scholarly journals Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins

2018 ◽  
Vol 4 (11) ◽  
pp. eaav2131 ◽  
Author(s):  
Han-Wen Chang ◽  
Maria E. Valieva ◽  
Alfiya Safina ◽  
Răzvan V. Chereji ◽  
Jianmin Wang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Anticancer Drugs ◽  
Protein Complex ◽  
Tight Binding ◽  
Histone Chaperone ◽  
Chaperone Activity ◽  
Multifunctional Protein ◽  
Transcription In Vitro ◽  
Facilitates Chromatin Transcription

Human FACT (facilitates chromatin transcription) is a multifunctional protein complex that has histone chaperone activity and facilitates nucleosome survival and transcription through chromatin. Anticancer drugs curaxins induce FACT trapping on chromatin of cancer cells (c-trapping), but the mechanism of c-trapping is not fully understood. Here, we show that in cancer cells, FACT is highly enriched within the bodies of actively transcribed genes. Curaxin-dependent c-trapping results in redistribution of FACT from the transcribed chromatin regions to other genomic loci. Using a combination of biochemical and biophysical approaches, we have demonstrated that FACT is bound to and unfolds nucleosomes in the presence of curaxins. This tight binding to the nucleosome results in inhibition of FACT-dependent transcription in vitro in the presence of both curaxins and competitor chromatin, suggesting a mechanism of FACT trapping on bulk nucleosomes (n-trapping).

Cytotoxic Effect of the Combination of Gemcitabine and Atorvastatin Loaded in Microemulsion on the HCT116 Colon Cancer Cells

2017 ◽  
Vol 9 (2) ◽  
Author(s):  
Mayson H. Alkhatib ◽  
Dalal Al-Saedi ◽  
Wadiah S. Backer
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Therapeutic Potential ◽  
Morphological Changes ◽  
In Vitro Study ◽  
Colon Cancer Cells ◽  
Apoptosis Detection ◽  
Hct116 Cells

The combination of anticancer drugs in nanoparticles has great potential as a promising strategy to maximize efficacies by eradicating resistant, reduce the dosage of the drug and minimize toxicities on the normal cells. Gemcitabine (GEM), a nucleoside analogue, and atorvastatin (ATV), a cholesterol lowering agent, have shown anticancer effect with some limitations. The objective of this in vitro study was to evaluate the antitumor activity of the combination therapy of GEM and ATVencapsulated in a microemulsion (ME) formulation in the HCT116 colon cancer cells. The cytotoxicity and efficacy of the formulation were assessed by the 3- (4,5dimethylthiazole-2-yl)-2,5-diphyneltetrazolium bromide (MTT) assay. The mechanism of cell death was examined by observing the morphological changes of treated cells under light microscope, identifying apoptosis by using the ApopNexin apoptosis detection kit, and viewing the morphological changes in the chromatin structure stained with 4′,6-diamidino-2-phenylindole (DAPI) under the inverted fluorescence microscope. It has been found that reducing the concentration of GEM loaded on ME (GEM-ME) from 5μM to 1.67μM by combining it with 3.33μM of ATV in a ME formulation (GEM/2ATV-ME) has preserved the strong cytotoxicity of GEM-ME against HCT116 cells. The current study proved that formulating GEM with ATV in ME has improved the therapeutic potential of GEM and ATV as anticancer drugs.

Anti-proliferative activity of the combination of salan Ti(iv) complexes with other organic and inorganic anticancer drugs against HT-29 and NCI-H1229 cells: synergism with cisplatin

RSC Advances ◽  
2015 ◽  
Vol 5 (11) ◽  
pp. 7874-7879 ◽  
Author(s):  
Nitzan Ganot ◽  
Boris Redko ◽  
Gary Gellerman ◽  
Edit Y. Tshuva
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Proliferative Activity ◽  
Human Colon ◽  
Lung Cancer Cells ◽  
Ht 29

