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 G2/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.

Substrate Affinity Is Not Crucial for Therapeutic L-Asparaginases: Antileukemic Activity of Novel Bacterial Enzymes

“…According to the most recent studies, it appears that the use of L-asparaginase as a single agent does not have the desired effect in this cell line. Although our experiments do not allow us to unequivocally confirm such a hypothesis, similar observations have already been demonstrated in in vivo studies in mice (engrafted with RAJI cells), which revealed that EcAII as a single agent showed little antitumor activity, but in combination with etoposide significantly suppressed tumor burden and improved survival time compared to the control group [43].…”

Etoposide, dexamethasone, and pegaspargase with sandwiched radiotherapy in early-stage natural killer/T-cell lymphoma: A randomized phase III study

“… 35 Of note, a recent study provided new evidence that L-asparaginase may enhance the antitumor effect of etoposide by inhibiting c-Myc expression and the PI3K/Akt/mTOR signaling pathway in EBV-positive lymphoma cells. 36 …”