren K, Zhang W et al. Synergistic anti-cancer effects of galangin and berberine through apoptosis induction and proliferation inhibition in oesophageal carcinoma cells. Biomedicine & Pharmacotherapy. 2016 Dec;84:1748-1759. 

Berberine and gefinitib

• Anticancer activity in non‐small‐cell lung cancer cells treated with berberine and gefitinib⁸²Zheng F, Li J et al. Novel regulation of miR-34a-5p and HOTAIR by the combination of berberine and gefitinib leading to inhibition of EMT in human lung cancer. Journal of Cellular and Molecular Medicine. 2020;24(10):5578-5592.

Berberine and lapatinib

• Lapatinib and berberine enhanced Akt signaling and decreased triple-negative breast cancer cell proliferation in cell studies⁸³Jabbarzadeh Kaboli P, Luo S et al. Pharmacotranscriptomic profiling of resistant triple-negative breast cancer cells treated with lapatinib and berberine shows upregulation of PI3K/Akt signaling under cytotoxic stress. Gene. 2022;816:146171.

Berberine and palmatine

• Anticancer effects in rhabdomyosarcoma cells treated with berberine and palmatine⁸⁴Shinji S, Nakamura S, Nihashi Y, Umezawa K, Takaya T. Berberine and palmatine inhibit the growth of human rhabdomyosarcoma cells. Bioscience, Biotechnology, and Biochemistry. 2020;84(1):63-75.

Berberine photodynamic therapy

• Berberine photosensitized cervical cancer cells to enhance the response to photodynamic therapy⁸⁵Oliveira PM, Lopes TZ, Tedesco AC, Rahal P, Calmon MF. Effect of berberine associated with photodynamic therapy in cell lines. Photodiagnosis and Photodynamic Therapy. 2020;32:102045.
• Berberine photodynamic therapy sensitized melanoma cells to cisplatin⁸⁶Wang X, Gong Q et al. Berberine-photodynamic therapy sensitizes melanoma cells to cisplatin-induced apoptosis through ROS-mediated P38 MAPK pathways. Toxicology and Applied Pharmacology. 2021;418:115484.
• Anticancer activity in renal carcinoma cells treated with berberine associated photodynamic therapy⁸⁷Lopes TZ, de Moraes FR et al. Berberine associated photodynamic therapy promotes autophagy and apoptosis via ROS generation in renal carcinoma cells [published correction appears in Biomedicine & Pharmacotherapy. 2020 May;125:110038] [published correction appears in Biomedicine & Pharmacotherapy. 2021 Apr;136:111175]. Biomedicine & Pharmacotherapy. 2020;123:109794.
• Anticancer activity in cervical carcinoma cells treated with berberine and photodynamic therapy⁸⁸Floriano BF, Carvalho T et al. Effect of berberine nanoemulsion photodynamic therapy on cervical carcinoma cell line. Photodiagnosis and Photodynamic Therapy. 2021;33:102174.

Berberine and resveratrol

• Lower viability of hepatocellular cancer cells treated with berberine and resveratrol⁸⁹Skonieczna M, Adamiec-Organisciok M et al. Hepatocellular cancer cell lines, Hep-3B and Hep-G2 display the pleiotropic response to resveratrol and berberine. Advances in Medical Sciences. 2022;67(2):379-385; D’Arcy MS, Pike CVS, Coussons PJ. A novel combined resveratrol/berberine phytochemotherapeutic using the HePG2 cell line as a model for the treatment of hepatocarcinoma. Cellular Biology International. 2021;45(12):2499-2509. 

Berberine and vincristine

• Anticancer effects in hepatoma cells treated with berberine and vincristine⁹⁰Wang L, Wei D et al. The combinational effect of vincristine and berberine on growth inhibition and apoptosis induction in hepatoma cells. Journal of Cellular Biochemistry. 2014 Apr;115(4):721-30.

