Inducing apoptosis in quiescent cells, a potential new therapeutic strategy for chemotherapy and the treatment of fibrotic disease

Web Published:
12/5/2011
Description:

Princeton Docket # 11-2633

The ability to selectively kill quiescent cells could be a powerful tool in medicine. In particular, the ability to kill the quiescent tumor stem cells could be an important addition to our chemotherapeutic repertoire. A better understanding of the transition between quiescent and activated cellular states of fibroblasts may also suggest new strategies to treat fibrotic disease.

Using metabolomics technology, researchers in the department of Molecular Biology at Princeton University have discovered that the pentose phosphate pathway is active in cultured primary dermal fibroblasts made quiescent by contact inhibition. Treatment with a small molecule inhibitor of the pentose phosphate pathway for 4 days resulted in a higher induction of apoptosis in quiescent, contact-inhibited fibroblasts than in proliferating fibroblasts. Induction of apoptosis was even higher in fibroblasts made quiescent by a second method, serum starvation.

Quiescent, primary dermal fibroblasts are also found to activate autophagy. Treating proliferating and quiescent fibroblasts with an inhibitor of autophagy resulted in a time-dependent induction of apoptosis in serum-starved fibroblasts but had little effect on proliferating or contact-inhibited fibroblasts.

A combination treatment with both the pentose phosphate pathway inhibitor and the autophagy inhibitor was found to be more effective in inducing apoptosis in quiescent, serum-starved cells than treatment with either inhibitor alone. Pentose phosphate pathway inhibition alone resulted in a six-fold induction of apoptosis after 24 hours, while autophagy inhibition alone had less than a two-fold effect on apoptosis. Pentose phosphate pathway inhibition in combination with autophagy inhibition resulted in an approximately sixteen-fold induction of apoptosis in the serum-starved fibroblasts after 24 hours. In contact-inhibited fibroblasts, the induction was approximately four-fold in response to both inhibitors. In proliferating fibroblasts, the induction was approximately two-fold.

Inventor

Hilary Coller

Hilary Coller is an assistant professor of molecular biology at Princeton University. The Coller lab uses genomic approaches to gain insight into cell cycle control in normal tissues and cancer. Because uncontrolled cell division is so dangerous for an organism, the well-behaved cell must know not only when to divide, but¿crucially¿when not to. Shutting down cell division prevents tumors and maintains the proper form of tissues. Many cells, though, including fibroblasts, must also retain the ability to start dividing again when conditions are right¿when the organism must grow, or a damaged tissue must be repaired. A cell in such a temporary, non-dividing state is said to be ¿quiescent.¿ Signals that send a cell into quiescence include loss of contact with the underlying surface, too much contact with neighboring cells, and not receiving specific growth factors from the surroundings.

Publications:

Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, Pollina EA, Rabitz HA, Rabinowitz JD, Coller HA. (2010) Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol. 8: e1000514. (Selected for Nature Research Highlights and Faculty of 1000).

Intellectual Property and status:

Patent pending

Contact

Laurie Tzodikov

Princeton University Office of Technology Licensing ¿ (609) 258-7256¿ tzodikov@princeton.edu

PU #11-2633

Patent Information:
For Information, Contact:
Laurie Tzodikov
Licensing Associates
Princeton University
tzodikov@Princeton.EDU
Inventors:
Hilary Coller
Keywords:
cancer/oncology
drug discovery
small molecule