Repurposed malaria drug Chloroquine effective with certain brain tumours

Repurposed malaria drug Chloroquine effective with certain brain tumours

Chloroquine (or Chloroquinone) is an anti-malaria drug that can be repurposed for use in oncology, as it can reduce tumour growth, proliferation and metastasis; it also seems to increase the effectiveness and longevity of chemotherapy drugs such as temozolomide and is particularly potent against BRAF and p53 deficient cancer cells.

Chloroquinone and anti-BRAF benefits with brain cancer and melanoma

Scientists at the University of Colorado’s Anshutz Medical Campus have shown that an anti-malaria drug, chloroquinone, can be 'repurposed' for use in oncology and have a significant effect in increasing survival times in people with certain types of GBM brain cancer.

Many cancers, and particularly many brain tumours, depend on autophagy to survive, and use it to defeat drugs. Autophagy is a natural process of cells where they collect anything that might be harmful to the cell and process it to protect the cell. So too with cancer cells attacked by drugs.

Dr. Jean Mulcahy-Levy at UC Cancer Center was looking at brain tumours as a whole and his initial work was disappointing until he concluded that different sub-sets of brain cancer had different responses to drugs. In particular, cancers with a BRAF mutation were particular strong on autophagy. One version BRAFV600E, even stronger especially in brain cancers.

BRAF is a gene which codes a particular protein that causes cancers to grow. Drugs such as Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar) are kinase inhibitors developed originally for melanoma, where they reduce tumour size for a while.

At Anshutz, the drug Vermurafenib was being tested on paediatric brain tumours with the BRAF protein. After a while, as usual, it lost its potency because of autophagy.  The cancer cells defended themselves.

But the anti-malarial drug, chloroquinone, is known to block autophagy and so the researchers added that into the mix and immediately the BRAF inhibiting drug started working again. By the end of 2016 a number of patients had been treated with this repurposed drug and all responded.

Go to: Integrative brain cancer treatments increase survival times

Chloroquine suppresses the environment of cancer cells

A 2014 review (2) of chloroquinone had found that it could suppress tumour growth and metastasis. Although it showed this action on cancer cells in vitro, researchers have shown in real life it can also act on the blood vessels of a tumour. With cisplatin, it did not work on cell cultures but did when used in vivo, greatly increasing the toxicity of the drug.  

In 2017 research (3), University of Kentucky scientists Vivek Rangnekar and Ravshan Burikhanov showed that chloroquinone empowered normal cells with wild type p53, to express a protein Par-4, and stop metastasis in p53 deficient cancer cells (about 50% of cancer cells). Par-4 is essential for cell death and cancer cells switch it off.

As long ago as 2002, scientists from the Chase Cancer Center (4) argued that glutathione-S-transferase was what cancer cells used to block cancer drugs after a period of time but that drugs like chloroquinone could prevent that extending the life of many drugs in most cancers.

Chris Woollams, former Oxford University Biochemist and a founder of CANCERactive said, "The research is mounting along a number of avenues, and given that some affect brain cancer and melanoma for which existing treatments are poor, we will regularly follow chloroquine and produce updates. It is known to cause oxidative stress in Plasmodium, the malarial bug. It is exactly this oxidative stress that gives it anti-cancer properties too. It seems to help Temozolomide become more effective and work for longer. It reduces the state of hypoxia in brain cancer cells and clinical trials are taking place (5)."

References

1. Mulcahy Levy JM, Zahedi S, Griesinger AM, et al. Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors. Elife. 2017 Jan 17;6. doi: 10.7554/eLife.19671

2. Maes, Kuchnio. https://stke.sciencemag.org/content/7/339/ec217

3. https://reliawire.com/chloroquine-metastatic-cancer-treatment/

4. https://www.nature.com/articles/1206940

5. https://clinicaltrials.gov/ct2/show/NCT02378532

 

2018 Research
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