Hormetic Effect of Berberine May Attenuate the Anticancer Activity of Chemotherapeutic Agents

Depending on Dosage

Rhizoma coptidis is a highly valued traditional Chinese medicine which has been widely applied in complementary and alternative medicines in China, Korea, India, Japan, and other Asian countries, especially for the treatment of dysentery, cancer, diabetes mellitus, and eczema, mostly used in formulas (Tang, et al., 2009). Berberine is one of the major active components of Rhizoma coptidis, which is an isoquinoline alkaloid with abundant pharmacological activities (Lu et al., 2012). 

As with all medicines, dosing is critical, none more so than with botanicals. Many botanicals are bi-directional that is, they may have opposite effects at low or at high dose. This is called hormesis and is the phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. 

Results published by Bao et al., (2015) demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, they observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways.  These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

Berberine hydrochloride has been approved by China Food and Drug Administration as anti-dysentery drug for many years. In recent years, berberine has been demonstrated significant anticancer activities in various types of cancer (Jabbarzadeh Kaboli, et al., 2014; Ortiz, et al., 201. Moreover, berberine also showed synergistic anticancer effects in combination treatment of cancer with chemotherapeutic agents (Tong, et al., 2012) or radiotherapy (Zhang, et al., 2014). The encouraging results of studies suggest that berberine might have potential to be developed as an effective adjuvant anticancer agent.

It was shown that Coptidis Rhizoma extract and berberine may repress tumor progression by regressing abnormal cell proliferation, arresting cell cycle and inducing cell death. Studies also highlighted the actions of Coptidis Rhizoma extract and berberine in inhibiting tumor cell invasion and angiogenesis, which in turn abolish cancer metastasis. 

Some studies have also been conducted to reveal the potential effect of Coptidis Rhizoma extract and berberine in regulating tumor stromal microenvironment, as well as in preventing carcinogenesis. Most of the results have been demonstrated with in vivo models, but results of high-quality clinical trials are not yet available (Wang et al., 2015)


Bao J, Huang B, Zou L, et al. PLoS One. 2015; 10(9): e0139298. doi:  10.1371/journal.pone.0139298


Jabbarzadeh Kaboli P, Rahmat A, Ismail P, Ling KH. Targets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancer. Eur J Pharmacol. 2014 Oct 5; 740():584-95.

Lu JJ, Bao JL, Chen XP, et al. Alkaloids isolated from natural herbs as the anticancer agents. Evid Based Complement Alternat Med. 2012; 2012():485042.

Ortiz LM, Lombardi P, Tillhon M, Scovassi AI. Berberine, an epiphany against cancer. Molecules. 2014 Aug 15; 19(8):12349-67.

Tong N, Zhang J, Chen Y, et al. Berberine sensitizes mutliple human cancer cells to the anticancer effects of doxorubicin in vitro. Oncol Lett. 2012 Jun; 3(6):1263-1267.

Tang J, Feng Y, Tsao S, et al. Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmacol. 2009 Oct 29; 126(1):5-17.

Wang N, Tan HY, Li L, Yuen MF, Feng Y. Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives. J Ethnopharmacol. 2015 Dec 24;176:35-48. doi: 10.1016/j.jep.2015.10.028.

Zhang Q, Zhang C, Yang X, et al. Berberine inhibits the expression of hypoxia induction factor-1alpha and increases the radiosensitivity of prostate cancer. Diagn Pathol. 2014 May 27; 9():98.

Why Most Clinical Research Is Not Useful.

Practicing doctors and other health care professionals will be familiar with how little of what they find in medical journals is useful. The term “clinical research” is meant to cover all types of investigation that address questions on the treatment, prevention, diagnosis/screening, or prognosis of disease or enhancement and maintenance of health. Experimental intervention studies (clinical trials) are the major design intended to answer such questions, but observational studies may also offer relevant evidence. “Useful clinical research” means that it can lead to a favorable change in decision making (when changes in benefits, harms, cost, and any other impact are considered) either by itself or when integrated with other studies and evidence in systematic reviews, meta-analyses, decision analyses, and guidelines.

There are many millions of papers of clinical research — approximately 1 million papers from clinical trials have been published to date, along with tens of thousands of systematic reviews — but most of them are not useful. Waste across medical research (clinical or other types) has been estimated as consuming 85% of the billions spent each year (Macleod, et al., 2014). John P. A. Ioannidis (2005) has previously written about why most published research is false and how to make more of it true

Useful research is patient centered (Mullins et al., 2014). It is done to benefit patients or to preserve health and enhance wellness, not for the needs of physicians, investigators, or sponsors. Useful clinical research should be aligned with patient priorities, the utilities patients assign to different problems and outcomes, and how acceptable they find interventions over the period for which they are indicated. Proposed surrogate outcomes used in research need to closely correlate with real patient-relevant outcomes for patients in the clinic (Ioannidis JP, 2014).

There is currently a heightened interest in patient-centered research, as exemplified by the Patient-Centered Outcomes Research Institute (PCORI), which was launched in 2012 in the United States to foster research relevant to patient needs (Selby & Lipstein, 2014). Similar activities are ongoing in the United Kingdom and elsewhere. However, patients are still rarely involved in setting research priorities, despite the frequent mismatch between patient priorities and research agenda. Patients and physicians are frequently bombarded with information that tries to convince them that surrogates or other unimportant outcomes are important—such short-cuts either have commercial benefits or facilitate fast publication and academic advancement.


Ioannidis JPA. Why Most Clinical Research Is Not Useful. PLOS Medicine | DOI:10.1371/journal.pmed.1002049 June 21, 2016


Ioannidis JP. Why most published research findings are false. PLoS Med. 2005; 2(8):e124.

Ioannidis JP. How to make more published research true. PLoS Med. 2014; 11(10):e1001747. doi: 10. 1371/journal.pmed.1001747

Macleod MR, Michie S, Roberts I, Dirnagl U, Chalmers I, et al. Biomedical research: increasing value, reducing waste. Lancet. 2014; 383(9912):101–4. doi:10.1016/S0140-6736(13)62329-6

Mullins CD, Vandigo J, Zheng Z, Wicks P. Patient-centeredness in the design of clinical trials. Value Health. 2014; 17(4):471 5. doi:10.1016/j.jval.2014.02.012

Selby JV, Lipstein SH. PCORI at 3 years–progress, lessons, and plans. N Engl J Med. 2014; 370(7):592–5. doi:10.1056/NEJMp1313061

Glucose Metabolism and Cancer

Cancer cells could predominantly produce energy by glycolysis even in the presence of oxygen. This alternative metabolic characteristic is known as the “Warburg Effect.” Although the exact mechanisms underlying the Warburg effect are unclear, recent progress indicates that glycolytic pathway of cancer cells could be a critical target for drug discovery. With a long history in cancer treatment, traditional Chinese medicine (TCM) is recognized as a valuable source for seeking bioactive anticancer compounds.

It  is  well  known  that  malignant  cells  have  accelerated  glucose  uptake  and  metabolism  in  order  to  maintain  their  fast  proliferation rates. With the increased influx of glucose into cancer cells, glycolysis is facilitated through a coordinated regulation of metabolic enzymes and pyruvate consumption.

Shifting from mitochondrial oxidative phosphorylation to glycolysis and other pathways such as pentose phosphate pathway (PPP) and denovo fatty acid synthesis in the breast tumor  provides  not  only  energy  but  also  the  materials  needed  for  cell  proliferation.  Glucose  augmentation  in  tumor  cells  can  be  due  to  the  elevated  level  of  glucose  transporter (GLUT) proteins, such  as  the  over-expression  of  GLUT 1 and  expression  of  GLUT 5 in  breast  cancers.  Moreover, other  factors  such  as  hypoxia-inducible  factor-1 (HIF-1), oestrogen  and  growth  factors  are  important  modulators  of  glucose  metabolism  in  the  progression  of  breast  carcinomas.  

Therapies  targeting  at  the  glycolytic  pathway, fatty  acid  synthesis  and  GLUTs  expression  are  currently  being  investigated. Restoring tumor cells to its normal glucose metabolic state would endow tumor specific and accessible treatment that targets glucose metabolism 


Glucose Metabolism in Breast Cancer and its Implication in Cancer Therapy. https://www.researchgate.net/publication/228469933_Glucose_Metabolism_in_Breast_Cancer_
[accessed Jun 6, 2016].