Sun Lichun, Qian Qingqing, Sun Guangchun, Mackey L Vienna, Fuselier Joseph A, Coy David H, Yu Cui-Yun
a Department of Pharmacy , The Fifth People's Hospital of Shanghai, Fudan University , Shanghai , China .
b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and.
J Drug Target. 2016;24(2):169-77. doi: 10.3109/1061186X.2015.1066794. Epub 2015 Jul 27.
Human pancreatic carcinoids, a type of neuroendocrine tumors, are asymptomatic and difficult to diagnose, with the effects of traditional anti-cancer therapies being limited. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was evaluated for its effects alone and in combination with receptor-targeting peptide-drug conjugate via increasing drug internalization.
The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST).
VPA induced proliferation suppression, cell apoptosis and cell cycle arrest. VPA acts as a HDAC inhibitor to induce a decrease of HDAC4 and an increase of acetylated histone 4 (AcH4). Meanwhile, most importantly, besides activating Notch signaling, VPA was observed to stimulate the expression of somatostatin receptor type 2 (SSTR2) that has been applied for receptor-targeting therapies. This characteristic was used for a combination therapy of VPA and CPT-SST. The combination displayed much more potent anti-tumor effects on carcinoid tumor growth by increasing SSTR2 density and drug internalization in target tumor cells.
The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.
人胰腺类癌是一种神经内分泌肿瘤，无症状且难以诊断，传统抗癌疗法的效果有限。通过增加药物内化作用，评估了组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸（VPA）单独及与受体靶向肽-药物偶联物联合使用的效果。
采用体外和体内试验评估VPA和生长抑素受体靶向喜树碱-生长抑素偶联物（CPT-SST）的效果。
VPA诱导增殖抑制、细胞凋亡和细胞周期阻滞。VPA作为HDAC抑制剂可诱导HDAC4减少和乙酰化组蛋白4（AcH4）增加。同时，最重要的是，除激活Notch信号外，还观察到VPA可刺激已用于受体靶向治疗的2型生长抑素受体（SSTR2）的表达。这一特性被用于VPA和CPT-SST的联合治疗。该联合治疗通过增加靶肿瘤细胞中SSTR2密度和药物内化作用，对类癌肿瘤生长显示出更强的抗肿瘤作用。
VPA与SSTR2靶向剂联合使用为类癌肿瘤治疗提供了一种有前景的方法。
