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The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLC) to tyrosine kinase inhibitors (TKIs) has been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression and their dysregulation has been implicated in tumorigenesis. To understand the role of microRNAs in TKI-resistant NSCLC, we examined TK receptor-mediated microRNA changes. Here we report that miR-30b/c and miR-221/222, modulated by both EGF and MET receptors, and miR-103, -203, controlled only by MET, play important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition (EMT) of NSCLC cells, in vitro and in vivo, by inhibiting the expression of Bim, APAF-1, PKC-ε and SRC genes. The finding suggests that modulation of specific microRNAs may provide a therapeutic approach for future treatment of NSCLC.

Disulfide bonds have been widely used to develop reduction-responsive drug-delivery systems (DDS) for cancer therapy. We propose that disulfide bonds might be also used as an oxidation-responsive linkage just like thioether bonds, which can be oxidized to hydrophilic sulfoxide or sulphone in the presence of oxidation stimuli. To test our hypothesis, we design three novel paclitaxel-citronellol conjugates linked via different lengths of disulfide-bond-containing carbon chain. The prodrugs can self-assemble into uniform-size nanoparticles with impressively high drug loading (>55%). As expected, the disulfide-bond-bridged prodrug nanoparticles show redox dual-responsive drug release. More interestingly, the position of disulfide bonds in the carbon chain linkage has profound impacts on the redox dual responsiveness, thereby affecting the drug release, cytotoxicity, pharmacokinetics, biodistribution, and in vivo antitumor efficacy of prodrug nanoassemblies. The redox dual-responsive mechanism is elucidated, and how the position of disulfide bonds in the carbon chain affects the redox dual responsiveness and antitumor efficiency of prodrug nanoassemblies is also clarified. Our findings give new insight into the stimuli responsiveness of disulfide bonds and provide a good foundation for the development of novel redox dual-responsive DDS for cancer therapy.

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