Anti-colorectal Cancer Effects Research Articles

Nodosin Exerts an Anti-Colorectal Cancer Effect by Inhibiting Proliferation and Triggering Complex Cell Death in Vitro and in Vivo

Colorectal cancer (CRC) is one of the most common digestive system cancer in the world. Its incidence and mortality are increasing annually. Presently, CRC lacks long-term effective treatment methods and drugs. Therefore, finding new treatment methods and drugs is of great significance for CRC treatment. Compounds derived from natural plants have been widely used in tumor research and treatment because of their good antitumor activity these years. This study found that nodosin, a diterpenoid extracted from the medicinal plant Rabdosia serra (Maxim.) Hara, inhibited the growth of CRC cells SW480, HT-29 and LoVo in a dose- and time-dependent manner, with inhibitory concentrations (IC50) of 7.4, 7.7, and 6.6 μM respectively. We selected highly metastatic and poorly differentiated SW480 cells for further studies. We found that nodosin could inhibit cell proliferation by inhibiting DNA synthesis and induce cell death by inducing oxidative stress, apoptosis and autophagy in cells. Through in vitro assays combined with transcriptomic analysis, it was found that nodosin could downregulate tribbles pseudokinase 3 and upregulate oxidative stress-induced growth inhibitor 1 to induce oxidative stress in cells; nodosin-induced reactive oxygen species were able to upregulate the expression of heme oxygenase 1 to induce apoptosis and the expression of cathepsin L. and light chain-3 to induce autophagy. In vivo, we found that nodosin inhibited tumor growth and induced cells to undergo apoptosis and autophagy without significant toxic effects. In conclusion, our findings suggest that nodosin exerts anti-CRC effects mainly through its ability to induce apoptosis and autophagy in vitro and in vivo. Therefore, our study contributes to the development of nodosin-based potential CRC therapeutic drugs.

Molecular Mechanism of Anti-Colorectal Cancer Effect of Hedyotis diffusa Willd and Its Extracts.

With the sharp change in our diet and lifestyle, the incidence of colorectal cancer (CRC) is increasing among young people and has become the second most common malignant tumor worldwide. Although the current treatment of CRC is getting updated rapidly, recurrence and metastasis are still inevitable. Therefore, new anticancer drugs are needed to break existing limitations. In recent years, Hedyotis diffusa Willd (HDW) extracts have been proved to demonstrate excellent anti-colorectal cancer effects and have been widely used in clinical practices. In this review, we aim to explore the advantages, potential signaling pathways, and representative active ingredients of HDW in the treatment of CRC from the perspective of molecular mechanism, in order to provide new ideas for the future treatment of CRC.

Pectin mediated green synthesis of Fe3O4/Pectin nanoparticles under ultrasound condition as an anti-human colorectal carcinoma bionanocomposite

This work described the one-pot synthesis of apple pectin encapsulated Fe 3 O 4 nanoparticles (Fe 3 O 4 /Pectin NPs) which is prepared by co-precipitation of Fe(II/(III) ions in alkaline solution mediated by pectin under ultrasound condition. This process led to formation of magnetic nanoparticles within the network of pectin. Physicochemical characterization of the as-synthesized Fe 3 O 4 /Pectin NPs was carried out through electron microscopy (SEM and TEM), energy dispersive X-ray spectroscopy (EDX), vibrating sample magnetometer (VSM) and X-ray diffraction (XRD). The in vitro cytotoxic and anti-colorectal cancer effects of biologically synthesized Fe 3 O 4 /Pectin NPs against Ramos.2G6.4C10, HCT-8 [HRT-18], HCT 116, and HT-29 cancer cell lines were assessed. The anti-colorectal cancer properties of the Fe 3 O 4 /Pectin NPs could significantly remove Ramos.2G6.4C10, HCT-8 [HRT-18], HCT 116, and HT-29 cancer cell lines in a time and concentration-dependent manner by MTT assay. The IC 50 of the Fe 3 O 4 /Pectin NPs were 317, 337, 187, and 300 µg/mL against Ramos.2G6.4C10, HCT-8 [HRT-18], HCT 116, and HT-29 cancer cell lines. The antioxidant activity of Fe 3 O 4 /Pectin NPs was determined by DPPH method. The Fe 3 O 4 /Pectin NPs showed the high antioxidant activity according to the IC 50 value. It seems that the anti-human colorectal cancer effect of recent nanoparticles is due to their antioxidant effects.

