scholarly journals Enhancing the Therapeutic Efficacy of Daunorubicin and Mitoxantrone with Bavachinin, Candidone, and Tephrosin

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Sina Darzi ◽  
Seyed Abbas Mirzaei ◽  
Fatemeh Elahian ◽  
Sadegh Shirian ◽  
Amir Peymani ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell Line ◽  
Multidrug Resistant ◽  
Resistant Cell ◽  
Dependent Manner ◽  
Expression Levels ◽  
Treatment Research

The capability of flavonoids in sensitizing cancer cells was demonstrated in numerous works to chemotherapy and converse multidrug resistance by modulating efflux pumps and apoptosis mechanisms. Three flavonoids, namely, bavachinin, tephrosin, and candidone, have been recently introduced to cancer treatment research presenting various activities, such as antibacterial, immunomodulatory, cell death, and anticancer. Less information exists regarding the therapeutic significance of these flavonoids in cancer treatment, especially in overcoming multidrug resistance (MDR). Here, we tempted to investigate the potency of these agents in reversing MDR by analyzing their effects as chemosensitizers on cell cytotoxicity, P-gp and ABCG2 protein expression levels, and their function on two multidrug-resistant cell lines, P-gp-overexpressing human gastric adenocarcinoma cell line (EPG85.257RDB) and ABCG2-overexpressing human epithelial breast cancer cell line (MCF7/MX). The inhibitory concentration of 10% (IC10) of bavachinin, tephrosin, and candidone in EPG85.257RDB cells was 1588.7 ± 202.2, 264.8 ± 86.15, and 1338.6 ± 114.11 nM, respectively. Moreover, these values in MCF7/MX cell were 2406.4 ± 257.63, 38.8 ± 4.28, and 27.9 ± 5.59 nM, respectively. Expression levels of ABCG2 and P-gp were not significantly downregulated by these flavonoids. Maximum levels of daunorubicin and mitoxantrone accumulations and minimum rates of drug efflux in both cell lines were detected 48 hrs posttreatment with tephrosin and bavachinin, respectively. Chemosensitization to mitoxantrone and daunorubicin treatments was, respectively, achieved in MCF7/MX and EPG85.257RDB cells in response to IC10 of bavachinin and tephrosin, independently. These effects did not follow time-dependent manner, and each flavonoid had its cell-dependent patterns. Overall, bavachinin, tephrosin, and candidone showed potency to sensitize MDR cells to daunorubicin and mitoxantrone and could be considered as attractive MDR modulators for cancer treatment. However, their action was time and cell specific.

scholarly journals Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy

2021 ◽  
Vol 22 (10) ◽  
pp. 5098
Author(s):  
David Kreutzer ◽  
Henry Döring ◽  
Peter Werner ◽  
Christoph A. Ritter ◽  
Andreas Hilgeroth
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Cell Line ◽  
Efflux Pump ◽  
Cancer Cell Line ◽  
Multidrug Resistant ◽  
Cage Compounds ◽  
Uptake Assay ◽  
Overexpressing Cell ◽  
The Common

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.

Design, Synthesis and Cytotoxicity Evaluation of New 3, 5-Disubstituted-2-Thioxoimidazolidinones

2018 ◽  
Vol 18 (4) ◽  
pp. 573-582 ◽  
Author(s):  
Khaled R.A. Abdellatif ◽  
Mostafa M. Elbadawi ◽  
Mohammed T. Elsaady ◽  
Amer A. Abd El-Hafeez ◽  
Takashi Fujimura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Topoisomerase I ◽  
Cancer Cell Line ◽  
Cytotoxic Agents ◽  
Dependent Manner ◽  
Human Lung Fibroblast ◽  
Mcf 7

Background: Some 2-thioxoimidazolidinones have been reported as anti-prostate and anti-breast cancer agents through their inhibitory activity on topoisomerase I that is considered as a potential chemotherapeutic target. Objective: A new series of 3,5-disubstituted-2-thioxoimidazolidinone derivatives 10a-f and their S-methyl analogs 11a-f were designed, synthesized and evaluated for cytotoxicity against human prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and non-cancerous human lung fibroblast cell line (WI-38). </P><P> Results and Method: While compounds 10a-f showed a broad range of activities against PC-3 and MCF-7 cell lines (IC50 = 34.0 – 186.9 and 24.6 – 147.5 µM respectively), the S-methyl analogs 11a-f showed (IC50 = 22.7 – 198.5 and 16.9 – 188.2 µM respectively) in comparison with 5-fluorouracil (IC50 = 60.7 and 40.7 µM respectively). 11c (IC50 = 22.7 and 29.2 µM) and 11f (IC50 = 28.7 and 16.9 µM) were the most potent among all compounds against both PC-3 and MCF-7 respectively with no cytotoxicity against WI-38. Conclusion: The newly synthesized compounds showed good activity against PC-3 and MCF-7 cell lines in comparison with 5-fluorouracil. Compounds 11c and 11f bound with human topoisomerase I similar to its known inhibitors and significantly inhibited its DNA relaxation activity in a dose dependent manner which may rationalize their molecular mechanism as cytotoxic agents.

