The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells.
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ABSTRACT:
SUBMITTER: Huang R
PROVIDER: S-EPMC3739364 | biostudies-other | 2010 Jul
REPOSITORIES: biostudies-other
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Project description:BACKGROUND: Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. METHODS: ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. RESULTS: Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. CONCLUSION: Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells.
| S-EPMC2972283 | biostudies-literature
Project description:Stress granules (SGs) are cytoplasmic RNA multimeric bodies that form under stress conditions known to inhibit translation initiation. In most reported stress cases, the formation of SGs was associated with the cell recovery from stress and survival. In cells derived from cancer, SGs formation was shown to promote resistance to either proteasome inhibitors or 5-Fluorouracil used as chemotherapeutic agents. Despite these studies, the induction of SGs by chemotherapeutic drugs contributing to cancer cells resistance is still understudied. Here we identified sorafenib, a tyrosine kinase inhibitor used to treat hepatocarcinoma, as a potent chemotherapeutic inducer of SGs. The formation of SGs in sorafenib-treated hepatocarcionoma cells correlates with inhibition of translation initiation; both events requiring the phosphorylation of the translation initiation factor eIF2?. Further characterisation of the mechanism of sorafenib-induced SGs revealed PERK as the main eIF2? kinase responsible for SGs formation. Depletion experiments support the implication of PERK-eIF2?-SGs pathway in hepatocarcinoma cells resistance to sorafenib. This study also suggests the existence of an unexpected complex regulatory balance between SGs and phospho-eIF2? where SGs dampen the activation of the phospho-eIF2?-downstream ATF4 cell death pathway.
| S-EPMC4791277 | biostudies-other
Project description:Found in the skins of red fruits, including grapes, resveratrol (RES) is a polyphenolic compound with cancer chemopreventive activity. Because of this activity, it has gained interest for scientific investigations. RES inhibits tumor growth and progression by targeting mitochondria-dependent or -independent pathways. However, further investigations are needed to explore the underlying mechanisms.The present study is focused on examining the role of RES-induced, mitochondria-mediated, caspase-independent apoptosis of prostate cancer cells, namely transgenic adenocarcinoma of mouse prostate (TRAMP) cells. These cells were exposed to RES for various times, and cell killing, cell morphology, mitochondrial membrane potential (??m), expression of Bax and Bcl2 proteins, the role of caspase-3, and DNA fragmentation were analyzed.TRAMP cells exposed to RES showed decreased cell viability, altered cell morphology, and disrupted ??m, which led to aberrant expression of Bax and Bcl2 proteins. Furthermore, since the caspase-3 inhibitor, z-VAD-fmk (benzyloxycarbonyl-valine-alanine-aspartic acid-fluoromethyl ketone), had no appreciable impact on RES-induced cell killing, the killing was evidently caspase-independent. In addition, RES treatment of TRAMP-C1, TRAMP-C2, and TRAMP-C3 cells caused an appreciable breakage of genomic DNA into low-molecular-weight fragments.These findings show that, in inhibition of proliferation of TRAMP cells, RES induces mitochondria-mediated, caspase-independent apoptosis. Therefore, RES may be utilized as a therapeutic agent to control the proliferation and growth of cancer cells.
| S-EPMC5400554 | biostudies-literature
Project description:Natural compounds have been recognized as valuable sources for anticancer drug development. In this work, different parts from Momordica cochinchinensis Spreng were selected to perform cytotoxic screening against human prostate cancer (PC-3) cells. Chromatographic separation and purification were performed for the main constituents of the most effective extract. The content of the fatty acids was determined by Gas Chromatography-Flame Ionization Detector (GC-FID). Chemical structural elucidation was performed by spectroscopic means. For the mechanism of the apoptotic induction of the most effective extract, the characteristics were evaluated by Hoechst 33342 staining, sub-G1 peak analysis, JC-1 staining, and Western blotting. As a result, extracts from different parts of M. cochinchinensis significantly inhibited cancer cell viability. The most effective stem extract induced apoptosis in PC-3 cells by causing nuclear fragmentation, increasing the sub-G1 peak, and changing the mitochondrial membrane potential. Additionally, the stem extract increased the pro-apoptotic (caspase-3 and Noxa) mediators while decreasing the anti-apoptotic (Bcl-xL and Mcl-1) mediators. The main constituents of the stem extract are α-spinasterol and ligballinol, as well as some fatty acids. Our results demonstrated that the stem extract of M. cochinchinensis has cytotoxic and apoptotic effects in PC-3 cells. These results provide basic knowledge for developing antiproliferative agents for prostate cancer in the future.