Preclinical evidence for managing side effects

Animal studies have found that berberine reduces neuropathy from paclitaxel,⁹¹Rezaee R, Monemi A, SadeghiBonjar MA, Hashemzaei M. Berberine alleviates paclitaxel-induced neuropathy. Journal of Pharmacopuncture. 2019 Jun;22(2):90-94; Singh J, Saha L et al. Study of nuclear factor-2 erythroid related factor-2 activator, berberine, in paclitaxel induced peripheral neuropathy pain model in rats. Journal of Pharmacy and Pharmacology. 2019 May;71(5):797-805. although whether by reducing paclitaxel’s effect or not was not clear. Also see evidence that berberine reduces the effectiveness of these drugs in gastric cancer in Safety and precautions ›

Berberine derivatives and formulations

“There are significant barriers to the absorption of berberine. Microemulsions, liposomes, micelles, and other nanoparticles have been used as part of the nanoparticle drug delivery system in recent years to boost the bioavailability of berberine.”⁹²Samadi P, Sarvarian P, Gholipour E, et al. Berberine: a novel therapeutic strategy for cancer. IUBMB Life. 2020;72(10):2065-2079. We report here that research using berberine derivatives and formulations is finding better treatment effects than with berberine and that they may be a promising new treatment in the future.

We have not found that these derivatives and formulations are currently available outside research studies, nor could we find berberine derivatives for cancer treatment mentioned in any of the clinical practice guidelines or programs that we consulted. 

Preclinical evidence for derivatives and formulations improving treatment outcomes

Brain and nervous system cancer

• Salt modifications enhanced the anticancer effects of berberine in glioblastoma astrocytoma cells⁹³Xu F, Liu M et al. Improvement of anticancer effect of berberine by salt formation modifications. Phytomedicine. 2022;104:154314.
• Better anticancer effects in glioma cells and better solubility and stability of glucose-coated berberine nanoparticles compared to berberine water nanoparticles⁹⁴Wang S, An J et al. Glucose-coated berberine nanodrug for glioma therapy through mitochondrial pathway. International Journal of Nanomedicine. 2020;15:7951-7965.

Breast cancer

• Stronger anticancer activity in breast cancer cells treated with berberine derivatives compared to berberine⁹⁵Wang ZC, Wang J et al. Synthesis and anticancer activity of novel 9,13-disubstituted berberine derivatives. Bioorganic & Medicinal Chemistry Letters. 2020;30(2):126821.
• Anticancer activity in breast cancer stem cells and mice treated with targeting berberine liposomes⁹⁶Ma X, Zhou J et al. Modulation of drug-resistant membrane and apoptosis proteins of breast cancer stem cells by targeting berberine liposomes. Biomaterials. 2013 Jun;34(18):4452-65. 

Colorectal cancer

• Anticancer activity in colorectal cancer cells treated with the berberine analogue 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium chloride (B-12)⁹⁷Xu B, Jiang X et al. Structure-activity relationship study enables the discovery of a novel berberine analogue as the RXRα activator to inhibit colon cancer. Journal of Medicinal Chemistry. 2020;63(11):5841-5855.
• Stronger anticancer activity in colon cancer cells treated with berberine derivatives compared to berberine⁹⁸Wang ZC, Wang J et al. Synthesis and anticancer activity of novel 9,13-disubstituted berberine derivatives. Bioorganic & Medicinal Chemistry Letters. 2020;30(2):126821.
• Anticancer effects in  colon cancer cells treated with zinc nanoparticles biosynthesized with berberine⁹⁹Othman MS, Al-Bagawi AH et al. Antitumor activity of zinc nanoparticles synthesized with berberine on human epithelial colorectal adenocarcinoma (Caco-2) cells through acting on Cox-2/NF-kB and p53 pathways. Anti-cancer Agents in Medicinal Chemistry. 2022;22(10):2002-2010.

