phenanthrenes and Colorectal-Neoplasms

Mitochondrial fission and fusion are required for cell survival, and several studies have shown an imbalance between fission and fusion in cancer. High levels of mitochondrial fusion are observed in drug-resistant tumor cells, whereas mitochondrial fission may be important in sensitizing tumor cells to chemotherapy drugs. Based on current knowledge, we hypothesized that different chemotherapeutics might differentially affect mitochondrial dynamics and energy production. Thus, we selected chemotherapeutics with different mechanisms of action (camptothecin, triptolide and apoptosis inducer kit) and investigated their effect on mitochondria in colorectal carcinoma cells. We report that these chemotherapeutics decreased the activity of complex I and reduced the mitochondrial membrane potential, and also decreased the size of mitochondria in the colorectal carcinoma cell lines DLD1 and HCT-116. Treatment with camptothecin, triptolide and/or apoptosis inducer kit results in differential effects of fission on apoptosis in these cells. Our results suggest that fission is an important process in apoptosis induced by chemotherapeutics.

Topics: Apoptosis; Camptothecin; Colorectal Neoplasms; Diterpenes; Epoxy Compounds; Humans; Mitochondria; Phenanthrenes

Triptolide is a potent anti-inflammatory agent that also possesses anticancer activity, including against colorectal cancer (CRC), one of the most frequent cancers around the world. In order to clarify how triptolide may be effective against CRC, we analyzed the proteome and phosphoproteome of CRC cell line HCT116 after incubation for 48 h with the drug (40 nM) or vehicle. Tandem mass tagging led to the identification of 403 proteins whose levels increased and 559 whose levels decreased in the presence of triptolide. We also identified 3,110 sites in proteins that were phosphorylated at higher levels and 3,161 sites phosphorylated at lower levels in the presence of the drug. Analysis of these differentially expressed and/or phosphorylated proteins showed that they were enriched in pathways involving ribosome biogenesis, PI3K-Akt signaling, MAPK signaling, nucleic acid binding as well as other pathways. Protein-protein interactions were explored using the STRING database, and we identified nine protein modules and 15 hub proteins. Finally, we identified 57 motifs using motif analysis of phosphosites and found 16 motifs were experimentally verified for known protein kinases, while 41 appear to be novel. These findings may help clarify how triptolide works against CRC and may guide the development of novel treatments.

Topics: Colorectal Neoplasms; Diterpenes; Epoxy Compounds; Humans; Phenanthrenes; Phosphatidylinositol 3-Kinases; Proteome; Proteomics

Topics: Carcinogenesis; Cell Line, Tumor; Cell Transformation, Neoplastic; Colorectal Neoplasms; Glutamine; Humans; Lipids; Lipogenesis; Pancreatic Neoplasms; Phenanthrenes; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species; Signal Transduction

According to the special physiological and pharmacological activities of natural compounds, many drugs with special therapeutic effects have been developed. The Triptolide (TP) is a natural anti-tumor drug with a world patent, but its target and mechanism are yet unknown.. The study aims to explore and predict the target and mechanism of TP on Non-Small Cell Lung Cancer (NSCLC), Pancreatic Cancer (PC) and Colorectal Cancer (CC) through network pharmacology technology.. We screened the core targets of TP with NSCLC, PC and CC, respectively, and carried out network analysis, enrichment analysis and ligand-receptor docking to clarify its potential pharmacological mechanism.. By screening the core genes between TP with NSCLC, PC and CC, respectively, it was found that PTGS2 was the common target gene in the three cancers. NSCLC, CCL2, IL6, HMOX1 and COL1A1 are the specific target genes, while MMP2, JUN, and CXCL8 are the specific target genes in PC. In CC, the specific target genes includeERBB2, VEGFA, STAT1 and MAPK8. In enrichment analysis, it was found that the NF- κB, toll-like receptors and IL-17 signaling pathway were mainly involved in TP for these cancers. The binding energy of TP to the core target is less than that of cyclophosphamide.. This study preliminarily revealed that TP may prevent and treat cancers\\ through multiple targets and pathways. The possible mechanisms of TP include regulating immune and inflammatory responses, promoting apoptosis and inhibiting tumor development. It shows that TP may have potential in treating kinds of tumors.

