ABSTRACT
Sorafenib is a kinase inhibitor approved for the treatment of primary kidney cancer, advanced primary liver cancer, and radioactive iodine resistant advanced thyroid carcinoma. However, sorafenib usually causes serious side effects, which limit its antitumor effect. Nanoparticle based drug delivery systems have been widely used to enhance the therapeutic effects and reduce the side effects of this drug by the enhanced permeability and retention (EPR) effect. Herein, to improve the therapeutic effect of sorafenib, we developed poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PEG-PLGA) based nanoparticles by a dialysis method for sorafenib encapsulation. After intravenous injection of the sorafenib loaded nanoparticles (NPsorafenib), the tumor growth of mice bearing B16-F10, MC38 and LLC tumor was significantly inhibited. Meanwhile, the dose of sorafenib was reduced to one ninth and the side effects on the hematopoietic system and immune system were abrogated. More importantly, the tumor growth inhibition effect of NPsorafenib was dramatically reduced in B16-F10 bearing Rag1-/- mice which are adaptive immune cell defective, indicating that the antitumor effects of NPsorafenib are dependent on the adaptive immune cells. These results emphasize the indispensable role of the adaptive immune system in nano-drug mediated antitumor effects and the adaptive immune system should be considered as an important factor for clinical applications.
Subject(s)
Antineoplastic Agents/administration & dosage , Immunity, Cellular/drug effects , Nanoparticles/chemistry , Neoplasms, Experimental/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Homeodomain Proteins/metabolism , Lymphocytes/drug effects , Mice , Mice, Inbred C57BL , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/pharmacokinetics , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacokinetics , Polyesters/chemistry , Polyethylene Glycols/chemistry , SorafenibABSTRACT
AIM: Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from the Chinese herbal medicine Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), has shown anticancer activities in various cancer cell lines. The aim of this study was to investigate the anticancer activity and molecular targets of TBMS1 in human prostate cancer cells in vitro. METHODS: DU145 and P3 human prostate cancer cells were treated with TBMS1. Cell viability and apoptosis were detected. ROS generation, mitochondrial membrane potential and cell cycle profile were examined. Western blotting was used to measure the expression of relevant proteins in the cells. RESULTS: TBMS1 (5-100 µmol/L) significantly suppressed the viability of DU145 and P3 cells with IC50 values of approximately 10 and 20 µmol/L, respectively. Furthermore, TBMS1 dose-dependently induced apoptosis and cell cycle arrest at G0/G1 phase in DU145 and P3 cells. In DU145 cells, TBMS1 induced mitochondrial apoptosis, evidenced by ROS generation, mitochondrial dysfunction, endoplasmic reticulum stress, modulated Bcl-2 family protein and cleaved caspase-3, and activated ASK-1 and its downstream targets p38 and JNK. The G0/G1 phase arrest was linked to increased expression of p53 and p21 and decreased expression of cyclin E and cdk2. Co-treatment with Z-VAD-FMK (pan-caspase inhibitor) could attenuate TBMS1-induced apoptosis but did not prevent G0/G1 arrest. Moreover, co-treatment with NAC (ROS scavenger), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor) or salubrinal (ER stress inhibitor) significantly attenuated TBMS1-induced apoptosis. CONCLUSION: TBMS1 induces oxidative stress-mediated apoptosis in DU145 human prostate cancer cells in vitro via the mitochondrial pathway.
Subject(s)
Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , G1 Phase/drug effects , Oxidative Stress/drug effects , Prostatic Neoplasms/pathology , Resting Phase, Cell Cycle/drug effects , Saponins/pharmacology , Triterpenes/pharmacology , Acetylcysteine/pharmacology , Amino Acid Chloromethyl Ketones/pharmacology , Anthracenes/pharmacology , Caspase 3 , Cell Line, Tumor , Cell Survival/drug effects , Cinnamates/pharmacology , Cyclin E/metabolism , Cyclin-Dependent Kinase 2/metabolism , Dose-Response Relationship, Drug , Endoplasmic Reticulum Stress/drug effects , Humans , Imidazoles/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Kinase Kinase 5/metabolism , Male , Membrane Potential, Mitochondrial/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyridines/pharmacology , Reactive Oxygen Species/metabolism , Saponins/antagonists & inhibitors , Thiourea/analogs & derivatives , Thiourea/pharmacology , Triterpenes/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Vitexicarpin (3', 5-dihydroxy-3, 4', 6, 7-tetramethoxyflavone), a polymethoxyflavone isolated from Viticis Fructus (Vitex rotundifolia Linne fil.), has long been used as an anti-inflammatory herb in traditional Chinese medicine. It has also been reported that vitexicarpin can inhibit the growth of various cancer cells. However, there is no report elucidating its effect on human prostate carcinoma cells. The aim of the present study was to examine the apoptotic induction activity of vitexicarpin on PC-3 cells and molecular mechanisms involved. MTT studies showed that vitexicarpin dose-dependently inhibited growth of PC-3 cells with an IC50~28.8 µM. Hoechst 33258 staining further revealed that vitexicarpin induced apoptotic cell death. The effect of vitexicarpin on PC-3 cells apoptosis was tested using prodium iodide (PI)/Annexin V-FITC double staining and flow cytometry. The results indicated that vitexicarpin induction of apoptotic cell death in PC-3 cells was accompanied by cell cycle arrest in the G2/M phase. Furthermore, our study demonstrated that vitexicarpin induction of PC-3 cell apoptosis was associated with upregulation of the proapoptotic protein Bax, and downregulation of antiapoptotic protein Bcl-2, release of Cytochrome c from mitochondria and decrease in mitochondrial membrane potential. Our findings suggested that vitexicarpin may become a potential leading drug in the therapy of prostate carcinoma.