Plerixafor: Exposing Hidden Enemies & Cimetidine: Not Letting Them Hide

BLOODSTREAMIn an article published on May 25, 2016 in Science Translational Medicine, the researchers discuss how breast cancer cells are hunting for specific blood vessels that contain a molecule called E-selectin. (Ref.) This molecule exists in specific blood vessels in bone marrow and this is how cancer cells get there. Once they get there, they enter the tissue inside bones where are protected against therapies and usually lying dormant for years. This is how many years later, a patient can relapse.

This is a process characteristic not only to breast cancer but other cancers as well.

Now scientist are proposing two ways to work against these cells hidden in the bone marrow:

  1. If the cancer is catch in early enough stage, inhibit E-selectin so that the cancer cells will not be able to find their way to bone marrow. However, this is a nice to have situation, but many cancers are diagnosed at a point when some cancer cells have already had the chance to migrate.
  2. The other idea scientist had, was to use Plerixafor, an agent used in human bone marrow donors to push stem cells into the bloodstream for harvesting. Plerixafor, was able to force dormant cancer cells out of the bone tissue into the bloodstream by inhibitiong the mechanism used by the cancer cells to anchor in the bone marrow (SDF-1/CXCR4 interaction anchors the cancer cells in bone marrow and Plerixafor is a CXCR4 inhibitor). Once the cancer cells are flushed back in to the blood stream they may be killed by the immune system or various therapies.

I was specifically triggered by this finding as I already investigated and discussed Plerixafor in a previous post (Ref.) due to its other anti cancer action, i.e. the inhibition of M2-macrophages.

For a discussion on the anti M2-macrophages effects of Plerixafor, including the way to obtain it and administration procedure, go to the following link

Interestingly, an E-selectin inhibitor, that is easy accessible is Cimetidine (Ref.). Cimetidine is a well known over the counter drug, a histamine H₂ receptor antagonist that inhibits stomach acid production. It is very safe, cheap and accessible and as a result it is given by most cancer clinics in Germany to thir cancer patients, as a anti metastasis drug, at a daily dose of 800mg/day.

To conclude:

  • The above study again demonstrated the anti metastasis potential of Cimetidine
  • I find Plerixafor a very relevant treatment to be applied just before and after effective anti cancer therapies, including chemo. Administered before the therapy will get the hidden cancer cells back into the blood stream and expose them to the therapy. Administered after the therapy will reduce the chance of tumors to regrow (since Plerixafor  will inhibit M2-macrophages).

Additional Info on CXCR4

The chemokine receptor CXCR4 belongs to the large superfamily of G protein-coupled receptors and has been identified to play a crucial role in a number of biological processes, including the trafficking and homeostasis of immune cells such as T lymphocytes. CXCR4 has also been found to be a prognostic marker in various types of cancer, including leukemia and breast cancer, and recent evidence has highlighted the role of CXCR4 in prostate cancer. Furthermore, CXCR4 expression is upregulated in cancer metastasis, leading to enhanced signaling. These observations suggest that CXCR4 is important for the progression of cancer. The CXCR4-CXCL12 (stromal cell-derived factor 1 (SDF-1)) axis has additionally been identified to have a role in normal stem cell homing. Interestingly, cancer stem cells also express CXCR4, indicating that the CXCR4-SDF-1 axis may direct the trafficking and metastasis of these cells to organs that express high levels of SDF-1, such as the lymph nodes, lungs, liver, and bone.

When cancer cells express CXCR4, the receptor is still able to interact with CXCL12 (as in normal cells); this leads to cancerous cell retention in tissues that are rich in CXCL12 and facilitates the growth and spread of tumours. Recent studies have suggested that malignant cells use chemokine receptor/ligand interactions to home in on common metastatic sites like bone marrow and the lungs. In some cancers, over-expression of CXCR4 has been observed to lead to metastasis. Several independent studies have shown that cancer cells have higher levels of CXCR4 expression compared to normal cells . In breast and lung cancer in particular, over-expression of CXCR4 in patients led to a worse prognosis compared to those who did not over-express the molecule. CXCR4 is the predominant chemokine receptor in ovarian cancer and has also been implicated in many other cancers including prostate, colon, ovary and bladder.

CXCR4 expressions seems to also vary during the day, directly modulated by the typical daily cortisol variation: In humans, numbers of circulating native T cells strongly decline in the morning. This is mediated by cortisol increase, inducing a CXCR4 up-regulation with a subsequent extravasation of the cells. Metyrapone (a cortisol production inhibitor) completely blocked, the morning increase in CXCR4 expression on naive T cells. In parallel, both substances also hindered the decline in naive T-cell numbers with this effect, however, being less apparent after mifepristone.

