Metformin versus B-CLL- an unknown face of known antidiabetic drug

Dictionary Series - Health: diabetesLeukemia treatment is still an uneven fight. Despite huge progress in medicine there is no effective drug for this disease. For many years one of the drugs which is of more and more interest in scientific world is metformin. As the research of Italian scientists show, this drug may be extremely promising therapeutic tool in combat with chronic lymphocytic leukemia.

Results of the research proved that metformin has proapoptotic and antiproliferative influence on cancer cells which were previously taken from patients with chronic lymphocytic leukemia. Description of this study and conclusions were published in renowned Oncotarget magazine[1].

Metformin, which is 1,1-dimethylbiguanide, is a compound first used in medicine in 1957. Currently, it is known as one of the most often used oral hypoglycemic agents of biguanide group. Diabetes mellitus type 2 is a direct indication for its use because it is relatively cheap and well-tolerated by most of the patients [2]. Metformin raises more and more interest for many years in oncology, and that is why many research are being conducted worldwide. Their aim is to confirm its potential anticancer influence. One of the cancers which is a huge problem for contemporary hematology is chronic lyphocytic leukemia.

Chronic lyphocytic leukemia is the most frequent type of leukemia affecting adult people in Europe and North America. Prevalence increases with age. Usually, it affects people between 6th and 7th decade of life. It is a lymphoproliferative disorder which disrupts process of apoptosis. It is characterized by slow, clonal growth of morphologically adult lymphocytes present in blood, bone marrow, lymphatic tissue, and other organs. In 90% of cases the disease stems from B lymphocytes and that is why it is called B-CLL. Regarding the fact that its etiology is still vague, complete recovery of patients with CLL is practically impossible nowadays. What is more, in over 50% of patients diagnosis does not confirm specific clinical symptoms or during routine morphology they are diagnosed just with lymphocytosis and non-specific symptoms, what is a significant impediment in early diagnosis of the disease. According to clinical observations, mild course of the disease is diagnosed in only 30% of CLL patients. Deaths are mainly connected with progression of the cancer. In patients with advanced stage of chronic lyphocytic leukemia it is more often observed (2-7 times) that, in comparison with general population, they develop other proliferative diseases of the hematopoietic system, cancers of skin and lung, and melanoma [3,4]. Regarding abovementioned data, results of the scientists’ research seem to be extremely prospective.

Silvia Bruno, Bernardetta Ledda, Claudya Tenca with co-workers studied influence of metformin on CLL cells in in vitro conditions. It turned out that metfomin has cytotoxic influence on cells which do not proliferate, and cytostatic on CLL cells activated by culture with stable fibroblast line CD40L in relation 1:100 (fibroblasts: CLL cells). It was shown that metformin causes abovementioned effects mainly by inhibiting expression of antiapoptotic proteins Bcl-2 and Mcl-1. CLL cells subjected to this substance had significantly lower Mcl-1 level what was connected with increase in expression of Noxa (Phorbol-12-myristate-13-acetate-induced protein 1), protein from Bcl-2 protein family which is highly engaged in apoptosis mediated by p53. Moreover, metformin inactivates paths connected with transcription process such as STAT3, NF-kB, Akt or PI3. As the results of scientists’ research show, blocking of AMPK, which is 5’AMP-activated protein kinase, and gradual decreasing of glucose metabolism may have huge significance in inhibiting cancerogenous process. This information seems to be extremely important because leukemia cells, in comparison with healthy leukocytes, are dependent to a large extent on ATP and glycolysis process [5].

Anticancer potential of metformin is extremely promising. It turns out that metformin intensifies activity of traditional drugs currently used in leukemia treatment which block synthesis of DNA,RNA, and proteins. The scientists proved that metfotmin while inhibiting breathing in mitochondria of CLL cells, contributes to increase of proapoptotic influence of fludarabine. What is more, the drug has one more feature which is very important in terms of safety of use in therapy of chronic lyphocytic leukemia. According to results of research, there were no cytotoxic or cytostatic influence on healthy peripheral blood lymphocytes in doses which were applied to CLL cells. Also metformin is relatively well tolerated by patients with diabetes (standard dose is 1g twice a day).