Network Pharmacology and Molecular Docking Analyses of the Synergistic Mechanism of Babao Dan and Oxaliplatin in Colorectal Cancer

<bold>Objective</bold> To further explore the mechanism of Babao Dan (BBD) combined with oxaliplatin (L-OHP) in treating colorectal cancer (CRC) through a network pharmacology analysis. <bold>Methods</bold> The analysis involved the following steps: screen the chemical components of BBD through literature review of Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Chemistry Database, PubChem, and other databases; obtain L-OHP-related targets through GeneCards database; and search CRC-related targets through OMIM, GeneMap, TTD, DisGeNET, CTD, GeneCards, and other databases. After the intersection and mapping of drugs and disease, the protein-protein interaction (PPI) network and core targets were obtained using STRING database and CytoScape software. MetaScape database was used to analyze the core targets to obtain GO biological processes and KEGG pathways. <bold>Results</bold> BBD contained 495 chemical components with 204 active components screened out through the Swiss ADME database and 770 targets were obtained through the Swiss Target Prediction database. After the intersection of BBD and 775 targets of L-OHP with the CRC targets, it resulted in 74 potential targets. Twenty-four core targets were determined from the 74 intersection targets, which were related to the positive regulation of kinase activity, the positive regulation of cell migration, and peptidyl-serine modification in GO biological process. The KEGG pathway analysis showed that the core targets were related to pathway in cancer, proteoglycan in cancer, endocrine resistance, and microRNA in cancer, TNF signaling pathway, platinum resistance, and other pathways. Molecular docking showed that the core targets could bind to the most examined compounds. <bold>Conclusion</bold> Quercetin-7-olate, cyclo (L-tyrosyl-L-phenylalanyl), panaxadiol, and other compounds in BBD may play an anti-colorectal cancer effect in multiple pathways, including EGFR, AKT1, mTOR, and other targets in synergy with L-OHP.

Effects of ginsenoside compound K on colitis-associated colorectal cancer and gut microbiota profiles in mice.

BackgroundGinsenoside compound K (GC-K), generated from ginseng saponins bioconverted by gut microbiota, has potential anti-colorectal cancer (CRC) effects. Meanwhile, GC-K may interact with gut microbiota, playing important roles in the occurrence and development of CRC. However, the effects of gut microbiota on the preventive and therapeutic effects of GC-K in CRC remain to be elucidated.MethodsThe anti-CRC effects of GC-K were evaluated in an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated CRC Balb/c mice model under the dosage of 30 and 60 mg/kg. Stool samples were collected during the experiments for profiling gut microbiota by 16S rRNA sequencing. Correlative analysis between gut microbiota and anti-CRC effect of GC-K was also assessed. Finally, the anti-CRC effect of Akkermansia muciniphila (A. muciniphila) was validated in CRC cell lines.ResultsGC-K could significantly suppress tumor growth in vivo at the dosage of 60 mg/kg without exogenous interference of gut microbiota. Moreover, dysbiosis of gut microbiota was observed in the CRC model group, which could be recovered by GC-K treatment. In particular, A. muciniphila, which could inhibit the proliferation of HCT-116, HT-29, and LOVO cells, was significantly up-regulated by GC-K.ConclusionsGC-K was verified to suppress the tumor growth of AOM/DSS-induced colitis-associated CRC through the modulation of gut microbiota, partially by up-regulation of A. muciniphila.

Polysaccharide-Zein Composite Nanoparticles for Enhancing Cellular Uptake and Oral Bioavailability of Curcumin: Characterization, Anti-colorectal Cancer Effect, and Pharmacokinetics.

