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.
Subject(s)
Anticonvulsants/pharmacology , Carcinoma/drug therapy , Receptor, Notch1/metabolism , Receptors, Somatostatin/metabolism , Signal Transduction/drug effects , Valproic Acid/pharmacology , Animals , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Colchicine/therapeutic use , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclooxygenase 2/metabolism , Drug Combinations , G2 Phase Cell Cycle Checkpoints/drug effects , Gene Expression , Genes, p53/drug effects , HeLa Cells , Hormones/therapeutic use , Humans , Membrane Proteins/genetics , Mice , Mice, Nude , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , RNA, Messenger/metabolism , Receptor, Notch1/genetics , Somatostatin/therapeutic use , Tubulin Modulators/therapeutic useABSTRACT
In our previous study, we found that several tumor cell lines displayed high receptor-specific binding affinity, one of which, the human pancreatic carcinoid BON cell line, demonstrates high affinity binding of the bombesin (BN) and somatostatin (SST) receptor-specific ligands. In the present study, BON cells, as a representative model, were further applied to evaluate various peptide analogs and cytotoxic receptor-targeted peptide conjugates. We observed quick ligand-receptor internalization in BON cells as well as high binding affinity. Furthermore, BON cells have high expression of multidrug resistance-associated genes (MDR1) and show camptothecin (CPT) resistance. Various receptor-specific cytotoxic conjugates were synthesized and evaluated in the BON cell model via in vitro and in vivo studies. We found that all the tested conjugates displayed potent antitumor ability in xenografts. Especially, the CPT conjugates, CPT-SST, and CPT-BN, are most likely to increase sensitivity to CPT-resistant BON cells. Our findings suggest that appropriately defined tumor cell lines may provide physiologically relevant cell-based evaluations of novel peptide analogs and receptor-targeted chemotherapeutics.
