Cancer Cell Cycle Arrest Research Articles

Exploring the anticancer potential of caffeic acid nanoemulsion: ROS induced apoptosis and cell cycle arrest in HCT116 colorectal cancer cells

Exploring the anticancer potential of caffeic acid nanoemulsion: ROS induced apoptosis and cell cycle arrest in HCT116 colorectal cancer cells

Resistomycin Suppresses Prostate Cancer Cell Growth by Instigating Oxidative Stress, Mitochondrial Apoptosis, and Cell Cycle Arrest

Globally, prostate cancer is among the most threatening and leading causes of death in men. This study, therefore, aimed to search for an ideal antitumor strategy with high efficacy, low drug resistance, and no or few adverse effects. Resistomycin is a natural antibiotic derived from marine actinomycetes, and it possesses various biological activities. Prostate cancer cells (PC3) were treated with resistomycin (IC12.5: 0.65 or IC25: 1.3 µg/mL) or 5-fluorouracil (5-FU; IC25: 7 µg/mL) for 24 h. MTT assay and flow cytometry were utilized to assess cell viability and apoptosis. Oxidative stress, apoptotic-related markers, and cell cycle were also assessed. The results revealed that the IC50 of resistomycin and 5-FU on PC3 cells were 2.63 µg/mL and 14.44 µg/mL, respectively. Furthermore, treated cells with the high dose of resistomycin showed an increased number of apoptotic cells compared to those treated with the lower dose. Remarkable induction of reactive oxygen species generation and lactate dehydrogenase (LDH) leakage with high malondialdehyde (MDA), carbonyl protein (CP), and 8-hydroxyguanosine (8-OHdG) contents were observed in resistomycin-treated cells. In addition, marked declines in glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in PC3 cells subjected to resistomycin therapy were observed. Resistomycin triggered observable cell apoptosis by increasing Bax, caspase-3, and cytosolic cytochrome c levels and decreasing Bcl-2 levels. In addition, notable downregulation of proliferating cell nuclear antigen (PCNA) and cyclin D1 was observed in resistomycin-treated cancerous cells. According to this evaluation, the antitumor potential of resistomycin, in a concentration-dependent manner, in prostate cancer cells was achieved by triggering oxidative stress, mitochondrial apoptosis, and cell cycle arrest in cancer cells. In conclusion, our investigation suggests that resistomycin can be considered a starting point for developing new chemotherapeutic agents for human prostate cancer.

Gramicidin, a Bactericidal Antibiotic, Is an Antiproliferative Agent for Ovarian Cancer Cells.

Background and Objectives: Gramicidin, a bactericidal antibiotic used in dermatology and ophthalmology, has recently garnered attention for its inhibitory actions against cancer cell growth. However, the effects of gramicidin on ovarian cancer cells and the underlying mechanisms are still poorly understood. We aimed to elucidate the anticancer efficacy of gramicidin against ovarian cancer cells. Materials and Methods: The anticancer effect of gramicidin was investigated through an in vitro experiment. We analyzed cell proliferation, DNA fragmentation, cell cycle arrest and apoptosis in ovarian cancer cells using WST-1 assay, terminal deoxynucleotidyl transferase dUTP nick and labeling (TUNEL), DNA agarose gel electrophoresis, flow cytometry and western blot. Results: Gramicidin treatment induces dose- and time-dependent decreases in OVCAR8, SKOV3, and A2780 ovarian cancer cell proliferation. TUNEL assay and DNA agarose gel electrophoresis showed that gramicidin caused DNA fragmentation in ovarian cancer cells. Flow cytometry demonstrated that gramicidin induced cell cycle arrest. Furthermore, we confirmed via Western blot that gramicidin triggered apoptosis in ovarian cancer cells. Conclusions: Our results strongly suggest that gramicidin exerts its inhibitory effect on cancer cell growth by triggering apoptosis. Conclusively, this study provides new insights into the previously unexplored anticancer properties of gramicidin against ovarian cancer cells.

Pharmacophore mapping approach to find anti-cancer phytochemicals with metformin-like activities against transforming growth factor (TGF)-beta receptor I kinase: An in silico study.

