Molecular Targets, Anti-cancer Properties and Potency of Synthetic Indole-3-carbinol Derivatives

2019 ◽  
Vol 19 (7) ◽  
pp. 540-554 ◽  
Author(s):  
Mojgan Noroozi Karimabad ◽  
Mehdi Mahmoodi ◽  
Abdolah Jafarzadeh ◽  
Ali Darekordi ◽  
Mohamad Reza Hajizadeh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cellular Proliferation ◽  
Human Cancer ◽  
Molecular Targets ◽  
Tumor Formation ◽  
Mesenchymal Transition ◽  
Anti Cancer

The indole-3-carbinol (I3C) displays anti-cancer/proliferative activities against human cancer cells. Cellular proliferation is an event associated with the progress and its continuation. This manifest is described by variation in expression and/or functions of genes that are related with cell cycle relevant proteins. The constitutive activation of several signal transduction pathways stimulates cells proliferation as well. The immediate stages in cancer development are accompanied by a fibrogenic response and the progression of the hypoxic environment is in favor of survival and proliferatory functions of cancer stem cells. A main part for prevention of in cancer cells death may manifest through altering cell metabolism. Cellular proliferation and metastasis are reported to be supported with increased generation of responsible hormones (in hormone dependent malignancies), and further promotion the angiogenesis, with epithelial to mesenchymal transition. This may be facilitated by progression of autophagy phenomenon, as well as via taking cues from neighboring stromal cells. Several signaling pathways in association with various factors specific for cellular viability, including hypoxia inducible factor 1, NF-κB, insulin-like growth factor 1 (IGF-1) receptor, Human foreskin fibroblasts (HFF-1), phosphoinositide 3 kinase/Akt, Wnt, cell cycle related protein, with androgen and estrogen receptor signaling are reported to be inhibited by I3C. These evidences, in association with bioinformatics data represent very important information for describing signaling pathways in parallel with molecular targets that may serve as markers for early diagnosis and/or critical targets for designing and development of novel therapeutic regimes alone or combined with drugs, to prevent tumor formation and further progression. In particular, I3C and DIM have been extensively investigated for their importance against numbers human cancers both in vitro and in vivo. We aimed the present manuscript, current study, to review anticancer properties and the miscellaneous mechanisms underlying the antitumorigenicity in an in-depth study for broadening the I3C treating marvel.

scholarly journals Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin

2019 ◽  
Vol 20 (21) ◽  
pp. 5391 ◽  
Author(s):  
Wörthmüller ◽  
Salicio ◽  
Oberson ◽  
Blum ◽  
Schwaller
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Expression System ◽  
Single Agent ◽  
Wnt Signaling Pathway ◽  
Tumor Formation ◽  
Mesenchymal Transition

Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells’ growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.

scholarly journals Polyphenolic Compounds from Lespedeza Bicolor Root Bark Inhibit Progression of Human Prostate Cancer Cells via Induction of Apoptosis and Cell Cycle Arrest

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 451 ◽  
Author(s):  
Sergey A. Dyshlovoy ◽  
Darya Tarbeeva ◽  
Sergey Fedoreyev ◽  
Tobias Busenbender ◽  
Moritz Kaune ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Human Cancer ◽  
Phase Cell ◽  
Root Bark ◽  
Cycle Arrest ◽  
Lespedeza Bicolor

From a root bark of Lespedeza bicolor Turch we isolated two new (7 and 8) and six previously known compounds (1–6) belonging to the group of prenylated polyphenols. Their structures were elucidated using mass spectrometry, nuclear magnetic resonance and circular dichroism spectroscopy. These natural compounds selectively inhibited human drug-resistant prostate cancer in vitro. Prenylated pterocarpans 1–3 prevented the cell cycle progression of human cancer cells in S-phase. This was accompanied by a reduced expression of mRNA corresponding to several human cyclin-dependent kinases (CDKs). In contrast, compounds 4–8 induced a G1-phase cell cycle arrest without any pronounced effect on CDKs mRNA expression. Interestingly, a non-substituted hydroxy group at C-8 of ring D of the pterocarpan skeleton of compounds 1–3 seems to be important for the CDKs inhibitory activity.

scholarly journals Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 792 ◽  
Author(s):  
Dhanasekhar Reddy ◽  
Ranjith Kumavath ◽  
Preetam Ghosh ◽  
Debmalya Barh
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Mtor Signaling ◽  
Anti Cancer ◽  
Cancer Activity ◽  
Lanatoside C

Cardiac glycosides (CGs) are a diverse family of naturally derived compounds having a steroid and glycone moiety in their structures. CG molecules inhibit the α-subunit of ubiquitous transmembrane protein Na+/K+-ATPase and are clinically approved for the treatment of cardiovascular diseases. Recently, the CGs were found to exhibit selective cytotoxic effects against cancer cells, raising interest in their use as anti-cancer molecules. In this current study, we explored the underlying mechanism responsible for the anti-cancer activity of Lanatoside C against breast (MCF-7), lung (A549), and liver (HepG2) cancer cell lines. Using Real-time PCR, western blot, and immunofluorescence studies, we observed that (i) Lanatoside C inhibited cell proliferation and induced apoptosis in cell-specific and dose-dependent manner only in cancer cell lines; (ii) Lanatoside C exerts its anti-cancer activity by arresting the G2/M phase of cell cycle by blocking MAPK/Wnt/PAM signaling pathways; (iii) it induces apoptosis by inducing DNA damage and inhibiting PI3K/AKT/mTOR signaling pathways; and finally, (iv) molecular docking analysis shows significant evidence on the binding sites of Lanatoside C with various key signaling proteins ranging from cell survival to cell death. Our studies provide a novel molecular insight of anti-cancer activities of Lanatoside C in human cancer cells.

scholarly journals The Interaction Between MiR-141 and lncRNA-H19 in Regulating Cell Proliferation and Migration in Gastric Cancer

2015 ◽  
Vol 36 (4) ◽  
pp. 1440-1452 ◽  
Author(s):  
Xiaoying Zhou ◽  
Feng Ye ◽  
Chengqiang Yin ◽  
Ya Zhuang ◽  
Ge Yue ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Target Genes ◽  
Human Cancer ◽  
Luciferase Assay ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition ◽  
Proliferation And Invasion

Background/Aims: Non-coding RNAs including miRNA and lncRNA had been reported to regulate gene expression and were both related to cancer progression. MicroRNA-141 (miR-141) has been reported to play a role in the epithelial to mesenchymal transition (EMT) process and H19 has also been demonstrated to promote malignancy in various cancers. We aimed to determine the correlation between miR-141 and H19 and their roles in gastric cancer in this study. Methods: H19 and miR-141 expression were detected by qRT-PCR. By bioinformatic analysis and luciferase assay we examined the correlation between H19 and miR-141 in vitro. Results: H19 expression was found to be inversely correlated to miR-141 expression in gastric cancer cells and tissues. H19 promotes malignancy including proliferation and invasion whereas miR-141 suppresses malignancy in human cancer cells. MiR-141 binds to H19 in a sequence specific manner, and suppresses H19 expression and functions including proliferation and invasion. MiR-141 could also regulate H19 target genes and miR-141 inhibitor restores H19 siRNA function, while H19 regulates miR-141 target gene ZEB1. Conclusion: These results were the first to demonstrate that H19 and miR-141 could compete with each other and affect their target genes in gastric cancer, which provide important clues for understanding the key roles of lncRNA-miRNA functional network in cancer.

The in vitro anti-cancer effects of wogonin in human cancer cells

2008 ◽  
Vol 136 ◽  
pp. S164
Author(s):  
Mingjie Xie ◽  
Huaqiang Li ◽  
Liji Jin ◽  
Yongping Xu ◽  
Xiaoyu Li ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Human Cancer Cells ◽  
Anti Cancer

scholarly journals Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53

2005 ◽  
Vol 168 (4) ◽  
pp. 553-560 ◽  
Author(s):  
Kayoko Maehara ◽  
Kimi Yamakoshi ◽  
Naoko Ohtani ◽  
Yoshiaki Kubo ◽  
Akiko Takahashi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Human Cancer ◽  
Dominant Negative ◽  
Cycle Arrest ◽  
Risk Of Cancer

E2F/DP complexes were originally identified as potent transcriptional activators required for cell proliferation. However, recent studies revised this notion by showing that inactivation of total E2F/DP activity by dominant-negative forms of E2F or DP does not prevent cellular proliferation, but rather abolishes tumor suppression pathways, such as cellular senescence. These observations suggest that blockage of total E2F/DP activity may increase the risk of cancer. Here, we provide evidence that depletion of DP by RNA interference, but not overexpression of dominant-negative form of E2F, efficiently reduces endogenous E2F/DP activity in human primary cells. Reduction of total E2F/DP activity results in a dramatic decrease in expression of many E2F target genes and causes a senescence-like cell cycle arrest. Importantly, similar results were observed in human cancer cells lacking functional p53 and pRB family proteins. These findings reveal that E2F/DP activity is indeed essential for cell proliferation and its reduction immediately provokes a senescence-like cell cycle arrest.

scholarly journals Sperm associated antigen 9 (SPAG9) a promising therapeutic target of ovarian carcinoma

Tumor Biology ◽  
2018 ◽  
Vol 40 (5) ◽  
pp. 101042831877365 ◽  
Author(s):  
Nirmala Jagadish ◽  
Rukhsar Fatima ◽  
Aditi Sharma ◽  
Sonika Devi ◽  
Vitusha Suri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Western Blot ◽  
Cellular Proliferation ◽  
Cyclin B1 ◽  
In Vitro Assays ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
Paclitaxel Treatment

SPAG9 is a novel tumor associated antigen, expressed in variety of malignancies. However, its role in ovarian cancer remains unexplored. SPAG9 expression was validated in ovarian cancer cells by real time PCR and Western blot. SPAG9 involvement in cell cycle, DNA damage, apoptosis, paclitaxel sensitivity and epithelial- mesenchymal transition (EMT) was investigated employing RNA interference approach. Combinatorial effect of SPAG9 ablation and paclitaxel treatment was evaluated in in vitro. Quantitative PCR and Western blot analysis revealed SPAG9 expression in A10, SKOV-3 and Caov3 compared to normal ovarian epithelial cells. SPAG9 ablation resulted in reduced cellular proliferation, colony forming ability and enhanced cytotoxicity of chemotherapeutic agent paclitaxel. Effect of ablation of SPAG9 on cell cycle revealed S phase arrest and showed decreased expression of CDK1, CDK2, CDK4, CDK6, cyclin B1, cyclin D1, cyclin E and increased expression of tumor suppressor p21. Ablation of SPAG9 also resulted in increased apoptosis with increased expression of various pro- apoptotic molecules including BAD, BID, PUMA, caspase 3, caspase 7, caspase 8 and cytochrome C. Decreased expression of mesenchymal markers and increased expression of epithelial markers was found in SPAG9 ablated cells. Combinatorial effect of SPAG9 ablation and paclitaxel treatment was evaluated in in vitro assays which showed that ablation of SPAG9 resulted in increased paclitaxel sensitivity and caused enhanced cell death. In vivo ovarian cancer xenograft studies showed that ablation of SPAG9 resulted in significant reduction in tumor growth. Present study revealed therapeutic potential of SPAG9 in ovarian cancer.

scholarly journals Anti-cancer activity of сuraxin CBL0137 on the models of acute leukemia in vitro

2019 ◽  
Vol 6 (4) ◽  
pp. 58-68
Author(s):  
T. I. Fetisov ◽  
K. I. Kirsanov ◽  
A. A. Borunova ◽  
M. N. Zatsepina ◽  
E. A. Lesovaya ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Leukemia ◽  
Cell Cycle Arrest ◽  
Signaling Pathways ◽  
Gene Clusters ◽  
Solid Cancer ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Cancer Activity

Background. Curaxin CBL0137 is a novel non-genotoxic compound with anti-cancer activity based on CBL0137 ability of non-covalent interaction with DNA causing histone chaperone FACT relocation. Anti-cancer activity of this drug was demonstrated previously on the wide panel of solid cancer models in vitro and in vivo.Objectives. Estimation of anticancer effects of CBL0137 on the acute myeloblastic leukemia cells (THP-1) and acute lymphoblastic leukemia (CCRF-CEM).Materials and methods. CBL0137 cytotoxicity was analyzed using the MTT test, the effects on the cell cycle and the induction of apoptosis was assessed by flow cytometry, the activity of signaling pathways in cells treated with CBL0137 was determined by real-time polymerase chain reaction.Results. Cell treatment with CBL0137 led to cell cycle arrest and apoptosis induction. In the study of CBL0137 effect on target gene clusters of 10 signal transduction pathways involved in the pathogenesis of acute leukemia we have showed that CBL0137 inhibited the expression of down-stream genes of WNT and Hedgehog signaling in both cell lines. In THP-1 cells we also observed the inhibition of the expression of PPARγ target and hypoxia-activated genes. In CCRF-CEM cells CBL0137 also induced the expression of Notch signaling target genes.Conclusion. The antitumor activity of CBL0137 was demonstrated on acute leukemia cell cultures, the drug possesses cytotoxicity, causes cell cycle arrest and activation of apoptosis. Significant changes in the expression of efferent gene clusters of several signaling pathways were observed in the cells treated with CBL0137.

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