| S-EPMC8878451 | biostudies-literature
Project description:Penta-1,2,3,4,6-O-galloyl-beta-d-glucose (PGG) suppresses the in vivo growth of human DU145 and PC-3 prostate cancer xenografts in nude mice, suggesting potential utility as a prostate cancer chemotherapeutic or chemopreventive agent. Our earlier work implicates caspase-mediated apoptosis in DU145 and LNCaP prostate cancer cells as one mechanism for the anticancer activity. We show here that, in the more aggressive PC-3 prostate cancer cell line, PGG induced programmed cell deaths lacking the typical caspase-mediated apoptotic morphology and biochemical changes. In contrast, PGG induced patent features of autophagy, including formation of autophagosomes and lipid modification of light chain 3 after 48 hours of PGG exposure. The "autophagic" responses were also observed in the murine TRAMP-C2 cells. Caspase inhibition exacerbated PGG-induced overall death. As for molecular changes, we observed a rapid inhibition of the phosphorylation of mammalian target of rapamycin-downstream targets S6K and 4EBP1 by PGG in PC-3 and TRAMP-C2 cells but not that of mammalian target of rapamycin itself, along with increased AKT phosphorylation. Whereas the inhibition of phosphatidylinositol 3-kinase increased PGG-induced apoptosis and autophagy, experiments with pharmacologic inducer or inhibitor of autophagy or by knocking down autophagy mediator Beclin-1 showed that autophagy provided survival signaling that suppressed caspase-mediated apoptosis. Knocking down of death receptor-interacting protein 1 kinase increased overall death without changing light chain 3-II or caspase activation, thus not supporting death receptor-interacting protein 1-necroptosis for PGG-induction of autophagy or other programmed cell death. Furthermore, PGG-treated PC-3 cells lost clonogenic ability. The induction by PGG of caspase-independent programmed cell death in aggressive prostate cancer cell lines supports testing its merit as a potential drug candidate for therapy of caspase-resistant recurrent prostate cancer.
| S-EPMC2838500 | biostudies-literature
Project description:Hormone-refractory prostate cancer, its skeletal metastasis and complications remain a therapeutic challenge. Here we show that treatment with (S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one (EM011), the brominated analogue of a plant-derived non-toxic antitussive alkaloid, noscapine, achieved significant inhibition of hormone-refractory human prostate cancer implanted intratibially in the bone as shown by non-invasive, real-time bioluminescent imaging of tumour growth in nude mice. Mechanistically, in vitro data suggested that the antiproliferative and proapoptotic effects of EM011 in human prostate cancer cell lines were through blockade of cell-cycle progression by impairing the formation of a bipolar spindle apparatus. The G2/M arrest was accompanied by activation of the mitotic checkpoint, a pre-requisite for induction of optimal apoptosis. Attenuation of mitotic checkpoint by siRNA duplexes led to a reduction in mitotic arrest and subsequent apoptosis. Our results further demonstrated participation of an intrinsic mitochondrially mediated apoptotic pathway that ultimately triggered caspase-driven EM011-induced apoptosis. EM011 did not exert any detectable toxicity in normal tissues with frequently dividing cells such as the gut and bone marrow. Thus, these data warrant further evaluation of EM011 for the management of prostate cancer.
| S-EPMC2883633 | biostudies-literature
Project description:BackgroundNASP (Nuclear Autoantigenic Sperm Protein) is a histone chaperone that is present in all dividing cells. NASP has two splice variants: tNASP and sNASP. Only cancer, germ, transformed, and embryonic cells have a high level of expression of the tNASP splice variant. We examined the consequences of tNASP depletion for prostate cancer PC-3 cells.MethodstNASP was depleted from prostate cancer PC-3 cells, cervical cancer HeLa cells, and prostate epithelial PWR-1E cells using lentivirus expression of tNASP shRNA. Cell cycle changes were studied by proliferation assay with CFSE labeling and double thymidine synchronization. Gene expression profiles were detected using RT(2)Profiler PCR Array, Western and Northern blotting.ResultsPC-3 and HeLa cells showed inhibited proliferation, increased levels of cyclin-dependant kinase inhibitor p21 protein and apoptosis, whereas non-tumorigenic PWR-1E cells did not. All three cell types showed decreased levels of HSPA2. Supporting in vitro experiments demonstrated that tNASP, but not sNASP is required for activation of HSPA2.ConclusionsOur results demonstrate that PC-3 and HeLa cancer cells require tNASP to maintain high levels of HSPA2 activity and therefore viability, while PWR-1E cells are unaffected by tNASP depletion. These different cellular responses most likely arise from changes in the interaction between tNASP and HSPA2 and disturbed tNASP chaperoning of linker histones. This study has demonstrated that tNASP is critical for the survival of prostate cancer cells and suggests that targeting tNASP expression can lead to a new approach for prostate cancer treatment.
