Modern pharmaceutical companies spend billions of dollars and years of time developing the next big drug. What if they didn't have to? What if they could just take another drug, perhaps a malaria drug, and do a quick modification to target it for cancer and call it a day?
Well, that's exactly what a team from the Medical College of Wisconsin did… sort of. In a new study, they sought to examine how the anti-malarial and pneumonia drug Atovaquone (ATO) might be able to suppress the growth of pancreatic cancer cells in vitro. Other studies have shown that it has potential against several types of cancers, but this study sought to improve ATO's effectiveness as well.
Atovaquone itself attacks the energy production system of the organisms that cause malaria and pneumonia. By mimicking a critical intermediate, it can halt energy production at a crucial juncture, effectively killing the microorganisms. Recent studies have shown that this also translates into several cancer types, though with reduced strength. This study attempted to increase ATO's effectiveness against cancer cells by attaching a molecule called triphenylphosphonium (TPP+) to target ATO to the mitochondria (where energy production occurs).
Studies from other teams showed that attaching TPP+ to compounds helps target those compounds to the mitochondria, so the team reasoned it could increase ATO's potency. The team created several different candidates by varying the size of the TPP+.
The study circled around testing the TPP+-ATO candidates against pancreatic cells in vitro. They found that every TPP+-ATO candidate reduced cancer growth to a greater extent than ATO alone. Two of the candidates prevented energy production at an earlier point that ATO alone did, while two others could inhibit energy production at two points. They finally settled on a candidate they termed Mito10-ATO, which could suppress the growth of several cancer cell lines, and even reverse cancer-related immune suppression.
This study identified Atovaquone modified with triphenylphosphonium was more effective at suppressing cancer growth than ATO alone. This seemed to be due to better mitochondrial uptake of the drug, where it attacked the cell's energy production system at multiple points. The team even saw a reversal of the immunosuppressive environment present in some cells.
The study concludes, "In this study, we showed that TPP+-conjugated ATO analogs (Mito4-ATO, Mito10-ATO, Mito12-ATO, and Mito16-ATO) are considerably more potent than the parent drug, ATO, at inhibiting the proliferation of pancreatic and other cancer cell types."