Topics: Antineoplastic Agents, Alkylating; Carcinoma, Non-Small-Cell Lung; Chemokine CCL2; Collagen Type I, alpha 1 Chain; Colorectal Neoplasms; Cyclooxygenase 2; Diterpenes; Epoxy Compounds; Heme Oxygenase-1; Humans; Interleukin-17; Interleukin-6; Interleukin-8; Lung Neoplasms; Matrix Metalloproteinase 2; Mitogen-Activated Protein Kinase 8; Molecular Docking Simulation; Molecular Targeted Therapy; Network Pharmacology; NF-kappa B; Pancreatic Neoplasms; Phenanthrenes; Proto-Oncogene Proteins c-jun; Receptor, ErbB-2; STAT1 Transcription Factor; Structure-Activity Relationship; Toll-Like Receptors; Vascular Endothelial Growth Factor A

Colorectal cancer (CRC) is one of the most prevalent types of cancer in the world and ranks second in cancer deaths in the US. Despite the recent improvements in screening and treatment, the number of deaths associated with CRC is still very significant. The complexities involved in CRC therapy stem from multiple oncogenic mutations and crosstalk between abnormal pathways. This calls for using advanced molecular genetics to understand the underlying pathway interactions responsible for this cancer. In this paper, we construct the CRC pathway from the literature and using an existing public dataset on healthy vs tumor colon cells, we identify the genes and pathways that are mutated and are possibly responsible for the disease progression. We then introduce drugs in the CRC pathway, and using a boolean modeling technique, we deduce the drug combinations that produce maximum cell death. Our theoretical simulations demonstrate the effectiveness of Cryptotanshinone, a traditional Chinese herb derivative, achieved by targeting critical oncogenic mutations and enhancing cell death. Finally, we validate our theoretical results using wet lab experiments on HT29 and HCT116 human colorectal carcinoma cell lines.

Topics: Cell Death; Cell Proliferation; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Mutation; Phenanthrenes; Signal Transduction

The constitutive activation of signal transducer and activator of transcription 3(STAT3) is associated with aggressive development and metastasis in colorectal cancer (CRC), but STAT3-targeting drugs remain elusive in clinic. Here, structure-based strategy was used to remodel the natural compound cryptotanshinone into a more effective STAT3 inhibitor LYW-6. Using the Biolayer Interferometry assay, we observed that LYW-6 exhibited specific interactions with STAT3(KD = 6.6 ± 0.7 μM). Western blot analysis and electrophoretic mobility shift assays (EMSA) showed that LYW-6 inhibited the phosphorylation of STAT3 tyrosine 705 (Tyr-705) and had slight effects on STAT1 and STAT5 phosphorylation. Western blot analysis on the upstream kinases of STAT3 confirmed that the inhibitory mechanism on p-STAT3 was independent of upstream kinases. Further investigation demonstrated that LYW-6 downregulated the expression of downstream oncogenes to inhibit cell viability, cell cycle development, and potently increased cell apoptosis in human CRC cells. The invasion and metastasis linked signaling was also blocked by LYW-6 treatment. LYW-6 was found to reduce the metastasis foci in lung on tail-lung metastasis models. In addition, it was observed that LYW-6 markedly diminished STAT3 phosphorylation in tumor tissue and significantly inhibited tumor growth on xenograft models. Tumor development on chemically-induced colorectal cancer model also significantly inhibited by LYW-6 treatment. These findings provided adequate evidence that STAT3 inhibitor LYW-6 might be a potential candidate agent for CRC treatment.

Topics: Animals; Apoptosis; Caco-2 Cells; Cell Cycle; Cell Movement; Cell Proliferation; Colorectal Neoplasms; HCT116 Cells; Humans; Mice, Inbred ICR; Mice, Inbred NOD; Mice, SCID; Molecular Docking Simulation; Neoplasm Invasiveness; Neoplasm Metastasis; Phenanthrenes; Protein Binding; STAT3 Transcription Factor; Toxicity Tests, Acute; Xenograft Model Antitumor Assays

