title: Gambogenic acid synergistically potentiates bortezomib-induced apoptosis in multiple myeloma.
abstract: Background:Although the introduction of protease inhibitor bortezomib (BTZ) and immunomodulatory agent lenalidomide has led to improved outcomes in patients with multiple myeloma (MM), the disease remains incurable. Gambogenic acid (GNA), a polyprenylated xanthone isolated from the traditional Chinese medicine gamboge, has been reported to have potent antitumor activity and can effectively inhibit the survival and proliferation of cancer. In this study, we hypothesized that GNA could synergistically potentiate BTZ-induced apoptosis of MM cells and that combining BTZ and GNA may provide a more effective approach to treat MM. Hence, we investigate thein vitroandin vivoeffects of BTZ and GNA, alone or in combination, against myeloma MM.1S cells.Methods:Cell counting kit-8 (CCK-8) assay, combination index (CI) isobologram, flow cytometry, western blot, xenograft tumor models, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunochemistry were used in this study.Results:The results showed that BTZ and GNA combination treatment resulted in a strong synergistic action against the MM.1S cell line. Increased G2/M phase cells were triggered by BTZ, GNA and the combined treatment. The combined treatment could induce more markedly apoptosis of MM.1S cells via the activation of PARP cleavage, P53, Caspase-3 cleavage and Bax and inhibition of Bcl-2 expression. An increased antitumor effects of combination therapy of BTZ and GNA on MM.1S xenograft models were observed, and combining BTZ and GNA was found to be superior to a single agent.Conclusions:Our data support that a synergistic antitumor activity exists between BTZ and GNA, and provide a rationale for successful utilization of dual BTZ and GNA in MM chemotherapy in the future.
authors.affiliation: Department of Hematology and Oncology (Key Discipline of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
authors.forename: Runzhe
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Hematology and Oncology (Key Discipline of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Oncology (Key Discipline of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Hematology and Oncology (Key Discipline of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Hematology and Oncology (Key Discipline of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
authors.forename: Baoan
authors.initials: B
authors.lastname: Chen
keywords: apoptosis; bortezomib; gambogenic acid; multiple myeloma; synergism