Discovery of a novel Genipin derivative targeting YB-1 to enhance the P-glycoprotein-mediated paclitaxel sensitivity of paclitaxel-resistant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and its incidence rate and mortality are relatively high. Paclitaxel, a classic chemotherapy drug, has become one of the first-line drugs commonly used for patients with advanced NSCLC in clinical practice, but multidrug resistance has become a major factor seriously restricting its efficacy. Therefore, overcoming multidrug resistance to paclitaxel is an important issue that urgently needs to be addressed to improve its efficacy. In our study, twenty-three novel derivatives of Genipin were synthesized by using different intermediates of methylene indole ketones and Genipin. When they were combined with paclitaxel, most of them exhibited good reversal activity in P-gp-mediated paclitaxel-resistant non-small cell lung cancer cells (A549/Taxol cells). The most potent compound 13 could enhance the sensitivity of A549/Taxol cells with low cytotoxicity to paxlitaxel by targeting YB-1 and reducing the expression of total YB-1 protein and the level of YB-1 protein in the nucleus, thus inhibiting the expression and function of the downstream protein P-gp, further suppressing the efflux rate of paclitaxel and increasing the concentration of intracellular paclitaxel. In addition, tumour growth in paclitaxel-resistant lung cancer xenografts was significantly decreased by combination treatment with compound 13 and paclitaxel. H&E staining of mouse organs and IHC analysis of A549/Taxol tumour tissues indicated that compound 13 could enhance the paclitaxel sensitivity of paclitaxel-resistant NSCLC, with low cytotoxicity. These results clearly indicate that compound 13, by targeting YB-1, might be useful as a novel chemosensitizer in combination with paclitaxel to overcome MDR in the management of NSCLC.