Cancer is a devastating disease and metastasis is responsible for nearly 90% of all deaths. This term refers to the spread of cancer cells from their origin point to a different part of the body. The cells break off from the original tumor and travel through the blood or lymph system. The process is complex and can take months to years. Additionally, many times after treatment some cells remain behind and can develop resistance, which leads to tumor recurrence.
Researchers at the University of Salford in Salford, England are working on metastasis and they believe the key to this process lies in mitochondrial ATP (adenosine triphosphate) depletion. The ATP molecule is the primary energy source for all cells. Cells manufacture ATP via the TCA cycle, oxidative phosphorylation and glycolysis. If there is a misfunction in your mitochondria, this can lead to reduction of ATP levels, and cell death via apoptosis (programmed cell death) or necrosis (uncontrolled cell death). The team found that the cells that can metastasize need lots of ATP. Therefore, methods to deplete ATP can destroy these cancer cells.
The team focused on cancer stem cells (CSCs) and their mitochondria, as they felt they were responsible for drug resistance. Since mitochondria come from ancient bacteria, there are similarities between human mitochondria and bacteria, so certain antibiotics that are referred to as ‘bacteriostatic’ can actually disrupt the production of mitochondrial proteins. In studies with metastatic breast cancer cells, these cells had elevated mitochondrial activity, as seen in functional activity assays.
One of the antibiotics the team focused on is Doxycycline, which blocks the small mitochondrial ribosome. The team modified the compound to make it >5-fold more potent than the parent compound Doxycycline. This modified compound is called Doxy-Myr, since a myristic acid (14 carbon) moiety is covalently attached to the free amino group of 9-amino-Doxycycline. Interestingly, medicinal chemistry was used to generate modifications with longer (16 carbon; palmitic acid) or shorter (12 carbon; lauric acid) fatty acid chains but the team found these analogs were less potent than Doxy-Myr. Luckily, this modification of a fatty acid rendered the compound ineffective as an antibiotic so it means that antibiotic-resistant bacteria cannot grow. In vitro studies with MCF7 cancer cells or normal fibroblasts grown as 2D-monolyayers, the Doxy-Myr did not affect cell viability. In vitro studies using it did not show antibiotic activity against E. coli and Staphylococcus aureus using Gram-positive and Gram-negative strains.
By targeting the mitochondrial organelle of the cancer stem cells and depleting their ATP, you effectively inhibit their energy production. This discovery could impact the way we view cancer, and it can also open doors since existing FDA-approved compounds can be modified to target the CSCs.
Reference
Ozsvari B et al (2020) A myristoyl amide derivative of Doxycycline potently targets cancer stem cells (CSCs) and prevents spontaneous metastatis, without retaining antibiotic activity. Frontiers Oncol. 10: 10:1528. Link.