Researchers at the University of Louisville have uncovered a cadre of small molecules that tell certain proteins to kill lung cancer cells. The team, led by Chi Li, Ph.D., assistant professor of medicine, published its finding in the April 2014 issue of Molecular and Cellular Biology.
One of the characteristics of lung cancer is the dysregulation of apoptosis, or regulated cell death. Cancer cells are able to survive in the unnatural state. Proteins from the Bcl-2 family are major regulators of apoptosis. One of them, Bax, sometimes becomes erratic and loses its ability to maintain its killer function, which leads to lung tumor development. The researchers realized that this meant Bax potentially could be part of the cure as well.
The researchers used virtual screening in their study, a process where they ran through a computer program all the possible combinations of molecules that could bind with the Bax proteins to find the best combination. After trying more than 10 million molecules, they found the right one. This Bax-activating small molecule compound kills lung cancer cells as well as inhibits the growth of lung tumors transplanted into mice.
The scientific finding of Li and his team showed it is possible to identify small molecules capable of binding and activating Bax proteins that in turn induce apoptosis in cancerous cells. In the study, Li and his team were able to specifically induce tumor cell death while avoiding normal cell death.
The compound also shows synergy with the widely used chemotherapeutic drug carboplatin. This means that the potential application for this compound in cancer treatment is very broad.
The scientific discovery could form the basis for advanced therapeutic agents for cancer in patients, specifically lung cancer, which is especially prevalent in Kentucky.
The high mortality rate of lung cancer is partially attributed to ineffective therapeutic treatments. This makes it very important for scientists to develop new chemotherapeutic drugs for lung cancer.
Li says it could pave the way for new treatment for other types of cancer as well. "Lung cancer is a really big issue for us. We have a large mortality rate, and that's one of the reasons we wanted to go after lung cancer," he said. "We are in the process of trying to expand the application of our discovery onto different types of cancer."
Li and his team will have the opportunity for that expansion very soon. The National Institutes of Health recently awarded them a grant of $1.5 million to continue their groundbreaking research.
- G. Zhao, Y. Zhu, C. O. Eno, Y. Liu, L. DeLeeuw, J. A. Burlison, J. B. Chaires, J. O. Trent, C. Li. Activation of the Proapoptotic Bcl-2 Protein Bax by a Small Molecule Induces Tumor Cell Apoptosis. Molecular and Cellular Biology, 2014; 34 (7): 1198 DOI: 10.1128/MCB.00996-13
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