Resistance to chemotherapy is a major obstacle limiting the successful treatment of cancer patients.
The discovery of a novel antioxidant compound by a group of University of Arizona researchers led by pharmacology and toxicology assistant professor Donna D. Zhang has proven its ability to combat chemoresistance and enhance the efficacy of current chemotherapeutic drugs.
Zhang also is a member of the Arizona Cancer Center.
The finding, reported in the Proceedings of the National Academy of Sciences, represents a breakthrough in the effectiveness of cancer treatment.
The key to the discovery is an understanding of the transcription factor, or movement of genetic information of the protein Nrf2. Nrf2 regulates a multitude of genes that promote cell survival under detrimental environments, such as oxidative stress.
Oxidative stress is associated with an imbalance between the production and removal of chemically reactive molecules containing oxygen known as reactive oxygen species. During times of oxidative stress, the body's ability to detoxify and repair damage is disrupted and has been implicated in cancer and other diseases.
The ability of cells to properly regulate the Nrf2 defense response is important to protect against the damaging effects of oxidative stress.
Normally, Nrf2 is expressed at very low levels in most organs of the body. But recent studies have shown that high levels of Nrf2 are present in many types of tumors.
These studies, Zhang said, "suggested that Nrf2 has a dark side."
"Clearly, the control mechanism of Nrf2 has been hijacked by the cancer cells, and the high levels of Nrf2 are creating an environment for cancer cells to survive and thrive and promote chemoresistance," she added.
Her team searched for antioxidant compounds that were able to inhibit the Nrf2 defense response mechanism and found that brusatol, a quassinoid isolated from the fruit of the Brucea javanica tree, is a unique inhibitor of the Nrf2 pathway.
Zhang's team showed that brusatol can combat chemoresistance associated with cisplatin treatment, a platinum-based chemotherapy drug. Through a reduction in the protein level of Nrf2, brusatol is able to sensitize cancer cells to therapeutic treatments.
Their results show that when brusatol is used in combination with cisplatin, there is an increase in cell death, reduced cell proliferation, and a reduction in tumor growth compared to cisplatin treatment alone.
Zhang said, "As a result of this study, interest has been raised to develop brusatol into a commercial product that can be used in the clinic to enhance the effectiveness of current cancer treatments and combat chemoresistance."
This study was supported by grants from the American Cancer Society and the National Institute of Environmental Health Sciences.