As a key glycolysis enzyme, the significance of pyruvate dehydrogenase kinase 1 (PDK1) in the development of colorectal cancer (CRC) remains unknown. This study revealed that the prognosis of CRC patients with high levels of PDK1 was poor, and PDK1 knockdown significantly reduced liver metastasis of CRC in both nude mice and immune competent BALB/C mice. When combined with cryptotanshinone (CPT), an inhibitor of STAT3-p-Y705, the liver metastasis was further inhibited. PDK1 knockdown obviously increased reactive oxygen species level in anoikis conditions and subsequently resulted in an elevated anoikis, but the combination of PDK1 knockdown and CPT showed a reduced effect on anoikis. Based on this discrepancy, the adherence ability of CRC cells to matrix protein fibronectin was further detected. It showed that PDK1 knockdown significantly decreased the adherence of CRC cells to fibronectin when combined with CPT. These results suggest that inhibition of PDK1 can decrease the surviving CRC cells in blood circulation via up-regulation of anoikis, and inhibition of STAT3-p-Y705 can prevent it to settle down on the liver premetastatic niche, which ultimately reduces liver metastasis.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Phenanthrenes; Phosphorylation; Prognosis; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; STAT3 Transcription Factor; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

T-lymphokine-activated killer cell-originated protein kinase (TOPK) is a serine-threonine mitogen-activated protein kinase that is highly expressed in many types of human cancer. Due to its important role in cancer progression, TOPK is becoming an attractive target in chemotherapeutic drug design. In this study, a series of 1-phenyl phenanthridin-6(5H)-one derivatives have been identified as a novel chemical class of TOPK inhibitors. Some of them displayed very potent anti-cancer activity with IC

Topics: Animals; Antineoplastic Agents; Apoptosis; Colorectal Neoplasms; Heterografts; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Phenanthrenes; Phenanthridines; Quinolones; Xenograft Model Antitumor Assays

8-Acetonyldihydronitidine (8-AHN) is a potent antitumor compound extracted from Toddalia asiatica. However, the precise molecular antitumor mechanisms of 8-AHN have not been well elucidated. Here, we showed that 8-AHN significantly inhibited the proliferation of human colorectal cell lines via induction of G2/M cell cycle arrest and apoptosis. We found that the p53 played a central role in 8-AHN-induced cell proliferation inhibition. Mechanistically, 8-AHN induced p53 expression and enhanced transcriptional activity, subsequently elevating the expression of p53 target genes, including p21, FAS, and BAX, and then increased the level of activated caspase-3 and decreased the level of cyclin B and cyclin A. Moreover, pifithrin-α, the p53 inhibitor, markedly reversed the above responses induced by 8-AHN, and small interfering RNA-mediated knockdown of TP53 also significantly decreased 8-AHN-induced cell apoptosis. The experiments in vivo showed that 8-AHN significantly suppressed the growth of HCT116 xenograft tumors, associated with proliferation suppression and apoptosis induction in tumor tissues, without inducing any notable major organ-related toxicity. In summary, 8-AHN displays an antitumor effect through cell cycle arrest and apoptosis in colorectal cells via activating p53, which suggests that 8-AHN, exerted a therapeutic potential against colorectal cancer cells, and may be regarded as an effective lead compound.

Topics: Alkaloids; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; M Phase Cell Cycle Checkpoints; Male; Mice; Phenanthrenes; Transcription, Genetic; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Upregulation of RNA polymerase (Pol) III products, including tRNAs and 5S rRNA, in tumor cells leads to enhanced protein synthesis and tumor formation, making it a potential target for cancer treatment. In this study, we evaluated the inhibition of Pol III transcription by triptolide and the anti-cancer effect of this drug in colorectal tumorigenesis.. The effect of triptolide on colorectal cancer development was assessed in colorectal cancer mouse models, 3D organoids, and cultured cells. Colorectal cancer cells were treated with triptolide. Pol III transcription was measured by real-time quantitative polymerase chain reaction (PCR). The formation of TFIIIB, a multi-subunit transcription factor for Pol III, was determined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and fluorescence resonance energy transfer (FRET).. Together, our data suggest that inhibition of Pol III transcription with existing drugs such as triptolide provides a new avenue for developing novel therapies for colorectal cancer.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Diterpenes; Epoxy Compounds; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Mice; Phenanthrenes; Promoter Regions, Genetic; RNA, Ribosomal, 5S; RNA, Transfer; Transcription Factor TFIIIB; Transcription, Genetic; Tumor Burden; Xenograft Model Antitumor Assays