Metformin, which reduces CCN1 expression, significantly inhibits SDF-1 induced invasion, formation of tumor spheres (pancospheres) and also results in the down regulation of CXCR4 receptor

CXCL12 signaling at CXCR4 is important in glioblastoma growth promotion as a migration-directing chemokine and as a mitosis-stimulating cytokine system. Recent developments in other areas of medicine may have made it now possible to comprehensively block glioblastoma’s use of CXCL12 signaling. CXCL12 signaling at CXCR4 requires an active intermediate conductance Ca2+-activated K+ channel to function. Plerixafor (AMD3100) is a new small molecular weight inhibitor of CXCR4, FDA approved to aid in stem cell mobilization. Inhibition of CXCR4 by plerixafor is expected to inhibit particularly the glioblastoma stem cell population by inhibiting that sub-population’s homing to the protective hypoxic niche. Histamine signals through the H1 receptor in glioblastoma cells to activate the intermediate conductance Ca2+-activated K+ channel also, thereby forming a potential bypass for inhibition of CXCR4-initiated signaling. The antidepressant mirtazapine is perhaps the most potent H1 antagonist in common clinical use. By inhibiting H1 stimulation of intermediate conductance Ca2+-activated K+ channels, it could prevent circumvention of CXCR4 inhibition by that path. The anti-fungal clotrimazole directly inhibits the intermediate conductance Ca2+- activated K+ channel at clinically achievable and well-tolerated doses. These three drugs used simultaneously are potential low morbidity paths to deeply inhibit CXCR4/CXCL12 signaling during cytotoxic glioblastoma treatment. Ref.


Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone

Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin– and stromal cell–derived factor 1 (SDF-1)–rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1+ vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.

Scientists block breast cancer cells from hiding in bones


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3 thoughts on “Plerixafor: Exposing Hidden Enemies & Cimetidine: Not Letting Them Hide

  1. I was reading that Cimetidine prevents metastasis by inhibiting processes which allow cancer cells to stick together (adhesion), and thus to form tumours.

    I’m not 100% of the complete role of the protein, but CD56 is commonly expressed in various types of cancer cells, and is known as the Neural Cell Adhesion Molecule (NCAM) and normally aids in cell-to-cell adhesion. I haven’t been able to find that much online about it but it is possible that cimetidine would work better in CD56+ tumours.

    This was the only thing I could find on the hypothesis.

  2. Thank You, Daniel, for Your kind response in other post!!!

    It is important that You get enough sleep !

    According to Cimetidine :

    The only thing which makes me in concern is that Cimetidine has some estrogen stimulating properties? I am very cautious about hormones 🙂 …

    From Wikipedia:
    Antiandrogenic and estrogenic effects

    Cimetidine has been found to possess clinically significant albeit weak antiandrogen activity at high doses. It has been found to directly and competitively displace testosterone and dihydrotestosterone (DHT) and antagonize the androgen receptor (AR) in animals. In addition, cimetidine has been found to inhibit 2-hydroxylation of estradiol (via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increased levels of estrogen. By increasing estrogen levels, cimetidine can also decrease testosterone and increase prolactin levels.

    The biopsy of my primary tumor 4 years ago showed high amount of hormon receptors (100% Estrogen, 80%Progesteron, 100% Androgen).

    I had Neoadjuvant Chemotherapy 6xTAC, followed by surgery, which showed only 30% of Estrogen. (I think these changes are due to chemotherapy). I performed profilactic ovariectomy (in order to stop estrogen production).

    After ovariectomy I took Tamoxifen for 1.5 years.

    In this time lytic bone lesson appeared in spine T7 and with compression fracture in spine T6 (we think it was fast and agressive growing and during Tamoxifen using).
    I had radiosurgery to those 2 spots in spine. 3 month later Pet scan showed all is clear. (Just now I realize that this Pet did not included femur, where now I have bone mets).

    Then I changed from Tamoxifen to Anastrozole, which is Aromathase inhibitor (as I understand it depleates Estrogens but can upping Androgens).

    During these 2 years after first bone mets and on Aromathase inhibitor new bone spots appeared in Femur and small part of old grew in spine T7, but the old lytic spot in spine T6 is silent with no activity.


    Should I use Cimetine as I had hormon receptors and I am now on Aromathase inhibitor?

    Or Maybe I can use Cimetidine on short periods?

    Kind regards,

  3. It must be my naturopathic training, but I admit I have had an aversion to Cimetidine because of the lowering of stomach acid which can impact nutrient absorption (B12, calcium and potentially other nutrients) and digestion (low stomach acid has been associated with SIBO and decreased pancreatic output). Now, looking into the timing of dosing, it appears that 800mg before bed did not impact daytime acid secretion. There are likely advantages to 400mg twice a day in terms of keeping a steady influence on the body, as always, advantages and disadvantages need to be weighed. It seems cimetidine/cancer studies have used both dosing administrations.
    “Cimetidine 800 mg orally at bedtime reduces mean hourly H+ activity by greater than 85% over an 8-hour period in duodenal ulcer patients, with no effect on daytime acid secretion. Cimetidine 1600 mg orally h.s. produces 100% inhibition of mean hourly H+ activity over an 8-hour period in duodenal ulcer patients, but also reduces H+ activity by 35% for an additional 5 hours into the following morning. Cimetidine 400 mg b.i.d. and 300 mg q.i.d. decrease nocturnal acid secretion in a dose-related manner, i.e., 47%–83% over a 6-to 8-hour period and 54% over a 9-hour period, respectively.”

    Here is a nice older, but still relevant article summarizing some of the research on cimetidine from Life Extension:

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