Niacin reactivates myeloid cells, slows tumor growth in GBM mouse models

This was just published a few days ago in Science Translational Medicine.

Control of brain tumor growth by reactivating myeloid cells with niacin
Sarkar et al.
https://stm.sciencemag.org/content/12/537/eaay9924.editor-summary


"Although innate immune cells are typically present inside tumors, they often have an inactive phenotype such that they are ineffective at killing the cancer cells or even promote tumor growth. Sarkar et al. discovered that it may be possible to reprogram these cells to a more active type using niacin (vitamin B3). The authors showed that niacin-exposed monocytes can inhibit the growth of brain tumor–initiating cells. Moreover, niacin treatment of intracranial mouse models of glioblastoma increased monocyte and macrophage infiltration into the tumors, stimulated antitumor immune responses, and extended the animals’ survival, especially when combined with the chemotherapeutic drug temozolomide."

I have uploaded the full study to the Brain Tumor Library, follow this pathway:

Folder 0. Important Reference documents -> subfolder 1. New Uploads ->  "2020 Sarkar Niacin reactivates myeloid cells"

Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?

Hello all,
I spotted this paper and thought it was best to share: “Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?” Although I’ve not read the full paper, it’s worth noting that they concluded:

This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma

Should we abandon ACE inhibitors, etc?

Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?

This is a new paper (click here for abstract) brought to us by some of the same authors who earlier produced:

Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

The group concluded:

"This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma."

As with the previous study, there are some important caveats.  Some of the most intriguing data supporting the potential for angiotensin system blockers was in combination with bevacizumab:

Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab

It would have been interesting to look at outcomes in those using/not using ACE inhibitors or sartans in combination with bevacizumab, for example in the Avaglio and RTOG-0825 trials.

Angiotensin-II has been shown to increase tumor-promoting macrophages in preclinical models:

https://www.ncbi.nlm.nih.gov/pubmed/23333075

and these tumor-infiltrating myeloid cells may play a significant role in resistance to anti-VEGF therapies such as bevacizumab.

https://www.ncbi.nlm.nih.gov/pubmed/26404753

Article "Glioma-induced caspase-3 inhibition in microglia promotes a tumor-supportive phenotype."

"Glioblastomas are one of the most malignant forms of brain tumour and are difficult to surgically remove because the tumour cells invade the surrounding healthy brain tissue. Glioblastomas also affect the microglia -- immune cells of the brain -- in such a way that they stimulate the tumour cells instead of attacking them.
The multi-national research group has previously shown that pro-inflammatory activation of microglia is controlled by a group of enzymes called caspases. In the present study, they sought to examine if the way the cancer cells affect microglia also includes similar mechanism. By cultivating microglia and glioblastoma cells together, the researchers were able to show that the cancer cells inhibit caspase-3 activity in the microglia.
"We show that it's the same inhibition of caspase-3 that causes the microglia to stimulate the tumour cells instead of attacking them," says Bertrand Joseph, Principal Investigator at Karolinska Institutet's Department of Oncology-Pathology. "When we removed caspase-3 from the microglia in a glioblastoma mouse model, the tumours grew more quickly."
According to the study authors, their results demonstrate that the glioma cells use a nitric oxide-dependent mechanism to force microglia to modify caspase-3 to form a tumour-stimulating form of these cells.
"Two things surprised us," says Bertrand Joseph. "First and foremost, that affecting the signalling mechanism between glioblastoma cells and microglia that we discovered has such a major effect on tumour growth. Secondly, that basal caspase-3 activity, which is often considered to be an absence of activity, fulfills essential function in regulating microglia cell behavior."

Link to news article: https://www.sciencedaily.com/releases/2016/09/160912122352.htm?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+sciencedaily%2Fhealth_medicine%2Fbrain_tumor+%28Brain+Tumor+News+--+ScienceDaily%29

Link to scientific journal: http://www.nature.com/ni/journal/vaop/ncurrent/full/ni.3545.html

Low Dose Naltrexone

http://astrocytomaoptions.com/re-educating-the-immune-system/

As mentioned above, one of the main endogenous opioids with increased production following low dose naltrexone is met-enkephalin (also known as methionine enkephalin, and as opioid growth factor). A Chinese study published online in August 2016 examined the effects of met-enkephalin on microglial cells in culture [46]. As explained in this study and elsewhere, microglia (the resident macrophages of the nervous system) and macrophages infiltrating from the systemic circulation are actively recruited into tumors, polarized to a tumor-promoting M2 phenotype and away from a tumor-fighting M1 phenotype, and can make up as much as 30% of a GBM tumor. The investigators found that at the optimal concentration of met-enkephalin (1 picomolar), M1-type cytokine production and surface proteins were increased in the microglia, including interleukin-12, TNF-alpha, CD86, CD40, and iNOS. In contrast, M2 cytokines and markers were not affected, including interleukin-10, TGF-beta, CD163, and arginase. Phagocytosis (a main function of M1 macrophages) and cytotoxicity towards U87 glioblastoma cells was increased by met-enkephalin treatment. Thus, met-enkephalin (opioid growth factor), an endogenous opioid whose production is increased in humans following transient opioid receptor blockade by low dose naltrexone, may aid glioma patients by reverting tumor-associated microglia to an M1 anti-tumor phenotype.

View common questions and answers about the use of low dose naltrexone at LDN Science. Especially interesting areinterviews with Dr. Ian Zagon, who discovered the clinical benefits of naltrexone in very low doses.

The effective dose of low dose naltrexone ranges from 2.5 – 10 mg, with the most common dose being 4.5 mg daily. LDN may be taken in the morning or evening. Some individuals may experience sleep disturbances (such as nightmares) caused by LDN and these people may choose to take their daily dose in the morning.