scholarly journals Promising Anticancer Activity of [Bis(1,8-quinolato)palladium (II)] Alone and in Combination

2020 ◽  
Author(s):  
Md. Nur Alam ◽  
Mohammad Moni ◽  
Jun Yu ◽  
Philip Beale ◽  
Peter Turner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Anticancer Activity ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antitumour Activity ◽  
Epigallocatechin Gallate ◽  
Cancer Cell Line ◽  
Resistant Cell ◽  
Colorectal Cancer Cell Line

Abstract Due to similar coordination chemistry of palladium and platinum, a large number of palladium compounds too have been investigated for their anticancer activity. In the present study we describe synthesis, characterization and anticancer activity of palladium complex [Bis(1,8-quinolato)palladium (II)], coded as NH3 against seven different cancer cell lines. NH3 is found to have higher antitumour activity than cisplatin against both parent ovarian A2780 cell line and cisplatin-resistant cell lines. Also, NH3 has the lowest IC50 value against HT-29 colorectal cancer cell line. The higher antitumour activity of NH3 is due to the presence of bulky 8-hydroxy-quinoline ligand thus reducing its reactivity. Proteomic study has identified significantly expressed proteins which have been validated through bioinformatics. NH3 has been found to be less toxic than cisplatin at 2.5 mg/kg and 5 mg/kg dosages on mice models. Binary combinations of NH3 with curcumin and epigallocatechin gallate (EGCG) have demonstrated dose and sequence dependent synergism in ovarian and colorectal cancer models. All of the preclinical studies indicate promising therapeutic potentiality of NH3 [Bis(1,8-quinolato)palladium (II) ] as an anticancer drug.

scholarly journals Targeted Comparative RNA Interference Analysis Reveals Differential Requirement of Genes Essential for Cell Proliferation

2006 ◽  
Vol 17 (11) ◽  
pp. 4837-4845 ◽  
Author(s):  
Yuichi J. Machida ◽  
Yuefeng Chen ◽  
Yuka Machida ◽  
Ankit Malhotra ◽  
Sukumar Sarkar ◽  
...  
Keyword(s):  
Rna Interference ◽  
Cell Line ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Ribosome Biogenesis ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Breast Epithelial Cell ◽  
Epithelial Cell Line ◽  
Dependent Manner

Differences in the genetic and epigenetic make up of cell lines have been very useful for dissecting the roles of specific genes in the biology of a cell. Targeted comparative RNAi (TARCOR) analysis uses high throughput RNA interference (RNAi) against a targeted gene set and rigorous quantitation of the phenotype to identify genes with a differential requirement for proliferation between cell lines of different genetic backgrounds. To demonstrate the utility of such an analysis, we examined 257 growth-regulated genes in parallel in a breast epithelial cell line, MCF10A, and a prostate cancer cell line, PC3. Depletion of an unexpectedly high number of genes (25%) differentially affected proliferation of the two cell lines. Knockdown of many genes that spare PC3 (p53−) but inhibit MCF10A (p53+) proliferation induces p53 in MCF10A cells. EBNA1BP2, involved in ribosome biogenesis, is an example of such a gene, with its depletion arresting MCF10A at G1/S in a p53-dependent manner. TARCOR is thus useful for identifying cell type–specific genes and pathways involved in proliferation and also for exploring the heterogeneity of cell lines. In particular, our data emphasize the importance of considering the genetic status, when performing siRNA screens in mammalian cells.

The Potential Role of STAT's in Anti-Leukemic Therapy with Different Drugs

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5120-5120
Author(s):  
Hatice Demet Kiper ◽  
Burcin Tezcanli Kaymaz ◽  
Ozlem Purclutepe ◽  
Ceyda Tunakan Dalgic ◽  
Nur Selvi ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Drug Exposure ◽  
Conflicts Of Interest ◽  
Time Dependent ◽  
Blue Dye ◽  
Dependent Manner ◽  
Down Regulation ◽  
Expression Levels ◽  
Induced Apoptosis

