l‐Asparaginase synergizes with etoposide via the PI3K/Akt/mTOR pathway in Epstein−Barr virus‐positive Burkitt lymphoma

Abstract Burkitt lymphoma (BL) is an aggressive Epstein−Barr virus (EBV)‐driven B‐cell lymphoma characterized by the translocation and rearrangement of the c‐Myc proto‐oncogene. High‐intensity multidrug chemotherapy regimens have a limited effect on the survival of refractory or relapsed BL patients, mainly owing to the high EBV load and drug resistance. l ‐asparaginase ( l ‐Asp) and etoposide (VP‐16) play a beneficial role in EBV‐related lymphoproliferative diseases; however, their roles and mechanisms in BL remain unclear. In this study, we found that VP‐16 inhibited BL cell proliferation and arrested the cell cycle at the G 2 /M phase. It also induced autophagy and activated the extrinsic and intrinsic apoptotic signaling pathways in BL cells. Mechanistically, VP‐16 inhibited c‐Myc expression and regulated the PI3K/Akt/mTOR signaling pathway. Notably, VP‐16 also showed a specific synergistic effect with l ‐Asp to induce apoptosis in EBV‐positive BL cells but not in EBV‐negative BL cells. VP‐16 combined with l ‐Asp further inhibited c‐Myc expression and downregulated the PI3K/Akt/mTOR signaling pathway. Additionally, we found that VP‐16 inhibited the expression of latent membrane protein 1 (LMP1), and in combination with l ‐Asp further decreased LMP1 expression in Raji cells. Our in vivo data also showed that the dual‐drug combination significantly inhibited the growth of BL tumors and prolonged the survival of mice compared to VP‐16 alone. In conclusion, this study provides new evidence that l ‐Asp may enhance the antitumor effect of VP‐16 by inhibiting the PI3K/Akt/mTOR signaling pathway in EBV‐positive BL cells.