Curcumin (CUR) has demonstrated promising potential as a therapeutic agent against colorectal cancer (CRC). However, its intrinsic shortcomings, including oxidative instability, sensitivity to gastrointestinal (GI) hydrolytic/enzymatic action, and susceptibility to biotransformation and systemic elimination, have greatly undermined its value for application in clinical settings. The development of carriers, in particular oral formulations, for its efficient delivery has remained an important direction in nutraceutical research. In the present work, CUR-encapsulated nanoparticles were fabricated with zein alone (Zein-CUR) and with zein and a polysaccharide (PS) [gum Arabic (GA), hyaluronic acid (HA) and pectin (PC), respectively] (PS-Zein-CUR). Their physicochemical and biological properties were evaluated in a series of in vitro and in vivo assays. Dynamic light scattering analysis showed an increase in the particle size of the nanoparticles from 129.0 nm (Zein-CUR) to 188.8–346.4 nm (PS-Zein-CUR). The three PS-Zein-CUR formulations had significantly higher (17–22%) CUR encapsulation efficiency (EE) than Zein-CUR. Among them, HA-Zein-CUR exhibited the highest EE and loading capacity. Zeta potential and FTIR spectra indicated the involvement of electrostatic and hydrophobic interactions and hydrogen bonds in the formation of the PS-Zein-CUR. In human CRC cell lines (HCT8, HCT29, and HCT116), the three PS-Zein-CUR and CUR all effectively inhibited cell viability and colony formation (HA-Zein-CUR > PC-Zein-CUR > GA-Zein-CUR/CUR). HA-Zein-CUR and PC-Zein-CUR also resulted in significantly higher cellular uptake of CUR than GA-Zein-CUR and CUR. Simulated GI-digestion assay demonstrated significantly improved controlled-release properties of these two formulations. Further pharmacokinetics and tissue distribution assays in a CRC subcutaneous xenograft model in nude mice corroborated the enhanced pharmacokinetic properties of intragastric administration of HA-Zein-CUR compared with that of free CUR (3 times higher Cmax and 9.18 times higher plasma AUC). HA-Zein-CUR also led to enhanced delivery and accumulation of CUR in major organs/tissues, in particular CRC tumors and colon. These results together support that HA-Zein-CUR has promising potential as an oral agent for the control of CRC.

Discovery of 3,4-Dihydrobenzo[f][1,4]oxazepin-5(2H)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects.

The Traf2- and Nck-interacting protein kinase (TNIK) is a downstream signal protein of the Wnt/β-catenin pathway and has been thought of as a potential target for the treatment of colorectal cancer (CRC) that is often associated with dysregulation of Wnt/β-catenin signaling pathway. Herein, we report the discovery of a series of 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one derivatives as a new class of TNIK inhibitors. Structure-activity relationship (SAR) analyses led to the identification of a number of potent TNIK inhibitors with compound 21k being the most active one (IC50: 0.026 ± 0.008 μM). This compound also displayed excellent selectivity for TNIK against 406 other kinases. Compound 21k could efficiently suppress CRC cell proliferation and migration in in vitro assays and exhibited considerable antitumor activity in the HCT116 xenograft mouse model. It also showed favorable pharmacokinetic properties. Overall, 21k could be a promising lead compound for drug discovery targeting TNIK and deserves further studies.

Quxie Capsule Alleviates Colitis-associated Colorectal Cancer Through Modulating the Gut Microbiota and Suppressing A. fumigatus-induced Aerobic Glycolysis.

Quxie capsule (QX), a compound of 21 kinds of Traditional Chinese Medicine (TCM) herbs, has been used to treat patients with metastatic colorectal cancer (mCRC) and could suppress the growth of colon cancer. However, the mechanisms of QX inhibiting colorectal cancer remain unclear. In current study, we attempted to determine the anti-colorectal cancer (CRC) effects of QX and the mechanisms of QX in alleviating colorectal cancer. A colitis-associated colon cancer (CAC) model was established by intraperitoneally injecting mice with AOM followed by 3 cycles of 2% DSS in water. During establishment of CAC model, we orally gavaged mice with QX. Hematoxylin and eosin (H&E) and immunohistochemistry were performed to assess lesion of the colonic tumors. The expression of pro-inflammatory cytokines in colonic tumors was measured by qPCR. The proportion of immune cells in colonic tumors was analyzed by flow cytometry. Internal transcribed spacer (ITS) sequencing and 16S rRNA gene sequencing were performed to detect intestinal microbiota. The expression of glycolytic related enzymes, lactate production, and extracellular acidification rate (ECAR) were used to assess the level of aerobic glycolysis. QX markedly inhibited intestinal tumorigenesis by decreasing the expression of pro-inflammatory cytokines and the proportion of myeloid-derived suppressor cells (MDSCs), and increasing the proportion of CD8+ T cells in colon tumors. Fecal microbiota sequencing revealed that QX increased the relative abundances of intestinal symbiotic probiotics, such as, Lactobacillus, Bifidobacterium and Faecalibacterium genera. What's more, opportunistic pathogens, Bacteroides genera and Aspergillus-Aspergillus fumigatus, exhibited remarkably reduced abundances in mice treated with QX compared with untreated CAC mice. Further experiments showed that QX significantly reduced glycolysis of colon tumor and suppressed A. fumigatus-induced glycolytic metabolism of colon cancer cells. QX alleviates the development of CRC at least in part through modulating intestinal microbiota and reducing A. fumigatus-induced aerobic glycolysis of colon cancer cells.