The most frequently prescribed first-line treatment for type II diabetes mellitus is metformin. Recent reports asserted that this diabetes medication can also shield users from cancer. Metformin induces cell cycle arrest in cancer cells. However, the exact mechanism by which this occurs in the cancer system is yet to be elucidated. Here, we investigated the impact of metformin on cell cycle arrest in cancer cells utilizing transforming growth factor (TGF)-beta pathway. TGF-ß pathway has significant effect on cell progression and growth. In order to gain an insight on the underlying molecular mechanism of metformin's effect on TGF beta receptor 1 kinase, molecular docking was performed. Metformin was predicted to interact with transforming growth factor (TGF)-beta receptor I kinase based on molecular docking and molecular dynamics simulations. Furthermore, pharmacophore was generated for metformin-TGF-ßR1 complex to hunt for novel compounds having similar pharmacophore as metformin with enhanced anti-cancer potentials. Virtual screening with 29,000 natural compounds from NPASS database was conducted separately for the generated pharmacophores in Ligandscout® software. Pharmacophore mapping showed 60 lead compounds for metformin-TGF-ßR1 complex. Molecular docking, molecular dynamics simulation for 100 ns and ADMET analysis were performed on these compounds. Compounds with CID 72473, 10316977 and 45140078 showed promising binding affinities and formed stable complexes during dynamics simulation with aforementioned protein and thus have potentiality to be developed into anti-cancer medicaments.

Epiberberine induced p53/p21-dependent G2/M cell cycle arrest and cell apoptosis in gastric cancer cells by activating γ-aminobutyric acid receptor- β3

Background and PurposeEpiberberine (EPI) is one of the most important bioalkaloid found in the rhizome of Coptis chinensis, which has been observed to exhibit pharmaceutical effects against gastric cancer (GC). Nevertheless, the potential mechanism of EPI against GC cells still remains unclear. This study aimed to identify the core receptor on GC cells through which EPI inhibited the growth of GC cells and to explore the underlying inhibitory mechanisms. MethodsTo identify hub receptor targets that respond to EPI treatment, RNA sequencing (RNA-Seq) data from a tumor-bearing mouse model were analyzed using bioinformatics method and molecular docking. The binding interaction between EPI and GABRB3 was validated through western blotting based-cellular thermal shift assay (WB-CETSA). To further verify the binding region between EPI and GABRB3 through circular dichroism (CD) chromatography, fragments of the extracellular and transmembrane domains of the GABRB3 protein were expressed and purified in vitro. Stable cell lines with the overexpression or knockdown of GABRB3 were established using the recombinant lentivirus system. MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)) assay, colony formation assay, invasion and migration experiments, and flow cytometry were conducted to validate the inhibitory effect of EPI on the GC cells via GABRB3. Additionally, western blotting was utilized to explore the potential inhibitory mechanisms. ResultsThrough the combination of multiple bioinformatics methods and molecular docking, we found that the γ-aminobutyric acid type A receptor subunit -β3 (GABRB3) might be the critical receptor target in response to EPI treatment. The results of WB-CETSA analysis indicated that EPI significantly promoted the thermostability of the GABRB3 protein. Importantly, EPI could directly bind to GABRB3 and alter the secondary structure of GABRB3 fragments similar to the natural agonist, γ-aminobutyric acid (GABA). The EPI-induced suppression of the malignant phenotype of GC cells was dependent on the presence of GABRB3. GABRB3 expression was positively correlated with TP53 in patients with GC. The binding of EPI to GABRB3 stimulated p53 accumulation in GC cells. This activated the p21/CDK1/cyclinB1 pathway, resulting in G2/M cell cycle arrest, and induced the Bcl-2/BAX/Caspase axis-dependent cell apoptosis. ConclusionThis study revealed the target receptor for EPI in GC cells and provided new insights into its anticancer mechanisms.

9-oxo-ODAs suppresses the proliferation of human cervical cancer cells through the inhibition of CDKs and HPV oncoproteins

Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25–50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

Synthesis and Biological Evaluation of 12-Aryl-11-hydroxy-5,6-dihydropyrrolo[2″,1″:3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-8(9H)-one Derivatives as Potential Cytotoxic Agents.

