Reactive Oxygen Species Implicated in Cancer Drug Resistance

Study findings may change the development of cancer therapy.

Study findings may change the development of cancer therapy.

An increase in the amount of certain chemically reactive, oxygen-containing molecules may be responsible for chemotherapy resistance in cancer patients, according to a new study.

The findings of the study suggest that there is a direct link between chemotherapy resistance and reactive oxygen species (ROS) found in mitochondria. The discovery has important implications for cancer therapy development.

The researchers found that patients who undergo chemotherapy have higher levels of ROS, a factor that is associated with drug resistance.

“Based on our studies with responsive versus drug-resistant cancer cells, it appears that patients who still respond to therapy typically don’t have such high levels of ROS,” said Imoh Okon, assistant professor in Georgia State’s Center for Molecular and Translational Medicine.

Cancer drug resistance remains a major problem in cancer therapy despite efforts made to combat this issue because many patients who die from cancer become resistant to previously effective drugs.

Okon and his co-author propose that physicians need a measure of relative ROS levels under “normal” or basal conditions to help determine if patients are becoming resistant to cancer drugs. The researchers are developing a test that will detect early cancer treatment resistance in patients.

ROS is beneficial to the body at normal levels and is essential to human physiology. Under disease conditions, however, the regulatory redox balance becomes altered.

Treatments such as chemotherapy and radiation depend on higher levels of ROS to be effective. Ironically, these high levels of ROS are responsible for chemotherapy and radiation resistance.

The high levels even cause normal cells to have genetic abnormalities and mutations over time.

“If you know what the relative basal ROS level is, then you can really monitor over time whether it’s getting too high based on the specific treatment for that patient,” Okon said. “We also recommended having some sort of spacing in between these treatments to allow the cells to recover and ROS levels to come down to normal levels to get the cells going again before you hit cancer cells with another battery of targeted or chemotherapy drugs.”

When cancer cells alter their metabolism, they are able to grow and proliferate, causing tumors to become unresponsive to cancer drugs. Mitochondria control cellular metabolism, which when exposed to external factors such as chemotherapy and radiation, it triggers adaptations to normal function, and they begin to play abnormal roles that promote drug resistance.

The researchers recently proved that resistance to the new generation target-specific cancer drug gefitinib was positively associated with mitochondrial dysfunction and increased ROS in lung cancer cells.

While there are likely other contributors to cancer drug resistance, ROS plays a key role in metabolic events that may be central to the process, Okon said.