Lichun Sun1,2, Qingqing Qian1, Guangchun Sun1, L Vienna Mackey2, Joseph A Fuselier2, David H Coy2, Cui-Yun Yu2,3. 1. a Department of Pharmacy , The Fifth People's Hospital of Shanghai, Fudan University , Shanghai , China . 2. b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and. 3. c Department of Pharmacy , Institute of Pharmacy & Pharmacology, University of South China , Hengyang , China.
Abstract
BACKGROUND: 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. MATERIALS AND METHODS: The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST). RESULTS: 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. CONCLUSION: The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.
BACKGROUND:Humanpancreatic 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. MATERIALS AND METHODS: The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST). RESULTS: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. CONCLUSION: The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.
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