Xiao Kai, Li Yuan-Pei, Wang Cheng, Ahmad Sarah, Vu Michael, Kuma Krishneel, Cheng Yi-Qiang, Lam Kit S
National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China; Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
Biomaterials. 2015 Oct;67:183-93. doi: 10.1016/j.biomaterials.2015.07.033. Epub 2015 Jul 17.
Histone deacetylase (HDAC) inhibitors are an emerging class of targeted therapy against cancers. Thailandepsin A (TDP-A) is a recently discovered class I HDAC inhibitor with broad anti-proliferative activities. In the present study, we aimed to investigate the potential of TDP-A in the treatment of breast cancer. We demonstrated that TDP-A inhibited cell proliferation and induced apoptosis in breast cancer cells at low nanomolar concentrations. TDP-A activated the intrinsic apoptotic pathway through increase of pro-apoptotic protein Bax, decrease of anti-apoptotic Bcl-2, and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). TDP-A also induced cell cycle arrest at the G2/M phase, and promoted the production of reactive oxygen species (ROS). We have successfully encapsulated TDP-A into our recently developed disulfide cross-linked micelles (DCMs), improving its water solubility and targeted delivery. TDP-A loaded DCMs (TDP-A/DCMs) possess the characteristics of high loading capacity (>20%, w/w), optimal and monodisperse particle size (16 ± 4 nm), outstanding stability with redox stimuli-responsive disintegration, sustained drug release, and preferential uptake in breast tumors. In the MDA-MB-231 breast cancer xenograft model, TDP-A/DCMs were more efficacious than the FDA-approved FK228 at well-tolerated doses. Furthermore, TDP-A/DCMs exhibited synergistic anticancer effects when combined with the proteasome inhibitor bortezomib (BTZ) loaded DCMs (BTZ/DCMs). Our results indicate that TDP-A nanoformulation alone or in combination with BTZ nanoformulation are efficacious against breast cancer.
组蛋白去乙酰化酶（HDAC）抑制剂是一类新兴的癌症靶向治疗药物。泰国菌素A（TDP-A）是最近发现的一种具有广泛抗增殖活性的I类HDAC抑制剂。在本研究中，我们旨在探究TDP-A在乳腺癌治疗中的潜力。我们证明，TDP-A在低纳摩尔浓度下可抑制乳腺癌细胞的增殖并诱导其凋亡。TDP-A通过增加促凋亡蛋白Bax、降低抗凋亡蛋白Bcl-2以及切割半胱天冬酶-3和聚（ADP-核糖）聚合酶（PARP）来激活内源性凋亡途径。TDP-A还可诱导细胞周期停滞于G2/M期，并促进活性氧（ROS）的产生。我们已成功将TDP-A封装到我们最近开发的二硫键交联胶束（DCMs）中，提高了其水溶性和靶向递送能力。负载TDP-A的DCMs（TDP-A/DCMs）具有高负载量（>20%，w/w）、最佳且单分散的粒径（16±4nm）、对氧化还原刺激响应性崩解的出色稳定性、药物持续释放以及在乳腺肿瘤中优先摄取的特性。在MDA-MB-231乳腺癌异种移植模型中，在耐受性良好的剂量下，TDP-A/DCMs比美国食品药品监督管理局（FDA）批准的FK228更有效。此外，当与负载蛋白酶体抑制剂硼替佐米（BTZ）的DCMs（BTZ/DCMs）联合使用时，TDP-A/DCMs表现出协同抗癌作用。我们的结果表明，单独的TDP-A纳米制剂或与BTZ纳米制剂联合使用对乳腺癌均有效。
