Berberine, AML and Stem Cell Transplants

June 21, 2014

Jacob Schor, ND, FABNO

www.DenverNaturopathic.com

 

 

Using nutritional supplements during cancer treatment can in some situations be very helpful.  At the other times, when treating the same cancer, the same supplement may interfere.  One example of this is the supplement berberine, an alkaloid chemical that is extracted from several medicinal plants, the most common being Oregon Grape Root. 

 

[We’ve reviewed this supplement in the past for the Natural Medicine Journal and that and other articles in that journal should provide background: http://naturalmedicinejournal.com/journal/2012-12/clinical-applications-berberine ]

 

Berberine is useful for patients with acute myeloid leukemia (AML) for a number of reasons.  Let’s ignore berberine’s general anti-cancer actions and the fact that activation of AMPK, something that berberine does well, is desirable with AML, and just focus in on inhibition of a chemokine called stromal cell-derived factor 1 (SDF-1).  This chemical belongs to a family of chemicals that activate white blood cells and are often made in response to inflammatory triggers. 

Oregon Grape, a popular source of Berberine

 

SDF-1 binds to a receptor named CXCR-4 (short for C-X-C chemokine receptor type 4. SDF-1 is sometimes referred to as CXCL12, that’s where the CXC comes from, but let’s try to keep this simple).

 

Leukemia tumor cells express this CXCR-4 receptor either on their surface or inside the cell.  They notice and respond to SDF-1.  This cSFD-1/CXCR4 signaling pathway involved in the migration of leukemic cells though the body.  A 2008 paper by Li et al reported that because berberine  “… could partly inhibit SDF-1 induced AML [acute myeloid leukemia] cells as well as LSCs [leukemic stem cells] migration…… [the authors] hypothesized that berberine could inhibit AML cells migration partly by reducing the secreting of SDF-1 …... Therefore, [they] speculated that berberine might be a potentially effective agent for prevention of leukemia. [1] 

 

This hypothesis was based in part by an earlier paper by Tavor et al that looked at the role of CXCR4 in the development of acute myeloid leukemia stem cells.  These authors reported in 2004 that all AML cells were sensitive to SDF-1 and that growing AML cells in the presence of SDF-1 promoted their survival while adding antibodies that blocked CXCR4  and SDF-1 into the cell cultures blocked AML cell survival in growth cultures. Treating  mice who had been given human AML  with these same antibodies blocked the cancer cells’ ability to migrate into the blood, bone marrow or spleen.  Giving these same antibodies to mice who had been previously engrafted with human AML cells dramatically decreased presence of the disease in a dose and time dependent manner.   These findings strongly suggested that this SDF-1/CXCR4 axis is important in these cancers and it gives foundation to Li et al’s hypothesis that if berberine could inhibit this pathway, it might have value in treating AML. [2] 

 

AML is a fast progressing disease and is treated quickly and aggressively, typically with chemotherapy, radiation or stem cell transplant depending on disease subtype. 

 

This is where the use of berberine gets complicated. 

 

There are a range of chemotherapy drugs used to treat AML.[3]    Berberine may be helpful in combination with some of these drugs.  For example it protects the kidneys and liver from damage caused by cyclophosphamide. [4,5]    

 

With doxorubicin, berberine aids the drug in killing breast cancer or melanoma cells while at the same time protecting the heart from the heart damage this drug is known for causing. [6,7,8]     

It’s not yet clear whether berberine will improve doxorubicin’s action against AML the way it does with other cancers, but it well might.  Berberine does appear to help gemcitabine kill pancreatic cancer cells. [9] 

 

On the other hand, berberine can be a problem during stem cell transplants and sometimes in AML this is the necessitated treatment of choice. 

That’s because that chemokine SDF-1 and its receptor CXCR4 are critical during stem cell transplants to get the new stem cells to engraft into the bone marrow.  Doing things that increase CXCR4 expression appears to be useful in helping repopulate stem cells after a transplantation.[10] 

SDF-1 helps the new cells move about and recolonize the body.

