2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2025 Jun 27:297:117910. doi: 10.1016/j.ejmech.2025.117910.
Lulu Deng 1,  Gonghan Zhang 1,  Maofei He 1,  Yuehu Wang 2,  Jiang Li 1,  Xinglian Xu 1,  Xiaojiang Hao 3,  Yanhua Fan 4,  Shuzhen Mu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang, 550014, China; Natural Products Research Center of Guizhou Province, 3491 Baijin Road, Guiyang, 550014, China.
  • 2 Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Kunming, 650201, China.
  • 3 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang, 550014, China; Natural Products Research Center of Guizhou Province, 3491 Baijin Road, Guiyang, 550014, China; Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Kunming, 650201, China. Electronic address: haoxj@mail.kib.ac.cn.
  • 4 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang, 550014, China; Natural Products Research Center of Guizhou Province, 3491 Baijin Road, Guiyang, 550014, China. Electronic address: fanyhkyem@163.com.
  • 5 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang, 550014, China; Natural Products Research Center of Guizhou Province, 3491 Baijin Road, Guiyang, 550014, China. Electronic address: muzi0558@126.com.
PMID: 40602222 DOI: 10.1016/j.ejmech.2025.117910
Abstract

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.

Keywords

Genipin derivatives; Multidrug resistance; P-glycoprotein; Paclitaxel; Y box binding protein 1.

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