Evaluation of Anti-Colorectal Cancer Activity in Methanolic Extract of Coleus forskohlii Root

In a multistage process that involves moving from a precancerous lesion to a malignant tumour state, cancer develops when normal cells undergo the change into tumour cells. Colon cancer, also known as colorectal cancer (CRC), is the third most common and second-deadliest malignant tumour in the world. The current study's objective was to assess the anticancer potential of a methanolic extract of Coleus forskohlii root on the cancer cell line HT-29 using the MTT assay. A variety of assay methods were used, including morphological investigations, cell growth inhibition, and cell viability. At various concentrations (12.5, 25, 50, 100, and 200 µg/ml), the Coleus forskohlii extract was tested against the HT-29 cell line for its ability to inhibit cell proliferation. This study revealed that when concentrations rise the cell growth inhibition levels rise. The conventional medicine Doxorubicin had a growth inhibition of 72.70% at a dose of 5 µg/ml while the lowest growth inhibition was determined to be 9.55% at 12.5 µg/ml and the highest growth inhibition was 71.16% at 200 µg/ml. IC50 was greater than 123.90 µg/ml. According to the study's findings, a human colon adenocarcinoma cell line could be resistant to the anti-colorectal cancer effects of Coleus forskohlii root methanolic extract (HT-29).

Bolbostemma paniculatum (Maxim.) Franquet extract suppresses the development of colorectal cancer through downregulation of PI3K/Akt pathway

Ethnopharmacological relevanceBolbostemma paniculatum (Maxim.) Franquet (BPF), a kind of Chinese medicine, has been traditionally used in treating mastitis, dysentery, phlegm nuclear, and sore swelling poison. Aim of the studyIn current study, we tried to investigate the possible anti-colorectal cancer (CRC) effects of BPF. Materials and methodsThe effects of BPF extract on human colon cancer cells HCT-116 and SW-620, and a colitis associated colorectal cancer (CACC) mouse model were evaluated using the method of experimental pharmacology combined with network pharmacology. ResultsThe ethyl acetate extract 3 (EA3) of BPF showed the most potent growth inhibitory effect in CRC cells. It could inhibit the clone formation, induce the apoptosis and cell cycle arrest in G1 phase as well as suppress the invasion and migration of CRC cells. And EA3 prevented ICR mice against CACC effectively. Both KEGG and GO analysis indicated that EA3 may inhibit CRC through influencing PI3K/Akt pathway. Results of Western blot analysis and ELISA confirmed that the molecules in the pathway were affected by EA3. ConclusionsThese results demonstrate that EA3 from BPF could suppress the development of CRC through inhibiting the activity of PI3K/Akt pathway.

Jujuboside B induces mitochondrial-dependent apoptosis in colorectal cancer through ROS-mediated PI3K/Akt pathway in vitro and in vivo

Jujuboside B (JUB) is a saponin isolated from the seeds of Zizyphus jujuba. The anti-colorectal cancer effect of JUB and its potential mechanism remain unclear. We demonstrated that JUB induced the apoptosis of colorectal cancer cells via mitochondrial membrane damage. JUB-induced apoptosis in colorectal cancer cells was dependent on the generation of intracellular reactive oxygen species (ROS) and downregulation of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway. Moreover, JUB significantly inhibited tumor growth in the colorectal cancer mouse model, and the molecular mechanism was consistent with the results in vitro. This study proved for the first tine that JUB can induce the apoptosis of colorectal cancer cells by promoting ROS generation and inactivating the PI3K/Akt signaling pathway in vitro and in vivo, providing a scientific basis for the application of JUB in the prevention and adjuvant treatment of colorectal cancer.