Liver cancer

• Salt modifications enhanced the anticancer effects of berberine in liver cancer cells¹⁰⁰Xu F, Liu M et al. Improvement of anticancer effect of berberine by salt formation modifications. Phytomedicine. 2022;104:154314.
• Anticancer activity in hepatocellular carcinoma cells treated with coptisine¹⁰¹Kim SY, Hwangbo H et al. Coptisine induces autophagic cell death through down-regulation of PI3K/Akt/mTOR signaling pathway and up-regulation of ROS-mediated mitochondrial dysfunction in hepatocellular carcinoma Hep3B cells. Archives of Biochemistry and Biophysics. 2021;697:108688.

Lung cancer

• Anticancer activity in non-small-cell lung cancer cells treated with the berberine derivatives 9-O-decylberberrubine bromide (B6) and 9-O-dodecylberberrubine bromide (B7),¹⁰²Chang JM, Kam KH et al. Berberine derivatives suppress cellular proliferation and tumorigenesis in vitro in human non-small-cell lung cancer cells. International Journal of Molecular Sciences. 2020;21(12):4218. or 9-O-gernylberberrubine bromide (B4) and 9-O-farnesylberberrubine bromide (B5)¹⁰³Chang JM, Wu JY et al. 9-O-terpenyl-substituted berberrubine derivatives suppress tumor migration and increase anti-human non-small-cell lung cancer activity. International Journal of Molecular Sciences. 2021;22(18):9864.  
• Salt modifications enhanced the anticancer effects of berberine in lung cancer cells ¹⁰⁴Xu F, Liu M et al. Improvement of anticancer effect of berberine by salt formation modifications. Phytomedicine. 2022;104:154314.
• Anticancer activity and inhibition of invasion or migration in non-small cell lung cancer cells treated with berberine-loaded liquid crystalline nanoparticles¹⁰⁵Paudel KR, Mehta M et al. Berberine-loaded liquid crystalline nanoparticles inhibit non-small cell lung cancer proliferation and migration in vitro. Environmental Science and Pollution Research International. 2022;29(31):46830-46847.
• Anticancer activity in mice with lung cancer treated with berberine-loaded chitosan nanoparticles¹⁰⁶Mahmoud MA, El-Bana MA et al. Synthesis and characterization of berberine-loaded chitosan nanoparticles for the protection of urethane-induced lung cancer. International Journal of Pharmaceutics. 2022;618:121652.
• Anticancer activity in adenocarcinomic human alveolar basal epithelial cells treated with berberine monoolein loaded liquid crystalline nanoparticles¹⁰⁷Mehta M, Malyla V et al. Berberine loaded liquid crystalline nanostructure inhibits cancer progression in adenocarcinomic human alveolar basal epithelial cells in vitro. Journal of Food Biochemistry. 2021;45(11):e13954.
• Stronger anticancer effects in lung cancer cells treated with a GSH-responsive paclitaxel-ss-berberine conjugate compared to paclitaxel alone¹⁰⁸Cheng Y, Ji Y. Mitochondria-targeting nanomedicine self-assembled from GSH-responsive paclitaxel-ss-berberine conjugate for synergetic cancer treatment with enhanced cytotoxicity. Journal of Controlled Release. 2020;318:38-49.
• Anticancer activity against non-small lung cancer in cells and animals treated with berberine derivative 8-cetylberberine (HBBR)¹⁰⁹Xiao Y, Tian C et al. 8-Cetylberberine inhibits growth of lung cancer in vitro and in vivo. Life Sciences. 2018;192:259-269.

Melanoma and other skin cancer

• Salt modifications enhanced the anticancer effects of berberine in melanoma cancer cells and animals with melanoma¹¹⁰Xu F, Liu M et al. Improvement of anticancer effect of berberine by salt formation modifications. Phytomedicine. 2022;104:154314.
• Less cell migration and invasion in in skin cancer cells treated with 13-butoxyberberine bromide compared to berberine¹¹¹Laomethakorn P, Tayeh M, Samosorn S, Tananyuthawongse C, Watanapokasin R. 13-butoxyberberine bromide inhibits migration and invasion in skin cancer A431 cells. Molecules. 2023;28(3):991. 

