Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma
- Equal contributors
1 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China
Journal of Hematology & Oncology 2013, 6:53 doi:10.1186/1756-8722-6-53Published: 18 July 2013
Burkitt leukemia/lymphoma is a major subtype of aggressive B-cell lymphoma. Biological targeted therapies on this disease need to be further investigated and may help to improve the clinical outcome of the patients.
This study examined the anti-tumor activity of the histone deacetylases (HDAC) inhibitor valproic acid (VPA) combined with the mammalian target of rapamycin (MTOR) inhibitor temsirolimus in Burkitt leukemia/lymphoma cell lines, as well as in primary tumor cells and a murine xenograft model.
Co-treatment of VPA and temsirolimus synergistically inhibited the tumor cell growth and triggered the autophagic cell death, with a significant inhibition of MTOR signaling and MYC oncoprotein. Functioned as a class I HDAC inhibitor, VPA potentiated the effect of temsirolimus on autophagy through inhibiting HDAC1. Molecular silencing of HDAC1 using small interfering RNA (siRNA) attenuated VPA-mediated regulation of CDKN1A, CDKN1B and LC3-I/II, regression of tumor cell growth and induction of autophagy. Meanwhile, VPA counteracted temsirolimus-induced AKT activation via HDAC3 inhibition. HDAC3 siRNA abrogated the ability of VPA to modulate AKT phosphorylation, to suppress tumor cell growth and to induce autophagy. Strong antitumor effect was also observed on primary tumor cells while sparing normal hematopoiesis ex vivo. In a murine xenograft model established with subcutaneous injection of Namalwa cells, dual treatment efficiently blocked tumor growth, inhibited MYC and induced in situ autophagy.
These findings confirmed the synergistic effect of the HDAC and MTOR inhibitors on Burkitt leukemia/lymphoma, and provided an insight into clinical application of targeting autophagy in treating MYC-associated lymphoid malignancies.