SPIB acts as a tumor suppressor by activating the NFkB and JNK signaling pathways through MAP4K1 in colorectal cancer cells

Spi-B transcription factor (SPIB) is a member of the E-twenty-six (ETS) transcription factor family. Previous studies have shown that the expression of SPIB is downregulated in human colorectal cancer tissues. The purpose of our study was to explore the biological function and related mechanism of SPIB in colorectal cancer cells. Our study found that SPIB could inhibit the proliferation, migration and invasion of CRC cells; inhibit angiogenesis; and induce CRC cells cycle arrest in G2/M phase and promote the apoptosis of CRC cells. We also found that compared with the control group, the 50% inhibitory concentration (IC50) values of oxaliplatin and 5-FU in the SPIB overexpression group were significantly reduced. Western blot results showed that the overexpression of SPIB upregulated cleaved-PARP(c-PARP), nuclear factor kB p65 (NFkB p65), phospho-NFkB p65 (p-NFkB P65), JNK1, and C-Jun protein expression levels compared with the control group. The silence of SPIB downregulated c-PARP, NFκB p65, p-NFκB p65, JNK1, and C-Jun protein expression levels. A dual-luciferase reporter assay showed that SPIB could activate the promoter of MAP4K1 and enhance the expression of MAP4K1. After silencing MAP4K1, the protein expression levels of c-PARP, NFkB P65, p-NFkB P65, JNK1, and C-Jun were downregulated. In summary, we found that SPIB is a tumor suppressor in colorectal cancer cells and that SPIB sensitizes colorectal cancer cells to oxaliplatin and 5-FU, SPIB exerts its anti-colorectal cancer effect by activating the NFkB and JNK signaling pathways through MAP4K1. The above findings may provide a reference for new molecular markers and therapeutic targets for CRC.

Anti-colorectal Cancer Effect of Ganjang Prepared with Washed-Dehydrated Solar Salt on C57BL/6 Mice

Anti-colorectal Cancer Effect of Ganjang Prepared with Washed-Dehydrated Solar Salt on C57BL/6 Mice

Shinan Sea Salt Intake Ameliorates Colorectal Cancer in AOM/DSS with High Fat Diet-Induced C57BL/6N Mice

The anticancer effects of Shinan (Shinan-South Korea) sea salts on azoxymethane (AOM)/dextran sodium sulfate (DSS) with high fat diet (HFD)-induced colon cancer and obesity in C57BL/6N mice were studied. We prepared three types of sea salt: generally manufactured sea salt (GS), generally manufactured after filtering seawater (FS), and manufactured with only new seawater (NS). Sea salt intake increased colon length and reduced colon length/weight ratio, tumor number, and progression of colon cancer in colon tissue. The differently prepared sea salts also ameliorated liver injury. In addition, the mineral composition of each salt was different. Moreover, the sea salts enhanced activation of natural killer cell (CD56) expression in colon and spleen tissues. However, the mineral compositions of sea salts were not simply associated with anticancer effects in AOM/DSS+HFD induced mice. Thus, the anticolorectal cancer effects of sea salts may be mediated by different factors, which remain to be identified.

Novel artemisinin derivatives with potent anticancer activities and the anti-colorectal cancer effect by the mitochondria-mediated pathway

Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC50 = 0.12 ± 0.05 μM), but also low toxicity against normal cell line L02 (IC50 = 12.46 ± 0.10 μM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca2+ levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer.

Anticolorectal Cancer Effects of AUCAN: Effects to Suppress Proliferation, Metastasis, and Invasion of Tumor Cells.