In the present paper, a facile and efficient synthetic procedure has been applied to obtain dihydrodipyrrolo[1,2-a:2',1'-c]pyrazine-2,3-dicarboxylates (5a-s), which have subsequently gone through the cyclization in the presence of hydrazine hydrate to afford 12-aryl-11-hydroxy-5,6-dihydropyrrolo[2″,1″:3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-8(9H)-ones (7a-q). The molecular structures of these novel compounds were extensively examined through the analysis of spectroscopic data in combination with X-ray crystallography techniques. Following that, the in vitro cytotoxic activities of all derivatives against three human cancer cell lines (Panc-1, PC3, and MDA-MB-231) were comprehensively evaluated alongside the assessment on normal human dermal fibroblast (HDF) cells using the MTT assay. Among the compounds, the 3-nitrophenyl derivative (7m) from the second series showed the best antiproliferative activity against all tested cell lines, particularly against Panc-1 cell line, (IC50 = 12.54 μM), being nearly twice as potent as the standard drug etoposide. The induction of apoptosis and sub-G1 cell cycle arrest in Panc-1 cancer cells by compound 7m was confirmed through further assessment. Moreover, the inhibition of kinases and the induction of cellular apoptosis by compound 7m in Panc-1 cancer cells were validated using the Western blotting assay.

Compound-composed Chinese medicine of Huachansu triggers apoptosis of gastric cancer cells through increase of reactive oxygen species levels and suppression of proteasome activities

BackgroundHuachansu (HCS), a known Chinese patent drug extracted from the Chinese toad skin, is frequently used for the treatment of various advanced cancers, especially gastric cancer, due to the good therapeutic effect. However, it is rather difficult to clarify the active substances and molecular mechanisms involved owing to the lack of appropriate research strategies. We recently proposed the concept and research ideas of compound-composed Chinese medicine formula. PurposeTo discover compound-composed Chinese medicine from Huachansu and to explore its mechanism of action in inducing apoptosis of gastric cancer cells. MethodNetwork pharmacology combined with serum pharmacochemistry was utilized to screen the predominant active constituents from HCS against gastric cancer. Then, the compound-composed Chinese medicine of HCS (CCMH) was prepared according to their relative contents in serum. The pharmacological effects and potential mechanisms for CCMH were investigated by assays for cell viability, cell cycle, apoptosis, mitochondrial membrane potential (MMP), proteomics, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, proteasome activity, and western blot. ResultsCCMH was comprised of arenobufagin (11.14%), bufalin (18.67%), bufotalin (7.33%), cinobufagin (16.67%), cinobufotalin (16.74%), gamabufotalin (8.45%), resibufogenin (12.03%), and telocinobufagin (8.97%). CCMH evidently induced proliferation inhibition, cell cycle arrest, apoptosis, and MMP collapse in gastric cancer cells, possessing the better activities than HCS. Proteomic analysis showed that CCMH influenced ROS pathway, ubiquitin proteasome system, and PI3K/Akt and MAPK signaling pathways. CCMH markedly enhanced intracellular ROS levels in gastric cancer cells, which was reversed by NAC. Accordingly, NAC antagonized the apoptosis-inducing effect of CCMH. Significantly decreased proteasome 20S activity by CCMH was observed in gastric cancer cells. CCMH also regulated the expression of key proteins in PI3K/Akt and MAPK signaling pathways. ConclusionCCMH possesses more significant apoptotic induction effects on gastric cancer cells than HCS, which is achieved primarily through suppression of proteasome activities and increase of ROS levels, followed by regulating PI3K/Akt and MAPK signaling pathways. Network pharmacology combined with serum pharmacochemistry is an effective strategy for discovering compound-composed Chinese medicine from traditional Chinese medicine, which can help clarify the pharmacological substances and mechanisms of action for traditional Chinese medicine.

A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.

