The Inhibition of CDK4/6 regulates the activity of multidrug resistance pumps in glioblastoma.

Glioblastoma (GBM) is a highly malignant central nervous system tumor known for its resistance to current treatment options. Efflux pumps play a crucial role in the development of multidrug resistance (MDR), leading to poor clinical outcomes. In this context, new treatment modalities targeting the cell cycle have gained attention in the recent years. Abemaciclib (ABE), a selective CDK4/6 inhibitor, inhibits the activity of different drug efflux pumps in several types of cancer. However, the role of ABE in regulating these pumps in GBM remains unclear. In this study, the therapeutic efficacy of ABE in the regulation of multidrug resistance pumps was evaluated in TMZ-resistant T98G and TMZ-sensitive U87MG GBM cells. The cells treated with different doses of ABE for 24 h and then CCK-8, Annexin V, cell cycle, AO/PI, RT-PCR and immunofluorescence analysis were performed. Our findings demonstrated that ABE significantly reduced the viability of GBM cell lines. However, the activity of the efflux pumps, especially P-gp and MRP1 pumps, was different due to TMZ resistance. Particularly, ABE treatment reduced the P-gp gene and protein levels in T98G cells. Additionally, ABE differentially affected the cell cycle in terms of TMZ-sensitivity. In conclusion, ABE treatment differentially regulated the inhibition of efflux pump activities in GBM cells in terms of TMZ resistance. Our findings may provide new insights into the potential use of ABE as a therapeutic agent to overcome MDR in TMZ-resistant GBM.