Background Colorectal cancer (CRC) is an underlying deadly malignancy with poor prognosis, lacking effective therapies currently available to improve the prognosis. C18H17NO6 (AUCAN), a kind of dibenzofuran extracted from a special plant in Yunnan Province (China), is identified as a natural anticancer agent exerting strong inhibitory activities on various cancers. Our study was committed to investigating the potency of AUCAN against colorectal cancers and further exploring the potential mechanisms via proteomic analysis. Methods Cell Counting Kit-8 assay and immunofluorescence staining were used to investigate the effect of AUCAN on the viability and proliferation of HCT-116 cells and RKO cells. The apoptosis of HCT-116 and RKO cells after AUCAN administration was determined by the flow cytometry test. The effects of AUCAN on invasion and migration of tumor cells were investigated by the colony formation assay, wound healing test, and Transwell invasion test. Meanwhile, the energy metabolism and growth of tumor tissues after AUCAN administration with 10 mg/kg and 20 mg/kg were examined by PET-CT in vivo. The side effects of AUCAN treatment were also evaluated through blood routine and liver function examination. RKO cell proliferation and apoptosis in vivo were further determined by hematoxylin and eosin staining, TUNEL staining, and immunohistochemistry. Furthermore, the differentially expressed proteins (DEPs) involved in AUCAN treatment were determined by proteomic analysis followed by functional clustering analysis. Results The results showed that AUCAN suppressed the migratory abilities and enhanced apoptosis of HCT-116 and RKO cell lines. Meanwhile, AUCAN treatment dramatically depressed the growth and volume of colorectal tumors in nude mice and suppressed the survival of RKO cells in tumor tissues without any side effects on the blood routine and liver function. In addition, twenty-four upregulated and forty-two downregulated proteins were identified. Additionally, functional clustering analysis concealed enriched biological processes, cellular components, molecular functions, and related pathways of these proteins involved in cellular metabolic. Finally, the protein-protein interaction analysis revealed the regulatory connection among these DEPs. Conclusions Taken together, AUCAN exerted its significant antitumor effect without side effects in the blood routine and liver function and the underlying mechanisms were preliminarily investigated by proteomic analysis.

Anti-Colorectal Cancer Effects of Medicinal Plants: Euphorbia helioscopia, Ferula elaeochytris, and Sideritis albiflora

Phytochemicals, extracts, and mixtures obtained from plants have been offered as an option for cancer treatment and prevention for modern drug discovery in recent years. For this purpose, in this study, anti-colorectal cancer effects of the hexane, acetone, methanol, and water extracts obtained by sequential extraction from Euphorbia helioscopia L., Ferula elaeochytris Korovin, and Sideritis albiflora Hub.-Mor. on DLD-1 cell line were investigated in vitro by using Alamar blue assay. Dose-dependent inhibition was detected in the viability of DLD-1 cell line. In all three plants species, E. helioscopia (IC50: 140.83±0.31 µg/mL), F. elaeochytris (IC50: 67.93±0.12 µg/mL), and S. albiflora (IC50: 85.12±0.10 µg/mL) methanol extracts showed higher anti-colorectal effects on DLD-1 cell line compared to other extracts tested for the same species. In addition, the IC50 value of doxorubicin used as a standard was found as 6.10±0.55 µg/mL. With the results obtained, as the first report highlighting in vitro anti-colorectal cancer effects of the studied plant species on DLD-1 cell line, promising marks were obtained from the analysis of the extracts as anti-cancer sources for plant-derived drug applications.

Suppression of PKCδ/NF-κB Signaling and Apoptosis Induction through Extrinsic/Intrinsic Pathways Are Associated Magnolol-Inhibited Tumor Progression in Colorectal Cancer In Vitro and In Vivo.

Magnolol is one of the hydroxylated biphenyl compounds from the root and stem bark of Magnolia officinalis, which shown to possess anti-colorectal cancer (CRC) effects. However, the regulatory mechanism of magnolol on apoptosis and NF-κB signaling in human CRC has not been elucidated. Thus, we investigated the inhibitory mechanism of magnolol on human and mouse CRC (HT-29 and CT-26) in vitro and in vivo. Results from reporter gene assay indicated that both magnolol and rottlerin (PKCδ inhibitor) reduced the endogenous NF-κB activity. In addition, indolactam V (PKCδ activator)-induced NF-κB signaling was significantly suppressed with both magnolol and rottlerin treatment. Results from Western blotting also indicated that phosphorylation of PKCδ and NF-κB -related proteins involved in tumor progression were effectively decreased by magnolol treatment. The invasion capacity of CRC cells was also attenuated by both magnolol and rottlerin. Furthermore, magnolol triggered Fas/Fas-L mediated extrinsic apoptosis and mitochondria mediated intrinsic apoptosis were validated by flow cytometry. Most importantly, tumor growth in both HT-29 and CT-26 bearing mice were suppressed by magnolol, but no pathologic change was detected in mice kidney, spleen, and liver. As confirmed by immunohistochemistry (IHC) staining from tumor tissue, PKCδ/NF-κB signaling and downstream proteins expression were decreased, while apoptotic proteins expression was increased in the magnolol treated group. According to these results, we suggest that the induction of apoptosis through extrinsic/intrinsic pathways and the blockage of PKCδ/NF-κB signaling are associated with the magnolol-inhibited progression of CRC.

