To investigate the sensitizing effect of the high-chloride salt of the traditional Chinese medicine monomer derivative, dihydroperiplanarol (DP), in reversing the acquired resistance of colorectal cancer to oxaliplatin (L-OHP), and to elucidate its potential molecular mechanism based on the PI3K/Akt signaling pathway and the anti-apoptotic network.

The human colorectal cancer L-OHP-resistant cell line (SW480/L-OHP) was established by a stepwise concentration increment method. The synergistic sensitizing effect of low-toxicity DP combined with L-OHP was evaluated by the CCK-8 method and CompuSyn software, and the effect on the long-term proliferation potential of the cells was assessed by the plate colony formation experiment. The apoptosis level was detected by Annexin V-FITC/PI double staining flow cytometry. The expression changes of PI3K/Akt signaling pathway targets and downstream apoptosis-related proteins were detected by Western blot. Statistical analysis was performed using GraphPad Prism 9.0 software. Quantitative data were expressed as (

The resistant cell line SW480/L-OHP with epithelial-mesenchymal transition (EMT) characteristics and anti-apoptotic phenotype was successfully constructed. The CCK-8 and colony formation experiments showed that the combination of 10 μmol/L low-toxicity DP and L-OHP exhibited significant synergy (CI<1), and the half inhibitory concentration (IC50) of L-OHP for the resistant cells decreased from 40.9 μmol/L to 3.8 μmol/L, with a reversal ratio of 10.7, and effectively inhibited the colony formation ability (P<0.000 1). Flow cytometry indicated that the combination treatment overcame the apoptosis resistance of the resistant cells, and the total apoptosis rate increased to 21.1% (P<0.000 1). Mechanism analysis showed that the combination treatment effectively inhibited the phosphorylation levels of PI3K and Akt in the resistant cells, thereby down-regulating the anti-apoptotic protein Bcl-2 and up-regulating the expression of pro-apoptotic protein Bax, and reshaping the apoptosis protein homeostasis of the resistant cells.

Dihydroperiplanarol high-chloride salt is a clinically promising chemotherapy sensitizing agent for oxaliplatin. It can effectively reverse the acquired resistance phenotype of colorectal cancer cells by synergistically targeting and blocking the PI3K/Akt signaling pathway and reshaping the anti-apoptotic network, providing a new combined traditional Chinese and Western medicine treatment strategy to overcome clinical chemotherapy resistance.