In the light of recent studies, metformin seems to be a part of totally new strategy in treatment of not only CLL, but also other cancers. So far, conducted research involved its influence on cells of prostate cancer [6,7], breast cancer [8], pancreatic cancer [9, 10], lung cancer [11], colorectal cancer [12], stomach cancer [13], and glioblastoma [14, 15]. In the nearest future it will be known whether new properties of the long-known drug can be used in practice.

Therefore, it can be really said that 21st century is a time when metformin makes its comeback. Already today, this compound turns out to be invaluable in fight with diabetes mellitus type 2- a disease which is contemporary of epidemic size. Maybe next generations will remember metformin as a drug which helped to swing the balance in combat with cancers, especially chronic lyphocytic leukemia.

Written by: Magdalena Szydełko, Joanna Szydełko

Source:
1. Bruno S., Ledda B., Tenca C., Ravera S., Orengo A.M., Mazzarello A.N., Pesenti E., Casciaro S., Racchi O., Ghiotto F., Marini C., Sambuceti G., DeCensi A., Fais F., Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells. Oncotarget 2015 Jun 5. [Epub ahead of print]
2. Grzybowska M., Bober J., Olszewska M., Metformina – mechanizmy działania i zastosowanie w terapii cukrzycy typu 2. Postępy Higieny i Medycyny Doświadczalnej 2011; 65: 277-285.
3. Oscier D., Dearden C., Erem E. et al., Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. British Journal of Haematology 2012; 159(5): 541-564.
4. Warzocha K., Przewlekła białaczka limfocytowa. Zalecenia postępowania diagnostyczno-terapeutycznego w nowotworach złośliwych – 2013; 823-834.
5. Martinez Marignac V.L., Smith S., Toban N., Bazile M., Aloyz R., Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming. Oncotarget. 2013; 4:2550–2566.
6. Issam Ben Sahra, Kathiane Laurent, Sandy Giuliano, et al., Targeting Cancer Cell Metabolism: The Combination of Metformin and 2-Deoxyglucose Induces p53-Dependent Apoptosis in Prostate Cancer Cells. Cancer Research 2010; 70(6): 2465-2475.
7. Mayer M.J., Klotz L.H., Venkateswaran V., Metformin and prostate cancer stem cells: a novel therapeutic target. Prostate Cancer and Prostatic Diseases 2015 Jul 28. doi: 10.1038/pcan.2015.35. [Epub ahead of print]
8. Soo J.S., Ng C.H., Tan S.H., Malik R.A., Teh Y.C., Tan B.S., Ho G.F., See M.H., Taib N.A., Yip C.H., Chung F.F., Hii L.W., Teo S.H., Leong C.O., Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells. Apoptosis-an international journal on programmed cell death 2015 Aug 15. [Epub ahead of print]
9. Yue W., Zheng X., Lin Y., Yang C.S., Xu Q., Carpizo D., Huang H., DiPaola R.S., Tan X.L., Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget 2015 May 12. [Epub ahead of print]
10. Lonardo E., Cioffi M., Sancho P. et al., Metformin Targets the Metabolic Achilles Heel of Human Pancreatic Cancer Stem Cells. PLoS ONE 8(10): e76518.
11. Chen Y.Q., Chen G., Combined therapeutic effect and molecular mechanisms of metformin and cisplatin in human lung cancer xenografts in nude mice. Journal of Cancer Research and Therapeutics 2015; 11(2):324-330.
12. Anisimov V.N., Metformin for prevention and treatment of colon cancer: a reappraisal of experimental and clinical data. Current Drug Targets 2015 Mar 3. [Epub ahead of print]
13. Chen G., Feng W., Zhang S., Bian K., Yang Y., Fang C., Chen M., Yang J., Zou X., Metformin inhibits gastric cancer via the inhibition of HIF1α/PKM2 signaling. American Cancer for Journal Research 2015; 5(4):1423-1434.
14. Sesen J., Dahan P., Scotland S.J., Saland E., Dang V.T., Lemarié A., Tyler B.M., Brem H., Toulas C., Cohen-Jonathan Moyal E., Sarry J.E., Skuli N., Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS One 2015; 10(4):e0123721.
15. Ucbek A., Ozünal Z.G., Uzun O., Gepdıremen A., Effect of metformin on the human T98G glioblastoma multiforme cell line. Experimental and Therapeutic Medicine 2014; 7(5):1285-1290.

Would You like to know more? Watch on MEDtube.net: Blood – Acute Leukemia

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