Despite surgical advances, pancreatic cancer continues to be one of the most deadly and difficult cancers to manage due to a lack of effective therapies. However, researchers are hoping to change that with a novel combination of an experimental drug and a common antibiotic that has shown promising results in preclinical experiments. The results of these experiments were recently published in the journal Cancer Research.
The researchers found a potent synergistic effect when they combined the drug Sabutoclax and the antibiotic Minocycline. The combination was significantly toxic to pancreatic cancer cells and disrupted tumor growth and extended survival in several types of advanced pancreatic cancer mouse models.
Sabutoclax is a novel drug that inhibits B-cell lymphoma 2 (Bcl-2) family proteins, which have been shown to be overexpressed in the majority of pancreatic cancers. Bcl-2 proteins play a key role in cell survival by protecting against a form of cell suicide known as apoptosis. Minocycline, a synthetic tetracycline-based antibiotic, has shown only limited success as an anti-cancer agent because it promotes the expression of pro-survival Bcl-2 proteins and, subsequently, can lead to inhibition of caspase-3 and caspase-9 activation downstream in the cell death pathway. Caspases are enzymes that play key roles in apoptosis, necrosis and inflammation, and their activation is necessary for apoptotic cell death. However, studies have also shown that Minocycline is capable of inducing modest cancer cell death and growth inhibition in a variety of cancer types. The researchers hypothesized that Sabutoclax may negate Minocycline's Bcl-2 promotion and amplify its anti-cancer properties.
The synergistic effect of the two drugs completely eliminated Stat3 expression in pancreatic cancer cells. Stat3 is a protein that regulates a cell signaling pathway critical to tumor growth and development. Cell signaling pathways are a defined series of interactions between proteins that govern biological functions, initiated by receptors on the surface of cells. The researchers were able to reverse the lethal effects of the combination therapy by reintroducing activated Stat3 proteins.
The researchers hope to continue evaluating other tetracyclines in combination with Sabutoclax to determine if these anti-cancer effects extend outside of just Minocycline, and if these combinations are effective against other cancer types.
Based on material originally posted by Virginia Commonwealth University.