Cytotoxic salan Ti(iv) complex demonstrated synergism with cisplatin in vitro toward human colon and lung cancer cells at various ratios.

scholarly journals The Selective Class IIa Histone Deacetylase Inhibitor TMP195 Resensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

2019 ◽  
Vol 21 (1) ◽  
pp. 238 ◽  
Author(s):  
Chung-Pu Wu ◽  
Sabrina Lusvarghi ◽  
Jyun-Cheng Wang ◽  
Sung-Han Hsiao ◽  
Yang-Hui Huang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Histone Deacetylase ◽  
Anticancer Drugs ◽  
Drug Transport ◽  
Drug Repurposing ◽  
Binding Pocket ◽  
Multidrug Resistant ◽  
Drug Induced ◽  
In Silico Docking

Multidrug resistance caused by the overexpression of the ATP-binding cassette (ABC) proteins in cancer cells remains one of the most difficult challenges faced by drug developers and clinical scientists. The emergence of multidrug-resistant cancers has driven efforts from researchers to develop innovative strategies to improve therapeutic outcomes. Based on the drug repurposing approach, we discovered an additional action of TMP195, a potent and selective inhibitor of class IIa histone deacetylase. We reveal that in vitro TMP195 treatment significantly enhances drug-induced apoptosis and sensitizes multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2 to anticancer drugs. We demonstrate that TMP195 inhibits the drug transport function, but not the protein expression of ABCB1 and ABCG2. The interaction between TMP195 with these transporters was supported by the TMP195-stimulated ATPase activity of ABCB1 and ABCG2, and by in silico docking analysis of TMP195 binding to the substrate-binding pocket of these transporters. Furthermore, we did not find clear evidence of TMP195 resistance conferred by ABCB1 or ABCG2, suggesting that these transporters are unlikely to play a significant role in the development of resistance to TMP195 in cancer patients.

Application of Three-dimensional (3D) Tumor Cell Culture Systems and Mechanism of Drug Resistance

2019 ◽  
Vol 25 (34) ◽  
pp. 3599-3607 ◽  
Author(s):  
Adeeb Shehzad ◽  
Vijaya Ravinayagam ◽  
Hamad AlRumaih ◽  
Meneerah Aljafary ◽  
Dana Almohazey ◽  
...  
Keyword(s):  
Cell Culture ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Three Dimensional ◽  
3D Culture ◽  
3D Cell Culture ◽  
Cancer Therapeutics ◽  
In Vivo Model

: The in-vitro experimental model for the development of cancer therapeutics has always been challenging. Recently, the scientific revolution has improved cell culturing techniques by applying three dimensional (3D) culture system, which provides a similar physiologically relevant in-vivo model for studying various diseases including cancer. In particular, cancer cells exhibiting in-vivo behavior in a model of 3D cell culture is a more accurate cell culture model to test the effectiveness of anticancer drugs or characterization of cancer cells in comparison with two dimensional (2D) monolayer. This study underpins various factors that cause resistance to anticancer drugs in forms of spheroids in 3D in-vitro cell culture and also outlines key challenges and possible solutions for the future development of these systems.

A simple and rapid in vitro test for determining sensitivity of cancer cells to anticancer drugs

1986 ◽  
Vol 16 (5) ◽  
pp. 380-383 ◽  
Author(s):  
Hidehito Ichihashi ◽  
Masaki Nogaki ◽  
Masaji Yamauchi ◽  
Hiroshi Takagi ◽  
Tatsuhei Kondo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Anticancer Drugs ◽  
In Vitro Test ◽  
Vitro Test

scholarly journals VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4675
Author(s):  
Silpa Narayanan ◽  
Ying-Fang Fan ◽  
Nehaben A. Gujarati ◽  
Qiu-Xu Teng ◽  
Jing-Quan Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
B Cell Lymphoma ◽  
Mouse Tumor ◽  
Chemotherapeutic Drugs ◽  
Cancer Knowledge ◽  
Colon Cancers