The microtubule protein inhibitor C118P shows excellent anti-breast cancer effects. However, the potential targets and mechanisms of C118P in breast cancer remain unknown. Real-time cellular analysis (RTCA) was used to detect cell viability. Apoptosis and the cell cycle were detected by flow cytometry. Computer docking simulations, surface plasmon resonance (SPR) technology, and microscale thermophoresis (MST) were conducted to study the interaction between C118P and alanine-serine-cysteine transporter 2 (ASCT2). Seahorse XF technology was used to measure the basal oxygen consumption rate (OCR). The effect of C118P in the adipose microenvironment was explored using a co-culture model of adipocytes and breast cancer cells and mouse cytokine chip. C118P inhibited proliferation, potentiated apoptosis, and induced G2/M cell cycle arrest in breast cancer cells. Notably, ASCT2 was validated as a C118P target through reverse docking, SPR, and MST. C118P suppressed glutamine metabolism and mediated autophagy via ASCT2. Similar results were obtained in the adipocyte-breast cancer microenvironment. Adipose-derived interleukin-6 (IL-6) promoted the proliferation of breast cancer cells by enhancing glutamine metabolism via ASCT2. C118P inhibited the upregulation of ASCT2 by inhibiting the effect of IL-6 in co-cultures. C118P exerts an antitumour effect against breast cancer via the glutamine transporter ASCT2.

RED RICE BRAN EXTRACT SUPPRESSES COLON CANCER CELLS VIA APOPTOSIS INDUCTION/CELL CYCLE ARREST AND EXERTS ANTIMUTAGENIC ACTIVITY.

Red rice bran extract (RRBE) contains many biologically active substances exerting antioxidant and anti-inflammatory effects. To evaluate the anticancer potential of RRBE in human colon cancer cells and its mutagenic/antimutagenic effects on nonmalignant cells. The cytotoxic effect of RRBE was determined by trypan blue exclusion in HCT116, HT29 cell lines and a non-cancerous HEK293 cell line, and its antiproliferative effect using MTS and colony formation assay. The apoptosis induction was evaluated using ELISA, and the apoptotic rate and cell cycle progression were assessed by flow cytometry. The mutagenic/ antimutagenic potential of RRBE was analyzed by micronucleus assay in the V79 cell line. RRBE caused a dose-dependent reduction of cell viability in colon cancer cells and showed a limited cytotoxicity against HEK293 cells. The treatment with RRBE suppressed proliferation of HCT116 and HT29 cells and induced apoptosis as evidenced by the increased DNA fragmentation and the apoptotic cell counts. Furthermore, RRBE treatment significantly increased the number of cells at the G2/M phase triggering the arrest of the cell cycle in colon cancer cells. Interestingly, RRBE did not increase the micronucleus frequency in V79 cells but reduced the micronucleus formation caused by mitomycin C. RRBE effectively suppressed proliferation, induced apoptosis, and caused a cell cycle arrest in human colon cancer cells while being non-mutagenic and exerting antimutagenic effects in vitro.

RING induces cell cycle arrest and apoptosis in human breast cancer cells by regulating the HSF1/MT2A axis

It was reported that lowly expressed RING1 indicates poor prognosis in breast cancer (BC) patients, while the mechanism by which RING1 is involved in BC progression is not fully understood. Here, we found that RING1 was lowly expressed in BC tissues and cells than in normal mammary tissues and epithelial cells. Overexpression of RING1 suppressed the cell proliferative and colony formation abilities, and facilitated cell cycle arrest and cell apoptosis in BC cells (T47D and MCF-7 cells). Mechanistically, as an ubiquitin ligase, RING1 bound to HSF1 and induced its proteasome-dependent degradation. HSF1 could bind to the promoter region of MT2A to promote the transcriptional level of MT2A. While RING1 overexpression hindered the transcriptional activation of MT2A induced by HSF1. Moreover, ectopic expression of MT2A reversed the inhibitory effect of RING1 on cell proliferation and clonogenesis, and antagonized the promotion effect of RING1 on cell cycle arrest and apoptosis in BC cells. Additionally, T47D cells infected with or without lentivirus-mediated RING1 overexpression vector (LV-RING1) were injected subcutaneously into the right back of nude mice to evaluate tumorigenicity. And overexpression of RING1 impeded the growth of BC xenografts in mice. In conclusion, RING1 suppressed the transcriptional activation of MT2A induced by HSF1 by facilitating the ubiquitination degradation of HSF1, resulting in cell cycle arrest and apoptosis in BC cells.

HO-3867, a curcumin analog, elicits cell apoptosis and p38-mediated caspase activation in hepatocellular carcinoma.

