Abstract
Purpose:
We investigated the effects of the anti-epilepsy drug valproic acid (VPA) alone and in combination in treating cervical cancer.
Methods:
VPA was investigated for its effects on cervical cancer Hela cell proliferation and tumor growth via in vitro and in vivo assays.
Results:
VPA induce cell growth suppression and cell cycle arrest, with an increase of Notch1 that acts as a tumor suppressor and the change of other tumor-associated genes such as p21, p63 and PCNA. VPA was also found to induce cell morphological change, with an increase of certain cell transformation markers such as snail1, snail2 and N-cadherin. Moreover, VPA could significantly up-regulate somatostatin receptor type II (SSTR2). Our in vivo study further demonstrated that VPA via inducing SSTR2 up-regulation extremely enhanced the anti-tumor ability of the SSTR2-preferential cytotoxic COL-SST conjugate in xenografts.
Conclusions:
VPA could not only suppress tumor progression but also provide a novel promising therapeutic choice in combination with a receptor-targeted cytotoxic conjugate via activating the specific receptor.
MeSH terms
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Animals
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Anticonvulsants / pharmacology*
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Carcinoma / drug therapy*
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Colchicine / therapeutic use
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclooxygenase 2 / metabolism
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Drug Combinations
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G2 Phase Cell Cycle Checkpoints / drug effects
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Gene Expression
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Genes, p53 / drug effects
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HeLa Cells
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Hormones / therapeutic use
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Humans
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Membrane Proteins / genetics
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Mice
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Mice, Nude
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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RNA, Messenger / metabolism
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Receptors, Somatostatin / metabolism*
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Signal Transduction / drug effects*
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Somatostatin / therapeutic use
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Tubulin Modulators / therapeutic use
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Valproic Acid / pharmacology*
Substances
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Anticonvulsants
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CKAP4 protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Drug Combinations
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Hormones
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Membrane Proteins
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RNA, Messenger
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Receptor, Notch1
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Receptors, Somatostatin
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Tubulin Modulators
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Somatostatin
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Valproic Acid
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somatostatin receptor 2
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Cyclooxygenase 2
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Phosphatidylinositol 3-Kinases
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PTEN Phosphohydrolase
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Colchicine