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Int J Oncol. 2018 Aug;53(2):823-834. doi: 10.3892/ijo.2018.4438. Epub 2018 Jun 12.

Dihydrocelastrol exerts potent antitumor activity in mantle cell lymphoma cells via dual inhibition of mTORC1 and mTORC2.

Author information

1
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.
2
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.

Abstract

Mantle cell lymphoma (MCL) is a distinct and highly aggressive subtype of B-cell non-Hodgkin lymphoma. Dihydrocelastrol (DHCE) is a dihydro-analog of celastrol, which is isolated from the traditional Chinese medicinal plant Tripterygium wilfordii. The present study aimed to investigate the effects of DHCE treatment on MCL cells, and to determine the mechanism underlying its potent antitumor activity in vitro and in vivo using the Cell Counting kit-8 assay, clonogenic assay, apoptosis assay, cell cycle analysis, immunofluorescence staining, western blotting and tumor xenograft models. The results demonstrated that DHCE treatment exerted minimal cytotoxic effects on normal cells, but markedly suppressed MCL cell proliferation by inducing G0/G1 phase cell cycle arrest, and inhibited MCL cell viability by stimulating apoptosis via extrinsic and intrinsic pathways. In addition, the results revealed that DHCE suppressed cell growth and proliferation by inhibiting mammalian target of rapamycin complex (mTORC)1-mediated phosphorylation of ribosomal protein S6 kinase and eukaryotic initiation factor 4E binding protein. Simultaneously, DHCE induced apoptosis and inhibited cell survival by suppressing mTORC2-mediated phosphorylation of protein kinase B and nuclear factor-κB activity. In addition to in vitro findings, DHCE treatment reduced the MCL tumor burden in a xenograft mouse model, without indications of toxicity. Furthermore, combined treatment with DHCE and bortezomib, a proteasome inhibitor, induced a synergistic cytotoxic effect on MCL cells. These findings indicated that DHCE may have the potential to serve as a novel therapeutic agent for the treatment of MCL through dually inhibiting mTORC1 and mTORC2.

PMID:
29901111
DOI:
10.3892/ijo.2018.4438
[Indexed for MEDLINE]

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