HO-3867, a synthetic curcumin analog, has displayed various tumor-suppressive characteristics and improved bioabsorption over its parent compound. However, its influences on the development of hepatocellular carcinoma (HCC) are poorly defined. To address this, we tested the anticarcinogenic impact of HO-3867 and investigated the underlying mechanisms in fighting liver cancer. Our result demonstrated that HO-3867 reduced the viability of HCC cells, accompanied by promotion of cell cycle arrest at the sub-G1 stage and apoptotic responses. Furthermore, a distinctive profile of apoptosis associated proteins, encompassing elevated heme oxygenase-1 (HO-1) level and caspase activation, was detected in HO-3867-stimulated HCC cells. In addition, such HO-3867-mediated elevation in caspase activation was dampened by pharmacological suppression of p38 activities. Taken together, our findings unveiled that HO-3867 triggered cell cycle arrest and apoptotic events in liver cancer, involving a p38-mediated activation of caspase cascades. These data highlighted a usefulness of curcumin or its analogs on the management of hepatocarcinogenesis.

Ganodermanontriol Suppresses the Progression of Lung Adenocarcinoma by Activating CES2 to Enhance the Metabolism of Mycophenolate Mofetil.

New anti-lung cancer therapies are urgently required to improve clinical outcomes. Since ganodermanontriol (GDNT) has been identified as a potential antineoplastic agent, its role in lung adenocarcinoma (LUAD) is investigated in this study. Concretely, lung cancer cells were treated with GDNT and/or mycophenolate mofetil (MMF), after which MTT assay, flow cytometry and Western blot were conducted. Following bioinformatics analysis, carboxylesterase 2 (CES2) was knocked down and rescue assays were carried out in vitro. Xenograft experiment was performed on mice, followed by drug administration, measurement of tumor growth and determination of CES2, IMPDH1 and IMPDH2 expressions. As a result, the viability of lung cancer cells was reduced by GDNT or MMF. GDNT enhanced the effects of MMF on suppressing viability, promoting apoptosis and inducing cell cycle arrest in lung cancer cells. GDNT up-regulated CES2 level, and strengthened the effects of MMF on down-regulating IMPDH1 and IMPDH2 levels in the cells. IMPDH1 and IMPDH2 were highly expressed in LUAD samples. CES2 was a potential target for GDNT. CES2 knockdown reversed the synergistic effect of GDNT and MMF against lung cancer in vitro. GDNT potentiated the role of MMF in inhibiting tumor growth and expressions of CES2 and IMPDH1/2 in lung cancer in vivo. Collectively, GDNT suppresses the progression of LUAD by activating CES2 to enhance the metabolism of MMF.

Melatonin protects mice from 5-FU hepatotoxicity and improves 5-FU antitumor effects by an apoptotic pathway dependent on cell cycle arrest in A549 human lung cancer cells

Abstract Objectives This study determined if melatonin (MLT) can be used with 5-fluorouracil (5-FU), an anticancer drug as adjuvants to reduce A549 lung cancer cell proliferation and sensitise those cells to 5-FU at lower doses while protecting mice from hepatotoxicity. Methods In vitro, MTT assays assessed cell proliferation, and Annexin-V flow cytometry measured A549 cell apoptosis. RT-qPCR measured apoptotic markers tumour suppressor gene P53, KI-67, Bax, Bcl-2, and caspase3; and immunoblotting evaluated cell cycle parameters P21, CDK2, and cyclin E. ELISA biochemical analysis examined liver function, reactive oxygen species (ROS) and antioxidant assays, and inflammatory markers, in vivo. Masson’s trichome, haematoxylin, and eosin stains examined histopathological changes and fibrosis under a microscope. Key findings MLT combined with 5-FU elevated chemo-sensitization by decreasing A549 cell proliferation, lowering the IC50, increasing P21, P53, and Bax, decreasing Bcl-2, Ki-67, CDK2, and cyclin E, and inducing apoptosis and cell cycle arrest at G0/G1. After 5-FU [intraperitoneal (IP)]/MLT (oral) co-administration in vivo, all parameters improved and reversed. Liver enzymes (aspartate aminotransferase and alanine transaminase), bilirubin, albumin, total protein, albumin/globulin ratio, ROS, 4-HNE, H2O2, and pro-inflammatory cytokines; IL-6, IL-1β, and TNFα declined while antioxidant enzymes like SOD, CAT, GSH, and GPx, and IL-10 (anti-inflammatory) increased in combined MLT/5-FU treated groups compared with untreated and 5-FU alone treated groups. Histopathology confirmed these results. Conclusions MLT protected A549 cells from 5-FU-induced hepatotoxicity and enhanced 5-FU’s antitumor effect in vitro. These results support MLT/5-FU’s benefits, suggesting a more effective lung cancer treatment with fewer hepatotoxicity side effects. That could provide a novel therapeutic strategy for lung cancer.

