Abstract
BackgroundBurkitt 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.MethodsThis 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.ResultsCo-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.ConclusionsThese 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.
Highlights
Burkitt leukemia/lymphoma is a major subtype of aggressive B-cell lymphoma
We examined the combinatorial action of the histone deacetylases (HDAC) inhibitor valproic acid (VPA) with clinical relevant mammalian target of rapamycin (MTOR) inhibitor temsirolimus in Burkitt leukemia/lymphoma (BL) cells both in vitro and in vivo
Combination of the HDAC inhibitor VPA with the MTOR inhibitor temsirolimus induced synergistic cytotoxicity in BL cells The BL cell lines Namalwa and Raji were treated with different concentrations of VPA and/or temsirolimus for 48 hours
Summary
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. Burkitt leukemia/lymphoma (BL) is a highly aggressive subtype of B-cell neoplasm characterized by constitutive MYC expression and PI3K activation [1]. BL responds to intensive chemotherapy regimens, biologically targeted. Defect in autophagy is related to aggressive phenotype and poor prognosis in lymphoma patients [6,7]. These results indicated that reactivation of autophagy could be mechanistically important in lymphoma treatment
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.