A novel combination of an experimental drug and a common antibiotic has shown promising results in preclinical experiments. The results of these experiments were recently published in Cancer Research (2015; doi:10.1158/0008-5472.CAN-14-3013).
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.
The researchers, from Virginia Commonwealth University Massey Cancer Center and Institute of Molecular Medicine in Richmond, found a potent synergistic effect when they combined the drug sabutoclax and the antibiotic minocycline. The combination was significantly toxic to pancreatic cancer cells. It disrupted tumor growth and extended survival in several types of advanced pancreatic cancer mouse models.
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“Pancreatic cancer is so difficult to treat because it shows distinct genetic profiles among patients. This complexity contributes to its aggressive nature and resistance to conventional therapies such as chemotherapy and radiation therapy,” said corresponding author Paul B. Fisher, MPh, PhD, of VCU. “The multiple in vitro and in vivo models that we used have varying genetic backgrounds and yet they all still show susceptibility to this novel and exciting therapeutic combination.”
Sabutoclax is a novel drug that inhibits B-cell lymphoma 2 (Bcl-2) family proteins, which are 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 anticancer agent because it promotes the expression of prosurvival 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. 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.