Anti-colorectal cancer effects of scutellarin revealed by genomic and proteomic analysis

BackgroundColorectal cancer, one of the most common digestive tumors with high mortality and morbidity worldwide, currently lacks effective therapies available to improve the prognosis. This study was aimed to investigate the potency of Scutellarin against colorectal cancers, and explore the related mechanism via genomic and proteomic analysis.MethodsCell counting kit-8 assay was employed to detect the viability of HCT-116 and RKO cell lines treated with Scutellarin. The apoptosis of HCT-116 and RKO cells after Scutellarin administration was determined by TUNEL staining and Caspase 3/7 activity. Cell cycle was detected by flow cytometry analysis. The wound healing and transwell invasion test detected the role of Scutellarin in migration and invasion of HCT-116 and RKO cells. Meanwhile, the energy metabolism and growth of tumor tissues in vivo at day 28 were observed by PET-CT after Scutellarin administration with 50 mg/kg, 100 mg/kg and 300 mg/kg into 4-week-old nude mice. Blood routine and liver functions were also detected to evaluate the side effect of Scutellarin. Furthermore, the disease and function classifications which the differentially expressed genes and proteins involved after Scutellarin treatment were determined by genomic and proteomic analysis respectively.ResultsThe Scutellarin inhibited the migration and increased apoptosis of HCT-116 and RKO cell lines. Besides, Scutellarin treatment substantially decreased the growth and volume of colorectal tumors in nude mice without side effects on the blood routine and liver function. The differentially expressed genes in RKO cells after Scutellarin administration were mainly enriched in cell death and survival, organismal injury and abnormalities, and cancer. In addition, forty-seven upregulated and twenty-nine downregulated proteins were identified. Functional clustering analysis exhibited enriched biological processes, cellular components, molecular functions and related pathways of these proteins in cellular metabolic. Then protein–protein interactions analysis showed the regulatory relationship among these differentially expressed proteins.ConclusionsTaken together, the present findings revealed that Scutellarin exerted significant antitumor effect with no side effects in the blood and liver by regulating various important molecules in tumor proliferation, apoptosis and metastasis.

The Antitumor Activity of Betulinic Acid-Loaded Nanoliposomes Against Colorectal Cancer In Vitro and In Vivo via Glycolytic and Glutaminolytic Pathways.

The purpose of this study is to develop betulinic acid loaded nanoliposomes to improve the chemotherapy effect of colorectal cancer. The cellular uptake and anti-tumor effects of betulinic acid loaded nanoliposomes in vitro were characterized and evaluated, and their effects on glycolysis, glutamine decomposition and key anti-cancer targets were analyzed. Moreover, their anticancer efficacy was assessed in vivo. Compared with free betulinic acid in vitro, the cellular uptake and anti-tumor activity of betulinic acid-loaded nanoliposomes were significantly enhanced; these nanoliposomes significantly suppressed the proliferation and glucose uptake of colorectal cancer cells. Mechanistically, the anti-colorectal cancer effect of betulinic acid-loaded nanoliposomes was confirmed by their triggering of cellular apoptosis and regulating the potential glycolytic and glutaminolytic targets and pathways. After tumor proliferation was inhibited and colorectal cancer cells apoptosis, the anticancer effect of betulinic acid loaded nanoliposomes in vivo was significantly enhanced. All in all, betulinic acid loaded nanoliposomes are expected to be an effective drug delivery system for colorectal cancer treatment.