The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic drugs from cancer cells, thereby producing MDR. Our research efforts have led to the discovery of VKNG-1, a compound that selectively inhibits the ABCG2 transporter and reverses resistanctabe to standard anticancer drugs both in vitro and in vivo. VKNG-1, at 6 µM, selectively inhibited ABCG2 transporter and sensitized ABCG2-overexpressing drug-resistant cancer cells to the ABCG2 substrate anticancer drugs mitoxantrone, SN-38, and doxorubicin in ABCG2-overexpressing colon cancers. VKNG- 1 reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the mRNA and protein levels. Moreover, VKNG-1 inhibits the level of phosphorylated protein kinase B (PKB/p-AKT), and B-cell lymphoma-2 (Bcl-2) protein which may overcome resistance to anticancer drugs. However, the in vitro translocation of ABCG2 protein did not occur in the presence of 6 µM of VKNG-1. In addition, VKNG-1 enhanced the anticancer efficacy of irinotecan in ABCG2- overexpressing mouse tumor xenografts. Overall, our results suggest that VKNG-1 may, in combination with certain anticancer drugs, represent a treatment to overcome ABCG2-mediated MDR colon cancers.

scholarly journals Ameliorative effects of aqueous extract of Forsythiae suspensa fruits on oxaliplatin-induced neurotoxicity in vitro and in vivo

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jin-Mu Yi ◽  
Sarah Shin ◽  
No Soo Kim ◽  
Ok-Sun Bang
Keyword(s):  
Peripheral Neuropathy ◽  
Cancer Cells ◽  
Neurite Outgrowth ◽  
Pc12 Cells ◽  
Anticancer Drugs ◽  
Aqueous Extract ◽  
Neuroprotective Activity ◽  
Neuroprotective Effects

Abstract Background The dried fruits of Forsythia suspensa has generally been used to clear heat and detoxify in traditional Korean and Chinese medicine. Oxaliplatin is a first-line treatment chemotherapeutic agent for advanced colorectal cancer, but it induces peripheral neuropathy as an adverse side effect affecting the treatment regimen and the patient’s quality of life. The present study was conducted to evaluate the neuroprotective effects of an aqueous extract of F. suspensa fruits (EFSF) on oxaliplatin-induced peripheral neuropathy. Methods The chemical components from EFSF were characterized and quantified using the ultra-high performance liquid chromatography-diode array detector system. The cytotoxicities of anticancer drugs in cancer cells and PC12 cells were assessed by the Ez-Cytox viability assay. To measure the in vitro neurotoxicity, the neurite outgrowth was analyzed in the primary dorsal root ganglion (DRG) cells, and neural PC12 cells that were differentiated with nerve growth factor. To evaluate the in vivo neuroprotective activity, the von Frey test was performed in six-week-old male mice (C57BL/6) receiving EFSF (60–600 mg/kg) in the presence of 20–30 mg/kg cumulative doses of oxaliplatin. Thereafter, the mice were euthanized for immunohistochemical staining analysis with an antibody against PGP9.5. Results EFSF attenuated the cytotoxic activities of the various anticancer drugs in neural PC12 cells, but did not affect the anticancer activity of oxaliplatin in human cancer cells. Oxaliplatin remarkably induced neurotoxicities including cytotoxicity and the inhibited neurite outgrowth of DRG and neural PC12 cells. However, the co-treatment of EFSF (100 μg/ml) with oxaliplatin completely reversed the oxaliplatin-induced neurotoxicity. Forsythoside A, the major component of EFSF, also exerted remarkable neuroprotective effects against the oxaliplatin-induced neurotoxicity. In addition, EFSF (60–200 mg/kg) significantly alleviated the oxaliplatin-induced mechanical allodynia and loss of intra-epidermal nerve fiber to the levels of the vehicle control in the mouse peripheral neuropathy model. Conclusions EFSF could be considered a useful herbal medicine for the treatment of peripheral neuropathy in cancer patients receiving chemotherapy with oxaliplatin.

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