27 July, 2021

Metastasis Prevention – A New Weapon in the Fight Against Cancer

Despite years of research, cancer metastasis always remains incurable and fatal. There are no approved drugs for the prevention of metastasis and it is estimated that metastasis is responsible for 90% of cancer deaths. Now researchers have discovered a new therapeutic target to prevent cancer metastasis.  

Researchers from the University of Salford report that high mitochondrial ATP (adenosine triphosphate) production is the key player of cancer cell proliferation and ATP depletion can prevent spontaneous metastasis.  The study was published in Nature journal, Cell Death and Differentiation.

Cancer Metastasis

Metastasis is the dissemination of tumor cells from the primary site to the secondary site in sequential interrelated steps: Separation of tumor cells from the primary site; invasion through surrounding tissues; intravasation (tumor cells invade the basement membrane and enter into the circulation) and survival in the circulation; extravasation from the vasculature into the surrounding tissue; proliferation at the secondary site (distant organ). Metastasis, an extraordinary complex process can develop months to decades after the initial diagnosis of the primary tumor. 

The current treatment options for metastatic cancer are radiation therapy, surgery, chemotherapy, immunotherapy, and hormone therapy. The primary goal of the treatment is to eradicate all tumor cells, and conservative treatments are usually useful. However, many patients who respond to the treatment initially can develop resistance- a larger number of tumor cells become resistant to radiotherapy, chemotherapy, etc. -and metastases. Therefore, continue efforts to understand the underlying mechanism of drug resistance is important to develop effective treatment regimens to prevent metastasis.    

ATP-depletion, a new therapeutic strategy for metastasis prophylaxis

Although the mechanisms of metastasis have been widely studied, the Achilles’ heel of the metastasis remains largely unknown. Now researchers have identified that mitochondria as the therapeutic target, more specifically, the mitochondrial ATP-depletion is the new therapeutic strategy to prevent metastasis. 

ATP is the energy currency of all living cells and mitochondria, the organelle responsible for energy production is often referred as the ‘power house’ of the cell. Cells obtain ATP via the TCA cycle, oxidative phosphorylation (OXPHOS), and glycolysis and mitochondrial impairment can lead to ATP depletion resulting in apoptosis and/or necrosis. Researchers identified the metastatic cancer cells, the ‘fittest’ cancer cells require a large amount of ATP. Therefore, the ATP-depletion strategy can markedly eradicate the ‘fittest’ cancer cells. 

ATP-high cancer cells are aggressive, hyperproliferative, stem-like, anchorage-independent, and multi-drug resistant. However, the link between the ATP levels and characteristic features of the ATP-high cancer cells is still unclear. In MCF7 human breast cancer cells, 80-90% of ATP is produced via mitochondrial phosphorylation.

Bedaquiline inhibits ATP production and prevents metastasis

In this new study, researchers used a xenograft model to demonstrate that administration of Bedaquiline can cause mitochondrial ATP-depletion in MDA-MB-231 breast cancer cells, which in turn can prevent spontaneous metastasis. 

Researchers isolated ATP-high subpopulation of cells and for cancer metastasis, they used the bioinformatics approach and defined a mitochondrial-related gene signature, which features ATP5F1C- the gene that encodes gamma-subunit of the enzyme mitochondrial ATP-synthase. 

Using immunohistochemistry, researchers confirmed that high expression of ATP5F1C is associated with metastasis. They found approximately fivefold increased metastatic capacity in ATP-high MDA-MB-231 cells. ATP-high MDA-MB-231 cells showed aggressive cell invasion capacity and 20-40 fold increase in their migratory capacity in vitro and spontaneous metastasis in vivo. ATP-high cells overexpressed ATP5F1C, and researchers predicted that knockdown of ATP5F1C expression can considerably lower ATP-production, cell migration, and anchorage-independent growth. In this context, researchers investigated the therapeutic administration of Bedaquiline and found the drug downregulated the expression of ATP5F1C and prevented spontaneous metastasis; however, had no impact on the primary tumor. The drug showed no significant toxicity. 

Overall, the findings suggest ATP depletion is a new therapeutic strategy to prevent tumor progression, more specifically, the mitochondrial ATP5F1C is the promising new functional biomarker and molecular target for future drug development for metastasis prevention. 

Doxycycline derivative targets CSCs and prevent metastasis

Months ago, the same team targeted the mitochondria of the cancer stem cells (CSCs), the cells thought to be the cause of drug resistance resulting in recurrence and metastasis. Mitochondria emerged from bacterial ancestors and there are many striking similarities between human mitochondria and bacteria. Therefore, a subgroup of bacteriostatic antibiotics can impair mitochondrial translation. Accordingly, doxycycline inhibits the small mitochondrial ribosome as a side effect and functions as an inhibitor of the propagation of CSCs, suggesting that doxycycline can target and eradicate CSCs. Hence, the researchers tested the modified FDA-approved drug Doxycycline for the prevention of metastasis. The new Doxycycline derivative named Doxy-Myr showed fivefold more potent than Doxycycline and selectively targeted CSCs and prevented metastasis but showed no antibiotic activity. The findings suggest that Doxy-Myr can be used to eradicate CSCs. The study was published in the September 2020 edition of the journal Frontiers in Oncology

The above studies provide proof of principle that it is feasible to modify the existing FDA-approved drugs to prevent metastasis by targeting the process of mitochondrial ATP production.

https://www.nature.com/articles/s41418-021-00788-x

https://www.frontiersin.org/articles/10.3389/fonc.2020.01528/full

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