ABBV-744 induces autophagy in gastric cancer cells by regulating PI3K/AKT/mTOR/p70S6k and MAPK signaling pathways

The mortality rates of gastric cancer remain high due to limited therapeutic strategies. As a highly selective inhibitor of the BD2 domain of BET family proteins, ABBV-744 has potent chemotherapeutic activity against various human solid tumors. However, whether ABBV-744 has potential anti-tumor effects in gastric cancer remain largely unknown. In this study, we evaluated the effect of ABBV-744 on gastric cancer cells and explored the possible underlying mechanisms. We found that ABBV-744 inhibited the growth of gastric cancer cells and patient-derived tumor organoids in a dose-dependent manner. Cellular experiments revealed that ABBV-744 induced mitochondria damage, reactive oxygen species accumulation, cell cycle arrest and apoptotic cell death in gastric cancer cells. Transcriptomic analysis using RNA-sequencing data identified autophagy as a crucial pathway involved in the cell death caused by ABBV-744. Mechanically, further studies showed that ABBV-744 induced autophagy flux in gastric cancer cells by inactivating PI3K/AKT/mTOR/p70S6k and activating the MAPK signaling pathways. In vivo mouse xenograft studies demonstrated that ABBV-744 significantly suppressed the growth of gastric cancer cells via inducing autophagy. Taken together, our results suggest that ABBV-744 is a novel drug candidate for gastric cancer.

Extract of the bioconverted fine root of ginseng induces apoptosis and cell cycle arrest in mouse colon cancer cells

Cancer is the major cause of death worldwide, and the anticancer effect of ginseng and its main root has been studied. However, study of fine root of ginseng (FRG) is still insufficient. The purpose of this study was to discover a new anticancer effect from FRG, which does not show an anticancer effect, through a bioconversion technique. We measured and compared cell viability in FRG- and bioconverted fine root of ginseng (BFRG)-stimulated CT26 cells to investigate differences caused by bioconversion. Cell viability of CT26 was suppressed upon treatment with BFRG, unlike FRG. The effect of BFRG on apoptosis and cell cycle arrest was investigated by flow cytometry. BFRG-stimulated CT26 cells showed an increased apoptotic cells and cell cycle arrest. Additionally, BFRG induced mitochondrial impairment by reducing the expression of anti-apoptosis protein Bcl-2. When confirming the signaling pathway, it was found that the p38 MAPK pathway was activated by BFRG. Collectively, our results reveal anticancer effects against colorectal cancer and represent potential targets for anticancer drug development.

Anticancer Effects of Fucoxanthin through Cell Cycle Arrest, Apoptosis Induction, and Angiogenesis Inhibition in Triple-Negative Breast Cancer Cells.

The absence of progesterone receptors, estrogen receptors, and human epidermal growth factor receptor-2 restricts the therapy choices for treating triple-negative breast cancer (TNBC). Moreover, conventional medication is not highly effective in treating TNBC, and developing effective therapeutic agents from natural bioactive compounds is a viable option. In this study, the anticancer effects of the natural compound fucoxanthin were investigated in two genetically different models of TNBC cells: MDA-MB-231 and MDA-MB-468 cells. Fucoxanthin had a significant anticancer effect in both cell lines at a concentration range of 1.56-300 µM. The compound decreased cell viability in both cell lines with higher potency in MDA-MB-468 cells. Meanwhile, proliferation assays showed similar antiproliferative effects in both cell lines after 48 h and 72 h treatment periods. Flow cytometry and Annexin V-FITC apoptosis assay revealed the ability of fucoxanthin to induce apoptosis in MDA-MB-231 only. Cell cycle arrest analysis showed that the compound also induced cell cycle arrest at the G1 phase in both cell lines, accompanied by more cell cycle arrest in MDA-MB-231 cells at S-phase and a higher cell cycle arrest in the MDA-MB-468 cells at G2-phase. Wound healing and migration assay showed that in both cell lines, fucoxanthin prevented migration, but was more effective in MDA-MB-231 cells in a shorter time. In both angiogenic cytokine array and RT-PCR studies, fucoxanthin (6.25 µM) downregulated VEGF-A and -C expression in TNF-α-stimulated (50 ng/mL) MDA-MB-231, but not in MDA-MB-468 cells on the transcription and protein levels. In conclusion, this study shows that fucoxanthin was more effective in MDA-MB-231 TNBC cells, where it can target VEGF-A and VEGF-C, inhibit cell proliferation and cell migration, and induce cell cycle arrest and apoptosis-the most crucial cellular processes involved in breast cancer development and progression.

