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.

• Authors: Wei Sang, Dongyun Tu, Meng Zhang, Yuanyuan Qin, Wenjing Yin, Xuguang Song, Cai Sun, Dongmei Yan, Xiangmin Wang, Lingyu Zeng, Zhenyu Li, Kailin Xu, Linyan Xu
• Journal: Journal of biochemical and molecular toxicology (J Biochem Mol Toxicol) Vol. 36 Issue 8 Pg. e23117 (Aug 2022) ISSN: 1099-0461 [Electronic] United States
• PMID: 35757978 (Publication Type: Journal Article)
• Copyright: © 2022 Wiley Periodicals LLC.

Chemical References

• Etoposide
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Asparaginase

Topics

• Animals
• Apoptosis
• Asparaginase (pharmacology, therapeutic use)
• Burkitt Lymphoma (drug therapy, metabolism, pathology)
• Epstein-Barr Virus Infections (complications, drug therapy)
• Etoposide (pharmacology, therapeutic use)
• Herpesvirus 4, Human (metabolism)
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• TOR Serine-Threonine Kinases (metabolism)