Cryptotanshinone (CPT) is a natural compound extracted from herbal medicine that has been previously shown to possess antitumor properties in various types of human cancer cells. In the present study, we examined the potential role of CPT in the treatment of colorectal cancer. Using SW480, HCT116, and LOVO colorectal cancer cell lines, the effects of CPT on cell viability, apoptosis, and tumorigenicity were evaluated. The results showed that CPT significantly inhibited the growth and viability of SW480, HCT116, and LOVO cell lines by inducing apoptosis and prevented anchorage dependent growth on agar. In addition, CPT inhibited the activation of Signal transducer and activator of transcription 3 (Stat3) pathways in colorectal cancer cells. Stat3 is a transcription factor that mediates the expression of various genes associated with many cellular processes, such as inflammation and cell growth, and has been shown to promote several cancer types, including colorectal cancer. These findings indicate that CPT may be a potential candidate for the treatment and prevention of colorectal cancer in part by inhibiting the activation of Stat3.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Inhibitor of Apoptosis Proteins; Phenanthrenes; STAT3 Transcription Factor; Survivin

eIF4E binding protein 1 (4E-BP1), is critical for cap-dependent and cap-independent translation. This study is the first to demonstrate that 4E-BP1 expression correlates with colorectal cancer (CRC) progression. Compared to its expression in normal colon epithelial cells, 4E-BP1 was upregulated in CRC cell lines and was detected in patient tumor tissues. Furthermore, high 4E-BP1 expression was statistically associated with poor prognosis. Hypoxia has been considered as an obstacle for cancer therapeutics. Our previous data showed that YXM110, a cryptopleurine derivative, exhibited anticancer activity via 4E-BP1 depletion. Here, we investigated whether YXM110 could inhibit protein synthesis under hypoxia. 4E-BP1 expression was notably decreased by YXM110 under hypoxic conditions, implying that cap-independent translation could be suppressed by YXM110. Moreover, YXM110 repressed hypoxia-inducible factor 1α (HIF-1α) expression, which resulted in decreased downstream vascular endothelial growth factor (VEGF) expression. These observations highlight 4E-BP1 as a useful biomarker and therapeutic target, indicating that YXM110 could be a potent CRC therapeutic drug.

Topics: Adaptor Proteins, Signal Transducing; Alkaloids; Antineoplastic Agents; Caco-2 Cells; Cell Cycle Proteins; Cell Line, Tumor; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Neoplasms; Phenanthrenes; Phosphoproteins; Prognosis; Protein Biosynthesis; Quinolizidines; Treatment Outcome; Vascular Endothelial Growth Factor A

Triptolide attracts attention for its anti-inflammatory, immune modulation, anti-proliferative and pro-apoptotic activity, but the clinical application of triptolide is restricted by its serious toxicity. Here, we demonstrate LLDT-246, a new triptolide derivative, exhibited a little more potent activity of NF-κB inhibition and cytotoxicity whether acting alone or in combination with TNF-α on colorectal cancer HCT-116 cells than its maternal compound, and showed low toxic to non-cancer cells. Mechanism study revealed that LLDT-246 inhibited phosphorylation of AKT, p-GSK3β and p-mTOR, however, no significant effects were found on the level of p-ERK and p-JNK, along with HSP70, indicating LLDT-246 indirectly affects NF-κB and suppresses NF-κB signaling largely by interpreting AKT/GSK3β/mTOR pathway. Altogether, LLDT-246 is a promising anticancer derivative of triptolide, further studies in vivo and about detailed mechanism of LLDT-246 is required in the future.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Nucleus; Cell Survival; Colorectal Neoplasms; Diterpenes; Down-Regulation; Drug Synergism; Epoxy Compounds; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; I-kappa B Proteins; Inhibitory Concentration 50; Mice; Mitochondria; Neoplasm Proteins; NF-kappa B; NF-KappaB Inhibitor alpha; Phenanthrenes; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Up-Regulation

PPM1D is a p53-inducible Ser/Thr phosphatase. One of the main functions of PPM1D in normal cells is to act as a negative regulator of the p53 tumor suppressor by dephosphorylating p53 and several kinases. PPM1D is considered an oncoprotein owing to both its functions and the fact that gene amplification and overexpression of PPM1D are reported in several tumors. Recently, PPM1D mutations resulting in C-terminal truncated alterations were found in brainstem gliomas and colorectal cancers, and these mutations enhanced the activity of PPM1D. Therefore, C-terminal truncated PPM1D should be also considered as a potential candidate target of anticancer drugs. Here we showed that combination treatment with PPM1D-specific inhibitor SPI-001 and doxorubicin suppressed cell viability of HCT-116 cells overexpressing C-terminal truncated PPM1D through p53 activation compared with doxorubicin alone. Our results suggest that combination treatment with PPM1D inhibitor and doxorubicin may be a potential anti-cancer treatment in PPM1D-mutated cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Doxorubicin; HCT116 Cells; Humans; Mutation; Phenanthrenes; Phosphoprotein Phosphatases; Protein Phosphatase 2C; Tumor Suppressor Protein p53