Ebselen Inhibits the Growth of Lung Cancer Cells via Cell Cycle Arrest and Cell Death Accompanied by Glutathione Depletion.

Ebselen is a glutathione (GSH) peroxidase (GPx) mimic originally developed to reduce reactive oxygen species (ROS). However, little is known about its cytotoxicological effects on lung cells. Therefore, this study aimed to investigate the effects of Ebselen on the cell growth and cell death of A549 lung cancer cells, Calu-6 lung cancer cells, and primary normal human pulmonary fibroblast (HPF) cells in relation to redox status. The results showed that Ebselen inhibited the growth of A549, Calu-6, and HPF cells with IC50 values of approximately 12.5 μM, 10 μM, and 20 μM, respectively, at 24 h. After exposure to 15 μM Ebselen, the proportions of annexin V-positive cells were approximately 25%, 65%, and 10% in A549, Calu-6, and HPF cells, respectively. In addition, Ebselen induced arrest at the S phase of the cell cycle in A549 cells and induced G2/M phase arrest in Calu-6 cells. Treatment with Ebselen induced mitochondrial membrane potential (MMP; ΔΨm) loss in A549 and Calu-6 cells. Z-VAD, a pan-caspase inhibitor, did not decrease the number of annexin V-positive cells in Ebselen-treated A549 and Calu-6 cells. Intracellular ROS levels were not significantly changed in the Ebselen-treated cancer cells at 24 h, but GSH depletion was efficiently induced in these cells. Z-VAD did not affect ROS levels or GSH depletion in Ebselen-treated A549 or Ebselen-treated Calu-6 cells. In conclusion, Ebselen inhibited the growth of lung cancer and normal fibroblast cells and induced cell cycle arrest and cell death in lung cancer cells with GSH depletion.

Tumor suppressor Parkin induces p53-mediated cell cycle arrest in human lung and colorectal cancer cells

Tumor suppressor Parkin induces p53-mediated cell cycle arrest in human lung and colorectal cancer cells

Modulatory effects of point-mutated IL-32θ (A94V) on tumor progression in triple-negative breast cancer cells.

Breast cancer is a frequently diagnosed cancer and the leading cause of death among women worldwide. Tumor-associated macrophages stimulate cytokines and chemokines, which induce angiogenesis, metastasis, proliferation, and tumor-infiltrating immune cells. Although interleukin-32 (IL-32) has been implicated in the development and modulation of several cancers, its function in breast cancer remains elusive. Mutation of interleukin-32θ (IL-32θ) in the tissues of patients with breast cancer was detected by Sanger sequencing. RT-qPCR was used to detect the mRNA levels of inflammatory cytokines, chemokines, and mediators. The secreted proteins were detected using respective enzyme-linked immunosorbent assays. Evaluation of the inhibitory effect of mutant IL-32θ on proliferation, migration, epithelial-mesenchymal transition (EMT), and cell cycle arrest in breast cancer cells was conducted using MTS assays, migration assays, and Western blotting. A point mutation (281C>T, Ala94Val) was detected in IL-32θ in both breast tumors and adjacent normal tissues, which suppressed the expression of pro-inflammatory factors, EMT factors, and cell cycle related factors. Mutated IL-32θ inhibited the expression of inflammatory factors by regulating the NF-κB pathway. Furthermore, mutated IL-32θ suppressed EMT markers and cell cycle related factors through the FAK/PI3K/AKT pathway. It was inferred that mutated IL-32θ modulates breast cancer progression. Mutated IL-32θ (A94V) inhibited inflammation, EMT, and proliferation in breast cancer by regulating the NF-κB (p65/p50) and FAK-PI3K-GSK3 pathways.