Cancer drug resistance: redox resetting renders a way

Abstract

Disruption of redox homeostasis is a crucial factor in the development of drug resistance, which is a major problem facing current cancer treatment. Compared with normal cells, tumor cells generally exhibit higher levels of reactive oxygen species (ROS), which can promote tumor progression and development. Upon drug treatment, some tumor cells can undergo a process of 'Redox Resetting' to acquire a new redox balance with higher levels of ROS accumulation and stronger antioxidant systems. Evidence has accumulated showing that the 'Redox Resetting' enables cancer cells to become resistant to anticancer drugs by multiple mechanisms, including increased rates of drug efflux, altered drug metabolism and drug targets, activated prosurvival pathways and inefficient induction of cell death. In this article, we provide insight into the role of 'Redox Resetting' on the emergence of drug resistance that may contribute to pharmacological modulation of resistance.

Keywords: cancer therapy; drug efflux; drug resistance; oxidative stress; redox modifications.

Figure 1. General mechanisms of cancer drug resistance

The anticancer activity of a drug can be limited by reduced drug influx or increased drug efflux, changes in expression levels of drug target, mutation of drug target, and a lack of cell death induction.

Figure 2. Comparisons of ROS level between different stages of tumor progression and tumor drug-resistance

While in normal cells ROS generation and antioxidants are in balance, increased ROS levels are hallmarks of cancer cells. Marked increase in ROS can be achieved by chemotherapeutic agents, resulting in irreparable cellular damages and cancer cell death. However, some cancer cells can develop drug resistance by redox resetting.

Figure 3. Schematic diagrams showing the structures of MDR1, MRP1 and BCRP

All ABC transporters contain transmembrane and membrane-spanning domains. The disulfide bonds between the cysteine residues identified in the figure are required for maintenance of protein stability and transporter function.

Figure 4. Redox regulation of drug efflux transporters expression

(a) Oxidation of KEAP1 dissociates NRF2 from the complex, allowing the translocation and activation of NRF2; (b) Oxidative stress promotes the translocation of APE-1, facilitating transcription of numerous gene including MDRs, MRPs and BCRP; (c) FOXO can be activated by interacting with transportin through disulfide linkage under oxidative stress. The activation of these transcription factors contributes to the expression of drug efflux transporters.

Figure 5. 5-FU resistance in cancer cells by TYMS oxidation

The fluoropyrimidines (5-FU) are broken down into three metabolites, fluorodeoxyuridine monophosphate (FdUMP), fluoro-deoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). The principal mechanism of action of 5-FU is the inhibition of thymidylate synthase (TYMS), but alternative pharmacodynamic pathways acting through incorporation of drug metabolites into DNA and RNA. TYMS can also be activated through direct oxidation that leads to 5-FU resistance.

Figure 6. ROS-induced deregulation of apoptosis

S-nitrosylation of FLIP inhibits the interaction between procaspase-8 and FADD, leading to inactivation of caspase-8. S-glutathionylation and S-nitrosylation of caspase-3 inhibit cleavage to the active form. The high ROS level in drug-resistant cells may contribute to escape from apoptosis by S-nitrosylation of FLIP, as well as S-glutathionylation and S-nitrosylation of caspase-3.