Berberine: A promising suppressor of human gastric cancer cell growth

Berberine: A promising suppressor of human gastric cancer cell growth

by Maria Abbas (BS Biotechnology)

Image: https://www.explicitsupplements.com/berberine-supplements-how-they-help-dosage-side-effects/

Cancer is a group of diseases that is common all over the world and the death rate due to cancer is increasing day by day. Gastric cancer is contributing to the most number of deaths among cancer patients. Various therapies are available and chemotherapy is most widely used but they have many harmful effects and are also less efficient. For this purpose, investigations are being done on active ingredients derived from natural sources which will have minimum side effects and high efficiency one such is berberine.

What berberine is?

Berberine is quaternary ammonium salt derived from protoberberine group of isoquinoline alkaloids (2,3–methylenedioxy-9,10-dimethoxyprotoberberine chloride; C₂₀H₁₈NO₄⁺). It is usually concentrated in rhizomes and roots of various plants. It is an active ingredient derived from Berberis vulgaris and has many important medical uses. Previously, it has also been used as anti-inflammatory, anti-diabetic and anti-bacterial against many bacterial infections. Nowadays investigations are also being done on the usage of berberine for treating various types of cancers. Berberine is less toxic as compared to other different chemicals used in chemotherapy or some other therapies.

Pathway leading to uncontrolled cell growth

The mammalian target of rapamycin (mTOR) is linked with growth factors and is an active inhibitor of autophagy. An enzyme ribosomal protein S6 kinase (p70S6K) is involved in phosphorylation of mTOR. The autophagy regulatory signalling pathways of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) are the major contributors to the evolution of the different types of cancers among mammals. Different kinases lead to the activation of mTOR. mTOR is an intracellular signalling pathway that is usually involved in the development or growth of cancer cells. Berberine work by down-regulating mTOR signalling pathway i.e. inhibiting the mTOR pathway and promoting autophagy and thus the death of cancer cells. Since mTOR/p70S6K is involved in various growth factors and inhibition of mTOR/p60S70K, reduced the growth of cancer cells. So any drug that will inhibit the mTOR/p60S70K pathway will ultimately inhibit the growth of cancer cells.

How berberine controls cancer?

Berberine works by inhibiting mTOR and phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling pathways. Since induction or in some cases inhibition of autophagy play a major role in the treatment of cancer. Among various types of therapies involved in treating cancer, cytoprotective and cytostatic autophagy are two major functional forms of autophagy. Berberine stimulates cytostatic autophagy and represses the gastric cancer cell growth.

In vitro and in vivo investigations of cytostatic autophagy induced by berberine

MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay is a colorimetric assay which is used to evaluate the metabolic activity of a cell. MTT assays used for investigation of cytotoxicity showed that berberine strongly inhibited the growth of human gastric cancer BGC-823 cell growth showing maximum toxicity to gastric cancer cell while the normal cells were inhibited weakly verifying little toxicity to them. The formation of autophagosomes after staining with monodansylcadaverine (MDC), in vivo marker for autophagic vacuoles, and autophagosomes observed by green fluorescent protein (GFP)-fused LC3 marker it was confirmed that berberine caused autophagy. The autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) and Baf-A1 inhibited autophagy which was caused by berberine in GGC-823 cells which proved the role of berberine in cancer treatment. The mTOR/p70S6K signalling pathways which are regulated by the MPAK signalling pathway usually inhibits autophagy and growth of cell and berberine inhibit that pathway promoting autophagy and thus ultimately cancerous cell death.

Future of drugs derived from herbs or natural products

As we all know that chemotherapeutic drugs have a lot of side effects and also show very little efficiency against the treatment of certain diseases. On the other hand, the drugs derived from herbs or other natural products show very little harmful effects. In this article, the role of berberine which is active isoquinoline alkaloid is highlighted. Berberine has a potential role in cancer treatment. In some cases it inhibits autophagy whilst in others promotes autophagy both to treat cancer. So there is a need to discover and investigate more such drugs which will help in the treatment of disease when chemotherapeutic drugs play no significant role. Such drugs mostly act on diseased cells/parts while showing no or very little toxicity to normal cells/parts. These active ingredients derived from herbs may also be helpful for later stages of certain diseases where chemotherapeutic drugs are usually not effective.

Author

Maria Abbas, a student of BS biotechnology, has written this article and Ms Iqra (M.Phil Biochemistry), Lecturer & Recourse Person of Biochemistry at University of Management & Technology, Sialkot, Punjab, Pakistan, has motivated and mentored her students to write article summaries.  

Reviewer &  Editor

Muhammad Numan, PhD Scholar (Biochemistry), has reviewed and edited this article.

References

Rawla, P., & Barsouk, A. (2019). Epidemiology of gastric cancer: global trends, risk factors and prevention. Przeglad gastroenterologiczny, 14(1), 26

Caliceti, C., Franco, P., Spinozzi, S., Roda, A., & FG Cicero, A. (2016). Berberine: new insights from pharmacological aspects to clinical evidences in the management of metabolic disorders. Current medicinal chemistry, 23(14), 1460-1476.

Imenshahidi, M., & Hosseinzadeh, H. (2016). Berberis vulgaris and berberine: an update review. Phytotherapy research, 30(11), 1745-1764.

Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA: a cancer journal for clinicians, 69(1), 7-34.

 Zhang, Q., Wang, X., Cao, S., Sun, Y., He, X., Jiang, B., ... & Kang, N. (2020). 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. Biomedicine & Pharmacotherapy, 128, 110245.