Response of Medulloblastoma Cells to Vincristine and Lomustine: Role of TRKC, CTNNB1 and STK15

Background: Vincristine and lomustine are two important chemotherapeutic drugs used for the treatment of different types of neoplasms, including medulloblastomas. Materials and Methods: We investigated the effects of vincristine and lomustine on 12 primary medulloblastoma cell cultures and the DAOY cell line using the annexinV-flow cytometry and immunoblotting techniques, following treatment of cells for different periods of time. Results: Both drugs triggered apoptosis and cell cycle delay at the G 2 /M phase and also up-regulated p16. Furthermore, the expression of 8 different cancer-related genes were assessed and their mRNA and protein levels were found to be highly heterogeneous and did not correlate in several medulloblastoma cultures. Importantly, there was significant correlation between the level of cadherin-associated protein beta 1 (CTNNB1) and Aurora kinase A (STK15) proteins and neurotrophic tyrosine kinase receptor type 3 (TRKC) mRNA and the proportion of apoptosis induced by vincristine, the combination of both drugs, and lomustine, respectively. Conclusion: These genes could be of great importance as therapeutic biomarkers during the treatment of medulloblastoma patients with vincristine and lomustine. Medulloblastoma, aggressive tumor of the cerebellum, is the most common malignant brain tumor in children. It represents approximately 20% of pediatric intracranial neoplasms (1). Medulloblastoma, like all the other types of cancer, results from alterations in the equilibrium between cell growth and cell death, which drives the proliferation of cerebellar granule neuronal precursors. This equilibrium is under the control of different metabolic pathways. The most important ones for medulloblastoma-related carcinogenesis include wingless-type MMTV integration site family (WNT)/ CTNNB1 and AKT1 Kinase/ NFKB inhibitor interacting Ras-like 1 (AKT/NF-κB) (2). The WNT/β-catenin and AKT/NF-κB pathways include several transcription factors that control the expression of