Prostate cancer

• Stronger anticancer activity in prostate cancer cells treated with berberine derivatives compared to berberine¹¹²Wang ZC, Wang J et al. Synthesis and anticancer activity of novel 9,13-disubstituted berberine derivatives. Bioorganic & Medicinal Chemistry Letters. 2020;30(2):126821.

Berberine derivatives and formulations in combination with other therapies

Berberine with 10-HCPT microsphere

• Better anticancer activity in liver cancer cells or mice with liver cancer treated with 10-HCPT-BBR-loaded lipid microsphere compared to unmodified 10-HCPT or berberine alone¹¹³Qi Y, Liu G. Berberine-10-hydroxycamptothecin-loaded lipid microsphere for the synergistic treatment of liver cancer by inhibiting topoisomerase and HIF-1α. Drug Delivery. 2021;28(1):171-182.

Berberine derivative nanoparticle formulation combined with photodynamic and photothermal therapies

• Anticancer activity in breast cancer cells and animals with breast cancer treated with ABH, a berberine derivative nanoparticle formulation combined with photodynamic and photothermal therapies¹¹⁴Li RT, Chen M et al. AIE-based gold nanostar-berberine dimer nanocomposites for PDT and PTT combination therapy toward breast cancer. Nanoscale. 2022;14(27):9818-9831.

Berberine and doxorubicin nanodrug

• Anticancer effects, including less pulmonary metastasis in mice with breast cancer treated with a self-assembled nanodrug comprising doxorubicin and berberine¹¹⁵Zheng X, Zhao Y et al. Biomimetic co-assembled nanodrug of doxorubicin and berberine suppresses chemotherapy-exacerbated breast cancer metastasis. Biomaterials. 2021;271:120716.

Berberine with folic acid derivatives and paclitaxel liposome

• Anticancer activity in glioma cells treated with intelligent and tumor microenvironment (TME)-responsive folic acid derivatives and mitochondria-targeting berberine derivatives co-modified liposome coated with Tween 80 loading paclitaxel to improve penetration of the blood-brain barrier¹¹⁶Yang C, Yang Z et al. Berberine and folic acid co-modified pH-sensitive cascade-targeted PTX-liposomes coated with Tween 80 for treating glioma. Bioorganic & Medicinal Chemistry. 2022;69:116893.

Berberine and jatrorrhizine derivatives

• Anticancer activity in bladder tumor cells treated with jatrorrhizine and berberine derivatives¹¹⁷Qin QP, Wang ZF et al. Two telomerase-targeting Pt(ii) complexes of jatrorrhizine and berberine derivatives induce apoptosis in human bladder tumor cells. Dalton Transactions. 2019 Oct 14;48(40):15247-15254

Liposomal berberine and mitoxantrone 

• Less tumor growth and less cardiotoxicity in mice with breast cancer treated with mitoxantrone and berberine co-encapsulated liposomes compared to a liposomal formulation of mitoxantrone¹¹⁸Yang Z, Zhao L, Wang X, He Z, Wang Y. Ratiometric delivery of mitoxantrone and berberine co-encapsulated liposomes to improve antitumor efficiency and decrease cardiac toxicity. AAPS PharmSciTech. 2021;22(1):46. 

Berberine and phytantriol nanoparticles

• Anticancer activity in non-small-cell lung cancer cells treated with berberine–phytantriol-loaded liquid crystalline nanoparticles¹¹⁹Alnuqaydan AM, Almutary AG et al. Evaluation of the cytotoxic activity and anti-migratory effect of berberine-phytantriol liquid crystalline nanoparticle formulation on non-small-cell lung cancer in vitro. Pharmaceutics. 2022 May 24;14(6):1119.

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