Metformin and Temozolomide synergistically enhanced effect against astrocytomas and GBM brain cancer

Metformin and Temozolomide  synergistically enhanced effect against astrocytomas and GBM brain cancer

Metformin, the diabetes drug, has been shown in research to improve the effectiveness of brain cancer drug, Temozolomide, which despite its universal use, is really only effective for the 20% of GBM that have a methylated MGMT promoter. Other compounds also show synergistic effects with TMZ.

Treatment of Glioblastoma (GBM) brain cancer is still left wanting with the cancer resistant to many drugs, especially as many fail to get across the blood-brain barrier.

Prognosis is dismal and recurrence is often fast. Historically, life expectancy has been approximately 15 months after surgery.The source of the relapse and even chemo-resistance has been identified several times by different research groups as cancer stem cells  or self-renewing tumorigenic cells at the heart of the tumour (1).

Temozolomide, or Temodar, is the UK’s drug of choice when dealing with GBM and astrocytomas. Unfortunately it is only of benefit to about 20 per cent of GBM patients. The rest have an over-expression of Methylguanine Methyltransferase (MGMT) and this causes resistance.

Metformin works synergistically with Temozolomide

Metformin is a drug for type-2 diabetes. Primarily, it reduces blood sugar a known promoter of brain cancer.

But researchers have found added benefits:  In one study (2), Julie Sesen and a team of researchers from INSERM in the Research Center in Toulouse, showed metformin inhibited GBM cell growth, and affected metabolism in the mitochondria causing cell death (apoptosis).

Next researchers from Jilin Hospital in China have confirmed that combining Temozolomide (TMZ) with Metformin (MET) synergistically inhibited proliferation and induced apoptosis – in both glioma cells and glioma stem cells (GSCs).

Combination of TMZ and MET significantly reduced the secondary gliosphere formation and expansion of GSCs.

TMZ in combination with MET synergistically inhibits the GSCs proliferation through down-regulation of AKT-mTOR signaling pathway.

The researchers were clear that he combined treatment of two drugs inhibits the self-renewal capability of both glioma cells and glioma stem cells both in vitro and in vivo. Not only did metformin make Temozolomide work better, it widened the potential numbers of patients who would benefit (6).

McGill University in America are conducting a clinical trial using Temozolomide and metformin currently (3). They have completed Phase I and in Phase II are expecting to see at least 5 months extra survival. The trial also involves Radiotherapy.

We have also covered research in the past that tricyclic anti-depressant drug chlomipramine was capable of causing apoptosis in GBM cells (4).

Boswellic acid also seems to improve the action of temozolomide and Afatinib through its anti-inflammatory properties (7).

Go to: Herb Berberine shown to have anti-tumour activity in GBM


References

1. Genes Dev; 2015; June 15; Justin D. Latia et al.

2. Metformin inhibits growth of human Glioblastoma cells; PLoS 1;10 (4) Julie Sesen et al.

3. https://clinicaltrials.gov/ct2/show/NCT02780024

4. https://www.onko-i.si/fileonko/datoteke/dokumenti/Radiology_40_2_3.pdf

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431946/

6. Metformin and Temozolomide act synergistically - Zhiyun et al;  Oncotarget 2015; Oct 20 6(32)

7. Boswellic acid has anti-inflammatory properties and enhances the effects of Temozolomide and Afatinib in human glioblastoma cells; Phytother Research, 2019 June 15 33 (6) Manlio Barbarisi et all.

 

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