| S-EPMC3100250 | biostudies-literature
Project description:The 2,6,9-trisubstituted purine group of cyclin dependent kinase inhibitors have the potential to be clinically relevant inhibitors of cancer cell proliferation. We have recently designed and synthesized a novel dansylated analog of purvalanol B, termed VMY-1-103, that inhibited cell cycle progression in breast cancer cell lines more effectively than did purvalanol B and allowed for uptake analyses by fluorescence microscopy. ErbB-2 plays an important role in the regulation of signal transduction cascades in a number of epithelial tumors, including prostate cancer (PCa). Our previous studies demonstrated that transgenic expression of activated ErbB-2 in the mouse prostate initiated PCa and either the overexpression of ErbB-2 or the addition of the ErbB-2/ErbB-3 ligand, heregulin (HRG), induced cell cycle progression in the androgen-responsive prostate cancer cell line, LNCaP. In the present study, we tested the efficacy of VMY-1-103 in inhibiting HRG-induced cell proliferation in LNCaP prostate cancer cells. At concentrations as low as 1 ?M, VMY-1-103 increased both the proportion of cells in G(1) and p21(CIP1) protein levels. At higher concentrations (5 ?M or 10 ?M), VMY-1-103 induced apoptosis via decreased mitochondrial membrane polarity and induction of p53 phosphorylation, caspase-3 activity and PARP cleavage. Treatment with 10 ?M Purvalanol B failed to either influence proliferation or induce apoptosis. Our results demonstrate that VMY-1-103 was more effective in inducing apoptosis in PCa cells than its parent compound, purvalanol B, and support the testing of VMY-1-103 as a potential small molecule inhibitor of prostate cancer in vivo.
| S-EPMC3040852 | biostudies-other
Project description:BackgroundHepatocellular carcinoma (HCC) is the sixth most common type of cancer and has a high mortality rate worldwide. Sorafenib is the only systemic treatment demonstrating a statistically significant but modest overall survival benefit. We previously have identified the aurora kinases (AURKs) and FMS-like tyrosine kinase 3 (FLT3) multikinase inhibitor DBPR114 exhibiting broad spectrum anti-tumor effects in both leukemia and solid tumors. The purpose of this study was to evaluate the therapeutic potential of DBPR114 in the treatment of advanced HCC.MethodsHuman HCC cell lines with histopathology/genetic background similar to human HCC tumors were used for in vitro and in vivo studies. Human umbilical vein endothelial cells (HUVEC) were used to evaluate the drug effect on endothelial tube formation. Western blotting, immunohistochemical staining, and mRNA sequencing were employed to investigate the mechanisms of drug action. Xenograft models of sorafenib-refractory and sorafenib-acquired resistant HCC were used to evaluate the tumor response to DBPR114.ResultsDBPR114 was active against HCC tumor cell proliferation independent of p53 alteration status and tumor grade in vitro. DBPR114-mediated growth inhibition in HCC cells was associated with apoptosis induction, cell cycle arrest, and polyploidy formation. Further analysis indicated that DBPR114 reduced the phosphorylation levels of AURKs and its substrate histone H3. Moreover, the levels of several active-state receptor tyrosine kinases were downregulated by DBPR114, verifying the mechanisms of DBPR114 action as a multikinase inhibitor in HCC cells. DBPR114 also exhibited anti-angiogenic effect, as demonstrated by inhibiting tumor formation in HUVEC cells. In vivo, DBPR114 induced statistically significant tumor growth inhibition compared with the vehicle control in multiple HCC tumor xenograft models. Histologic analysis revealed that the DBPR114 treatment reduced cell proliferation, and induced apoptotic cell death and multinucleated cell formation. Consistent with the histological findings, gene expression analysis revealed that DBPR114-modulated genes were mostly related to the G2/M checkpoint and mitotic spindle assembly. DBPR114 was efficacious against sorafenib-intrinsic and -acquired resistant HCC tumors. Notably, DBPR114 significantly delayed posttreatment tumor regrowth and prolonged survival compared with the regorafenib group.ConclusionOur results indicated that targeting AURK signaling could be a new effective molecular-targeted agent in the treatment of patients with HCC.
| S-EPMC8781143 | biostudies-literature
Project description:Although the only effective drug against primary hepatocarcinoma, the multikinase inhibitor Sorafenib (SFB) usually fails to eradicate liver cancer. Since SFB targets mitochondria, cell metabolic reprogramming may underlie intrinsic tumor resistance. To characterize cancer cell metabolic response to SFB, we measured oxygen consumption, generation of reactive oxygen species (ROS) and ATP content in rat LCSC (Liver Cancer Stem Cells) -2 cells exposed to the drug. Genome wide analysis of gene expression was performed by Affymetrix technology. SFB cytotoxicity was evaluated by multiple assays in the presence or absence of metabolic inhibitors, or in cells genetically depleted of mitochondria. We found that low concentrations (2.5-5 μM) of SFB had a relatively modest effect on LCSC-2 or 293 T cell growth, but damaged mitochondria and increased intracellular ROS. Gene expression profiling of SFB-treated cells was consistent with a shift toward aerobic glycolysis and, accordingly, SFB cytotoxicity was dramatically increased by glucose withdrawal or the glycolytic inhibitor 2-DG. Under metabolic stress, activation of the AMP dependent Protein Kinase (AMPK), but not ROS blockade, protected cells from death. We conclude that mitochondrial damage and ROS drive cell killing by SFB, while glycolytic cell reprogramming may represent a resistance strategy potentially targetable by combination therapies.
| S-EPMC4361992 | biostudies-literature