A recent article published in the journal Cell Stem Cell describes research by scientists at the National Institute of Dental and Craniofacial Research (NIDCR) and their colleagues at the National Institutes of Health regarding a protein called mammalian target of rapamycin (mTOR). The scientists had helped to build the case that mTOR is frequently activated in epithelial, or skin, cells extracted from head and neck squamous cell carcinomas (HNSCC). This discovery raised an intriguing therapeutic possibility. Since almost 80% of patients with HNSCC will receive radiation therapy, what if the tumor cells were pretreated with the mTOR-inhibiting chemotherapy drug rapamycin? Would the drug sensitize the tumor cells and potentially allow oncologists to reduce the level of radiation needed to kill them? The scientists established a panel of 2 standard HNSCC-derived cell lines and included colonies of normal oral mucosa, or skin, cells as a control. They introduced the mTOR inhibitor to the cell lines followed by sublethal levels of ionizing radiation. In the HNSCC cells, a subtle effect was seen in the size and survival of the colonies. But it was extremely limited. They turned to the colonies of normal oral mucosal cells, assuming they had withered and died from the combination of rapamycin and radiation. To the researchers’ complete surprise, the colonies had grown significantly and were more efficient at forming new colonies. The implication being, rapamycin protects them from the effects of the radiation. More importantly, since each colony would have to arise from a single surviving progenitor cell, rapamycin also protects oral mucosal stem cells from radiation.
The scientists began thinking in a new direction. Possibly rapamycin has the potential to protect HNSCC patients treated with radiation from developing the painful side effect of oral mucositis. The condition occurs because oral mucosal cells near the tumor absorb energy from the radiation beam and die. Among the collateral damage are the stem cells that naturally repopulate damaged tissue with healthy new cells. Without functioning stem cells, the wounds can be extremely slow to heal, and patients are at great risk of developing secondary infections and often have difficulty chewing and swallowing.
Follow-up animal studies confirmed their cell-culture surprise, including the survival of the stem cells. The researchers also drilled down deeper into the cell biology, finding that rapamycin likely protects against oxidative damage (which can cause cell senescence and death) via increased expression of the protein manganese superoxide dismutase, a mitochondrial enzyme that has been linked to radiation resistance.
(Source: NIDCR, Science News in Brief, January 16, 2013)