 

So while berberine may be useful in preventing and slowing AML progression, and while it may be useful in combination with some of the chemotherapy drugs that might be chosen to treat the disease, at this point we must keep in mind that it may interfere with one of the more treatments of AML, a stem cell transplant.

 

At this point little is known about the duration of effect berberine has on SDF-1 and CXCR4, so any advice on how early a person should stop taking berberine prior to undergoing a stem cell transplant is probably just a guess.

 

 

References:

 

1. Li H, Guo L, Jie S, Liu W, Zhu J, Du W, Fan L, Wang X, Fu B, Huang S. Berberine inhibits SDF-1 induced AML cells and leukemic stem cells migration via regulation of SDF-1 level in bone marrow stromal cells. Biomed Pharmacother. 2008 Nov;62(9):573-8. doi: 10.1016/j.biopha.2008.08.003. Epub 2008 Sep 4.

 

 2. Tavor S1, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L, Shemtov N, Deutsch V, Naparstek E, Nagler A, Lapidot T. CXCR4 regulates migration and development of human acute myelogenous leukemia stemcells in transplanted NOD/SCID mice. Cancer Res. 2004 Apr 15;64(8):2817-24.

 

3.   Drugs Approved for Acute Myeloid Leukemia (AML):

Arsenic Trioxide

Cerubidine (Daunorubicin Hydrochloride)

Clafen (Cyclophosphamide)

Cyclophosphamide

Cytarabine

Cytosar-U (Cytarabine)

Cytoxan (Cyclophosphamide)

Daunorubicin Hydrochloride

Doxorubicin Hydrochloride

Idamycin (Idarubicin Hydrochloride)

Idarubicin Hydrochloride

Mitoxantrone Hydrochloride

Neosar (Cyclophosphamide)

Rubidomycin (Daunorubicin Hydrochloride)

Tarabine PFS (Cytarabine)

Trisenox (Arsenic Trioxide)

Vincasar PFS (Vincristine Sulfate)

Vincristine Sulfate

Drug Combinations Used in Acute Myeloid Leukemia (AML):

ADE

 

4.  Germoush MO, Mahmoud AM. Berberine mitigates cyclophosphamide-induced hepatotoxicity by modulating antioxidant status and inflammatory cytokines. J Cancer Res Clin Oncol. 2014 Jul;140(7):1103-9. doi: 10.1007/s00432-014-1665-8. Epub 2014 Apr 18.

 

5.  Xu X, Malavé A. Protective effect of berberine on cyclophosphamide-induced haemorrhagic cystitis in rats. Pharmacol Toxicol. 2001 May;88(5):232-7.

 

6.  Barzegar E, Fouladdel S, Movahhed TK, Atashpour S, Ghahremani MH, Ostad SN, Azizi E. Effects of berberine on proliferation, cell cycle distribution and apoptosis of human breast cancer T47D and MCF7 cell lines. Iran J Basic Med Sci. 2015 Apr;18(4):334-42.

 

7.  Mittal A, Tabasum S, Singh RP. Berberine in combination with doxorubicin suppresses growth of murine melanoma B16F10 cells in culture and xenograft.

Phytomedicine. 2014 Feb 15;21(3):340-7. doi: 10.1016/j.phymed.2013.09.002.

 

8.  Hao G, Yu Y, Gu B, Xing Y, Xue M. Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin.

 Xenobiotica. 2015 May 13:1-6. [Epub ahead of print]

 

9.  Park SH, Sung JH, Kim EJ, Chung N. Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines. Braz J Med Biol Res. 2015 Feb;48(2):111-9. doi: 10.1590/1414-431X20144293.

 

10.   Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T, Nagler A, Ben-Hur H, Many A, Shultz L, Lider O, Alon R, Zipori D, Lapidot T. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999 Feb 5;283(5403):845-8.