Chemotherapy is a major method in cancer treatment. Drug resistance, an essential factor leading to poor treatment and prognosis, is regarded as a serious problem in tumor therapy. However, the mechanism of the drug resistance in tumor therapy is complex and remains unveiled.

A recent study published in Chemical Science disclosed that high levels of glutathione (GSH) contributed a lot to drug resistance. LI Jia and ZANG Yi from Shanghai Institute of Materia Medica of Chinese Academy of Sciences (SIMMCAS) and SIMMCAS alumni LI Xin from Zhejiang University developed a novel probe (Na-8) to track endogenous GSH fluctuation in live cells and revealed the detailed roles of GSH in chemoresistance.

The researchers constructed a small library of probes and screened a naphthalimide–sulfoxide based fluorogenic probe (Na-8) for GSH detection. Through experiments, they confirmed that applying Na-8 in molecular assay with its specific reaction to GSH yielded a 2200-fold fluorescence enhancement. They then moved on to check its ability to image GSH in live cells. The result showed that Na-8 is more sensitive than monochlorobimane, a commercial dye, to detect endogenous GSH.

Because of its high sensitivity, Na-8 was used to monitor the dynamic changes of intracellular GSH levels in liver cancer cells (HepG2) and their normal counterpart cells (L02) challenged by cytotoxic drugs doxorubicin. As a result to adapt towards long-term intrinsic oxidative stress, a higher GSH level was observed in HepG2 cells than L02 cells, which protects them from aggravating oxidative stress caused by Doxorubicin.

Furthermore, in vitro the fluorescent products of Na-8 were found attenuated by peroxynitrite, and after which lighted up by GSH again. The intracellular imaging assay also proved this reversible reaction feasible, which provided new ideas to design novel types of probes in the concept of biologically reversible.

This work was supported by National Natural Science Foundations of China, Zhejiang Provincial Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality.