scholarly journals The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jaime N Wertman ◽  
Nicole Melong ◽  
Matthew R Stoyek ◽  
Olivia Piccolo ◽  
Stewart Langley ◽  
...  
Keyword(s):  
Hair Cells ◽  
Pediatric Cancer ◽  
Human Cancer ◽  
Otic Vesicle ◽  
Zebrafish Model ◽  
Cytotoxic Effects ◽  
Human Cancer Cells ◽  
Chemotherapy Agent ◽  
Pediatric Cancer Survivors

Dose-limiting toxicities for cisplatin administration, including ototoxicity and nephrotoxicity, impact the clinical utility of this effective chemotherapy agent and lead to lifelong complications, particularly in pediatric cancer survivors. Using a two-pronged drug screen employing the zebrafish lateral line as an in vivo readout for ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280 compounds and identified 22 that were both oto- and nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino acid active in the dopamine pathway, were further investigated. Dopamine and L-mimosine protected the hair cells in the zebrafish otic vesicle from cisplatin-induced damage and preserved zebrafish larval glomerular filtration. Importantly, these compounds did not abrogate the cytotoxic effects of cisplatin on human cancer cells. This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin.

scholarly journals A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

2021 ◽  
Vol 22 (16) ◽  
pp. 8372
Author(s):  
Ana María Zárate ◽  
Christian Espinosa-Bustos ◽  
Simón Guerrero ◽  
Angélica Fierro ◽  
Felipe Oyarzún-Ampuero ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Antitumour Activity ◽  
Anticancer Compounds ◽  
Human Cancer Cells ◽  
Cycle Arrest ◽  
Apoptosis Inducer ◽  
Purine Ring

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.

scholarly journals Cancer interception by interceptor molecules: mechanistic, preclinical and human translational studies with chlorophylls

2021 ◽  
Vol 43 (1) ◽  
Author(s):  
Roderick H. Dashwood
Keyword(s):  
Immune Modulation ◽  
Human Cancer ◽  
Alkylating Agents ◽  
Radical Scavenging ◽  
Molecular Complexes ◽  
Antimutagenic Activity ◽  
Human Cancer Cells ◽  
Translational Studies ◽  
Salmonella Assay

AbstractBefore ‘cancer interception’ was first advocated, ‘interceptor molecules’ had been conceived as a sub-category of preventive agents that interfered with the earliest initiation steps in carcinogenesis. Three decades ago, a seminal review cataloged over fifty synthetic agents and natural products that were known or putative interceptor molecules. Chlorophylls and their derivatives garnered much interest based on the potent antimutagenic activity in the Salmonella assay, and the subsequent mechanistic work that provided proof-of-concept for direct molecular complexes with planar aromatic carcinogens. As the ‘interceptor molecule’ hypothesis evolved, mechanistic experiments and preclinical studies supported the view that chlorophylls can interact with environmental heterocyclic amines, aflatoxins, and polycyclic aromatic hydrocarbons to limit their uptake and bioavailability in vivo. Support also came from human translational studies involving ultralow dose detection in healthy volunteers, as well as intervention in at-risk subjects. Antimutagenic and antigenotoxic effects of natural and synthetic chlorophylls against small alkylating agents also highlighted the fact that non-interceptor mechanisms existed. This gave impetus to investigations broadly related to free radical scavenging, anti-inflammatory effects, immune modulation and photodynamic therapy. Therapeutic aspects of chlorophylls also were investigated, with evidence for cell cycle arrest and apoptosis in human cancer cells. As the science has evolved, new mechanistic leads continue to support the use and development of chlorophylls and their porphyrin derivatives for cancer interception, beyond the initial interest as interceptor molecules.

scholarly journals Antioxidants, Phytochemicals, and Cytotoxicity Studies onPhaleria macrocarpa(Scheff.) Boerl Seeds

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Ma Ma Lay ◽  
Saiful Anuar Karsani ◽  
Behrooz Banisalam ◽  
Sadegh Mohajer ◽  
Sri Nurestri Abd Malek
Keyword(s):  
Human Cancer ◽  
Cytotoxic Effects ◽  
Nutritional Values ◽  
Water Fraction ◽  
Human Cancer Cells ◽  
Fiber Protein ◽  
Cytotoxicity Studies ◽  
Normal Human ◽  
Lung Cell Line ◽  
Mcf 7

In recent years, the utilization of certain medicinal plants as therapeutic agents has drastically increased.Phaleria macrocarpa(Scheff.) Boerl is frequently used in traditional medicine. The present investigation was undertaken with the purpose of developing pharmacopoeial standards for this species. Nutritional values such as ash, fiber, protein, fat, and carbohydrate contents were investigated, and phytochemical screenings with different reagents showed the presence of flavonoids, glycosides, saponin glycosides, phenolic compounds, steroids, tannins, and terpenoids. Our results also revealed that the water fraction had the highest antioxidant activity compared to the methanol extract and other fractions. The methanol and the fractionated extracts (hexane, chloroform, ethyl acetate, and water) ofP. macrocarpaseeds were also investigated for their cytotoxic effects on selected human cancer cells lines (MCF-7, HT-29, MDA-MB231, Ca Ski, and SKOV-3) and a normal human fibroblast lung cell line (MRC-5). Information from this study can be applied for future pharmacological and therapeutic evaluations of the species, and may assist in the standardization for quality, purity, and sample identification. To the best of our knowledge, this is the first report on the phytochemical screening and cytotoxic effect of the crude and fractionated extracts ofP. macrocarpaseeds on selected cells lines.

scholarly journals Potential anticancer activity of curcumin analogs containing sulfone on human cancer cells

2016 ◽  
Vol 68 (1) ◽  
pp. 125-133 ◽  
Author(s):  
Qiuyan Zhang ◽  
Dongli Li ◽  
Yue Liu ◽  
Hui Wang ◽  
Changyuan Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Human Cancer ◽  
Three Dimensional ◽  
In Vivo Studies ◽  
Anticancer Activities ◽  
Human Cancer Cells ◽  
Curcumin Analogs ◽  
Phosphorylated Akt ◽  
Transcription 3

Three curcumin analogs(S1-S3) containing sulfone were investigated for their effects on human prostate cancer PC-3, colon cancer HT-29, lung cancer H1299 and pancreatic cancer BxPC-3 cells. The three compounds were approximately 16-to 96-fold more active than curcumin in these cell lines as determined by the MTT assay. The effects of these compounds on cell growth were further studied in prostate cancer PC-3 cells in both two dimensional (2D) and three dimensional (3D) cultures. S1-S3strongly inhibited the growth and induced cell death in PC-3 cells, and the effects of these compounds were associated with suppression of nuclear factor kappa B (NF-?B) transcriptional activity. Moreover, treatment of PC-3 cells with all three compounds caused a decrease in the level of phosphorylated signal transducer and activator of transcription-3 (p-STAT3) (Tyr705),but not p-STAT3(Ser727). Only S1and S2decreased the presence of phosphorylated Akt (p-Akt) in PC-3 cells. These curcumin analogs warrant further in vivo studies for anticancer activities in suitable animal models.

Multicomponent and 1,3-dipolar cycloaddition synthesis of triazole- and isoxazole-acridinedione/xanthenedione heterocyclic hybrids: Cytotoxic effects on human cancer cells

2020 ◽  
Vol 1217 ◽  
pp. 128325 ◽  
Author(s):  
Abdelkader Naouri ◽  
Amar Djemoui ◽  
Mouhamad Ridha Ouahrani ◽  
Mokhtar Boualem Lahrech ◽  
Najet Lemouari ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Dipolar Cycloaddition ◽  
Cytotoxic Effects ◽  
Human Cancer Cells

scholarly journals Human Cancer Cells Express Slug-based Epithelial-Mesenchymal Transition Gene Signature Obtained in Vivo

2011 ◽  
Author(s):  
Jessica Kandel ◽  
Dimitris Anastassiou ◽  
Viktoria Rumjantseva ◽  
Wei-yi Cheng ◽  
Jianzhong Huang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Gene Signature ◽  
Mesenchymal Transition ◽  
Human Cancer Cells

scholarly journals Induction of apoptosis by in vitro and in vivo plant extracts derived from Menyanthes trifoliata L. in human cancer cells

2019 ◽  
Vol 71 (1) ◽  
pp. 165-180 ◽  
Author(s):  
Tomasz Kowalczyk ◽  
Przemysław Sitarek ◽  
Ewa Skała ◽  
Monika Toma ◽  
Marzena Wielanek ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Plant Extracts ◽  
Human Cancer ◽  
Human Cancer Cells ◽  
Induction Of Apoptosis ◽  
Menyanthes Trifoliata

IRF6 and TAK1 coordinately promote the activation of HIPK2 to stimulate apoptosis during palate fusion

2019 ◽  
Vol 12 (593) ◽  
pp. eaav7666 ◽  
Author(s):  
Chen-Yeh Ke ◽  
Hua-Hsuan Mei ◽  
Fen-Hwa Wong ◽  
Lun-Jou Lo
Keyword(s):  
Transcription Factor ◽  
Cell Apoptosis ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Human Cancer ◽  
Ectopic Expression ◽  
Interacting Protein ◽  
Human Cancer Cells

Cleft palate is a common craniofacial defect caused by a failure in palate fusion. The palatal shelves migrate toward one another and meet at the embryonic midline, creating a seam. Transforming growth factor–β3 (TGF-β3)–induced apoptosis of the medial edge epithelium (MEE), the cells located along the seam, is required for completion of palate fusion. The transcription factor interferon regulatory factor 6 (IRF6) promotes TGF-β3–induced MEE cell apoptosis by stimulating the degradation of the transcription factor ΔNp63 and promoting the expression of the gene encoding the cyclin-dependent kinase inhibitor p21. Because homeodomain-interacting protein kinase 2 (HIPK2) functions downstream of IRF6 in human cancer cells and is required for ΔNp63 protein degradation in keratinocytes, we investigated whether HIPK2 played a role in IRF6-induced ΔNp63 degradation in palate fusion. HIPK2 was present in the MEE cells of mouse palatal shelves during seam formation in vivo, and ectopic expression of IRF6 in palatal shelves cultured ex vivo stimulated the expression of Hipk2 and the accumulation of phosphorylated HIPK2. Knockdown and ectopic expression experiments in organ culture demonstrated that p21 was required for HIPK2- and IRF6-dependent activation of caspase 3, MEE apoptosis, and palate fusion. Contact between palatal shelves enhanced the phosphorylation of TGF-β–activated kinase 1 (TAK1), which promoted the phosphorylation of HIPK2 and palate fusion. Our findings demonstrate that HIPK2 promotes seam cell apoptosis and palate fusion downstream of IRF6 and that IRF6 and TAK1 appear to coordinately enhance the abundance and activation of HIPK2 during palate fusion.

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