15,16-Dihydrotanshinone I (DHTS) is a component of the traditional Chinese medicinal plant Salvia miltiorrhiza Bunge. In this study, DHTS at as low as 2.5 μg/ml concentration significantly inhibited proliferation of human benign (SW480) and malignant (SW620) colorectal cancer cells, as shown by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-diphenytetrazoliumromide (MTT) and flow cytometric analysis. Activating transcription factor (ATF)-3, a basic leucine zipper-type transcription factor, was found to be predominantly up-regulated in DHTS-treated SW480 and SW620 cells. The up-regulation of ATF3 was blocked by a c-JUN N-terminal kinase (JNK) or p38 inhibitor. Overexpression of ATF3 resulted in a significant augmentation of DHTS-induced apoptosis of SW480 cells, but resistance to DHTS-induced apoptosis of SW620 cells. These results suggest that DHTS has a strong therapeutic or preventive potential against cancer. In addition, ATF3 has a dual role in DHTS-induced apoptosis, depending on the degree of malignancy of colorectal cancer.

Topics: Activating Transcription Factor 3; Adenocarcinoma; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Furans; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Phenanthrenes; Phosphorylation; Quinones

Angiogenesis is essential for the survival and growth of most tumors. As such, targeting the tumor neovasculature is an attractive strategy for effective cancer therapy. Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. The functional domain within amino acid residues 120-180 of vasostatin (VAS) has been confirmed to be effective in inhibiting the proliferation, migration, and invasiveness of cancer cells by its suppressive capacity against angiogenesis. Triptolide (TPL) is an active component extracted from the traditional Chinese herbal medicine Tripterygium wilfordii Hook F that has shown antitumor activities in various cancer cell types. However, its therapeutic application is limited by its toxicity in normal tissues and complications caused in patients. In this study, we attempted to investigate the synergistic antitumor activity of TPL and VAS in solid tumor cells. Our results showed that the sensitivity of combined therapy using TPL and VAS was higher than that of monotherapy using TPL or VAS. Apoptosis induced by the combined treatment was accompanied by activation of caspase-9, caspase-8, and caspase-3. Upregulation of proapoptotic protein (Bax, Bak, and Bad) expression and suppression of NF-κB transcriptional activity and its targeting antiapoptotic genes (c-FLIP, cIAP, Bcl-2, Bcl-xl, and Mcl-1) may contribute to the synergistic effects of this combination therapy. Further, using a mouse xenograft model, we demonstrated that combined treatment completely suppressed tumor growth as compared with treatment with TPL or VAS alone. These results suggest that the combination of TPL and VAS at lower concentrations may produce a synergistic antitumor effect that warrants further investigation for its potential clinical applications.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Calreticulin; Cell Line; Cell Line, Tumor; Colorectal Neoplasms; Diterpenes; Drug Synergism; Drugs, Chinese Herbal; Epoxy Compounds; Ethnopharmacology; HCT116 Cells; Humans; Mice; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Peptide Fragments; Phenanthrenes; Random Allocation; Recombinant Proteins; Tripterygium; Xenograft Model Antitumor Assays

Triptolide, a diterpene triepoxide compound extracted from the traditional Chinese medicine herb Tripterygium wilfordii Hook F., is a potential cancer chemotherapeutic for tumors. However, the mechanism of anti-proliferative mechanism of triptolide in colon cancer cells is not entirely clear. Triptolide markedly inhibited HT29 and SW480 cells proliferation in a dose- and time-dependent manner. Triptolide decreased ERK and AKT phosphorylation, and GABPα expression in colon cancer cells. Beta-catenin expression and phosphorylation were not altered by incubation of triptolide. However, we found that triptolide repressed expression of LEF/TCF. Although it did not significantly affect cells apoptosis, triptolide induced G1 phase arrest dose-dependently. Further detection for the expression of cell cycle-related proteins suggesting that triptolide stimulate expression of p21 and repress cyclin A1. Increased p21 binded to CDK4/CDK6, therefore blocked function of CDK4/CDK6, and subsequently contribute to the G1 arrest. These data suggested that triptolide is a potential agent for treatment of colon cancer, and its anti-proliferation effect mainly occur through G1 phase arrest.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclin A1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p21; Diterpenes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Epoxy Compounds; G1 Phase Cell Cycle Checkpoints; GA-Binding Protein Transcription Factor; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Lymphoid Enhancer-Binding Factor 1; Mitogen-Activated Protein Kinase 1; Phenanthrenes; Phosphorylation; Proto-Oncogene Proteins c-akt; T Cell Transcription Factor 1; Up-Regulation

