Reactive Oxygen Turns Rapamycin into a Cancer Killer

Cancer researchers have found a way to exploit an inherent weakness in the functioning of a pro-cancer protein in order to turn a cytostatic drug into a potent tumor killer.

The Akt protein encourages cellular survival by inhibiting apoptotic processes. Akt is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to the growth and expansion of skeletal muscle as well as general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt has been implicated as a major factor in many types of cancer.

In the current study published in the December 9, 2008, issue of the journal Cancer Cell investigators at the University of Illinois (Chicago, USA) showed that while Akt protected cancer cells from most apoptotic processes; it was not able to defend them from the effects of increased intracellular levels of reactive oxygen species (ROS).

Previous studies had shown that the cytostatic drug rapamycin (sirolimus) stimulated Akt activity while increasing cellular ROS levels. Cancer cells treated with the drug stopped dividing and became resistant to most chemotherapeutic agents. However, further treatment with ROS-inducing agents triggered a form of apoptosis that was independent of Akt.

"We found that although Akt can protect cancer cells from many of the external signals that would ordinarily induce cell death, including many chemotherapy drugs, it cannot protect from ROS inducers,” said senior author Dr. Nissim Hay, professor of biochemistry and molecular genetics at the University of Illinois. "So even though cancer cells treated with rapamycin stop dividing, they activate Akt, which makes the cells more resistant to other chemotherapy drugs. We use that to our advantage because over activation of Akt sensitizes the cells to ROS mediated cell death. If we treat the cells with ROS inducers and rapamycin together we can now kill the cells, not just arrest their growth.”

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