The in vitro chemosensitizing effect of triptolide (PG490) on the cytotoxicity of 5-fluorouracil (5-FU) was determined in three colorectal cancer (CRC) cell lines. PG490 alone was toxic to CRC cell lines (IC(50)s: 1.39-5.51nM). The cytotoxicity of 5-FU to CRC cell lines was 4-15-fold sensitized by combining use of low concentration of PG490. CI-isobologram indicated that the effect of PG490 plus 5-FU was synergistic. PG490 and 5-FU treatment induced activated caspase 3 and Bax expression and inhibited Bcl-2 expression. PG490 simultaneously induced generation of reactive oxygen species (ROS) and inhibited NF-kappaB transcriptional activity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites, Antineoplastic; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Diterpenes; DNA Probes; Drug Agonism; Drug Therapy, Combination; Epoxy Compounds; Fluorouracil; Genes, Reporter; Humans; Luciferases; NF-kappa B; Phenanthrenes; Reactive Oxygen Species

To investigate the effects and possible mechanisms of tanshinone II-A, an alcohol extract of the root of Salvia miltiorrhiza Bunge, on tumor invasion and metastasis of human colon carcinoma (CRC) cells.. The effects of tanshinone II-A on invasion and metastasis of CRC cell lines HT29 and SW480 were evaluated by in vitro and in vivo assays. Western blotting was used to investigate possible molecular mechanisms of tanshinone II-A anti-cancer actions.. Tanshinone II-A inhibited migration and invasion of CRC cells in a dose-dependent manner. The inhibitory effect also depended on time, with the most significant effects observed at 72 h. Tanshinone II-A also significantly inhibited in vivo metastasis of colon carcinoma SW480 cells. It inhibited in vitro and in vivo invasion and metastasis of CRC cells by reducing levels of urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMP)-2 and MMP-9, and by increasing levels of tissue inhibitor of matrix metalloproteinase protein (TIMP)-1 and TIMP-2. Tanshinone II-A was also shown to suppress the nuclear factor-kappaB (NF-kappaB) signal.. Tanshinone II-A inhibited in vitro and in vivo invasion and metastasis of CRC cells. The effect resulted from changes in the levels of uPA, MMP-2, MMP-9, TIMP-1 and TIMP-2, and apparent inhibition of the NF-kappaB signal transduction pathway.

Topics: Abietanes; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Colonic Neoplasms; Colorectal Neoplasms; Dose-Response Relationship, Drug; HT29 Cells; Humans; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Phenanthrenes; Plant Extracts; Plant Roots; Salvia miltiorrhiza; Signal Transduction; Time Factors

Denbinobin is a phenanthraquinone derivative present in the stems of Ephemerantha lonchophylla. We showed that denbinobin induces apoptosis in human colorectal cancer cells (HCT-116) in a concentration-dependent manner. The addition of a pan-caspase inhibitor (zVAD-fmk) did not suppress the denbinobin-induced apoptotic effect, and denbinobin-induced apoptosis was not accompanied by processing of procaspase-3, -6, -7, -9, and -8. However, denbinobin triggered the translocation of the apoptosis-inducing factor (AIF) from the mitochondria into the nucleus. Small interfering RNA targeting of AIF effectively protected HCT-116 cells against denbinobin-induced apoptosis. Denbinobin treatment also caused DNA damage, activation of the p53 tumor suppressor gene, and upregulation of numerous downstream effectors (p21WAF1/CIP1, Bax, PUMA, and NOXA). A HCT-116 xenograft model demonstrated the in vivo efficacy and low toxicity of denbinobin. Taken together, our findings suggest that denbinobin induces apoptosis of human colorectal cancer HCT-116 cells via DNA damage and an AIF-mediated pathway. These results indicate that denbinobin has potential as a novel anticancer agent.

Topics: Animals; Anthraquinones; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Inducing Factor; Caspases; Cell Line, Tumor; Colorectal Neoplasms; DNA Damage; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, SCID; Orchidaceae; Phenanthrenes; Xenograft Model Antitumor Assays