Abstract Abstract 5120 STAT pathways play a pivotal role in oncogenesis and leukemogenesis, thus targeting STAT signalling appears to be an effective anticancer treatment strategy. It has been described that constitutive activation of STAT3 and STAT5 plays a pro-oncogenic role both in acute and chronic myeloid neoplasms. In this study, we aimed to clarify the potential relationship between drug-induced apoptosis with different agents and STAT pathway. A third-generation bisphosphonate; zoledronate, an angiotensin-converting enzyme inhibitor (ACE-I); enalapril, a proteasome inhibitor which is used for treatment of multiple myeloma; bortezomib and a second-generation tyrosine kinase inhibitor; dasatinib were examined in this goal. Cell viability and cytotoxicity tests were conducted by using Trypan blue dye exclusion and XTT assays, respectively. Apoptotic analyses were performed by AnnexinV-EGFP staining method and fluorescence microscopy. Expression levels of STAT3, −5A and −5B genes were analysed in myeloid cell lines by qRT-PCR. The results showed that zoledronate; bortezomib and dasatinib decreased viability and proliferation and induced apoptosis in CML cell line K562 in a dose- and time-dependent manner which is associated by prominent decrease of STAT3, STAT5A and STAT5B mRNA expressions. Enalapril was also found to be cytotoxic and induced apoptosis in APL cell line HL60 in a dose- and time-dependent manner and the expression levels of STAT5A gene have significantly reduced in enalapril-treated HL60 cells as compared to untreated controls. Treatments of cell lines with other drugs were also associated with significant apoptosis in certain time points. The results and changes in expression of STAT's in mRNA level at 72nd hours are summarized in table. Taken together all these data showed that targeting STAT pathways by different drugs may be an appropriate approach in anti-leukemic therapy. This finding is important to propose that discovery or identification of novel agents targeted STATs may open new windows to the other hematological and solid malignancies which are associated with aberrant STAT expression. Table: The changes in STAT expressions after drug exposure in time-dependent manner with the dose of IC50. DRUGS CELL LINE IC50 APOPTOSIS (%) STAT3 mRNA Down Regulation (%) STAT5A mRNA Down Regulation (%) STAT5B mRNA Down Regulation (%) ENALAPRIL HL-60 7 μM 20 20* 76 5* ZOLEDRONATE K562 60 μM 34 63 31 57 BORTEZOMIB K562 177 μM 37 98 100 99 DASATINIB K562 3,314 nM 75 NA 33 78 * : Not significant NA: not applied Disclosures: No relevant conflicts of interest to declare.

Amplification and expression of a multidrug resistance gene in human glioma cell lines

1990 ◽  
Vol 72 (1) ◽  
pp. 96-101 ◽  
Author(s):  
Tsuyoshi Matsumoto ◽  
Eiichi Tani ◽  
Keizo Kaba ◽  
Nobuo Kochi ◽  
Hideki Shindo ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cell Line ◽  
Cell Lines ◽  
Glioma Cell ◽  
Multidrug Resistant ◽  
Glioma Cell Line ◽  
Cross Resistance ◽  
Human Glioma ◽  
Human Glioma Cell ◽  
Glioma Cell Lines

✓ Two human glioma cell lines were examined for multidrug resistance (MDR). A vincristine (VCR)-resistant glioma cell line showed a cross resistance to Adriamycin (doxorubicin, ADR) and etoposide (VP-16) to varying extents, suggesting the presence of MDR; the resistance to VCR was considerably decreased by calcium entry blockers. On the other hand, another VCR-sensitive glioma cell line exhibited no cross resistance to ADR or VP-16. Double minute chromosomes and homogeneously staining regions as well as clonal aberrations of chromosome 7 were not observed in cytogenetic studies of multidrug-resistant and multidrug-sensitive glioma cell lines. In Northern and Southern blot analyses, MDR gene 1 (MDR1) messenger ribonucleic acid (mRNA) was shown to be overexpressed without any amplification of the MDR1 gene in multidrug-resistant glioma cell lines as compared to multidrug-sensitive glioma cell lines. It would be reasonable to suggest that amplification of the MDR1 gene may not be a sine qua non for acquisition of MDR and that the MDR1 mRNA level may be well correlated with the extent of MDR.

scholarly journals Effect of tamoxifen on cell lines displaying the multidrug-resistant phenotype [see comments]

Blood ◽  
1991 ◽  
Vol 77 (4) ◽  
pp. 818-825 ◽  
Author(s):  
E Berman ◽  
M Adams ◽  
R Duigou-Osterndorf ◽  
L Godfrey ◽  
B Clarkson ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Leukemia Cell ◽  
Multidrug Resistant ◽  
Leukemia Cell Line ◽  
Parent Cell ◽  
Continuous Exposure ◽  
Dependent Manner ◽  
Uptake Pattern ◽  
Dose Dependent

Abstract We examined the effect of tamoxifen (Tmx), verapamil, and daunorubicin (DNR) in two cell lines that displayed the multidrug-resistant (MDR) phenotype and used laser flow cytometry to quantitate intracellular DNR content. In the vinblastine-resistant human lymphoblastic lymphoma cell line CEM-VBL, simultaneous incubation of DNR with Tmx 10 mumol/L or Tmx 50 mumol/L increased intracellular DNR fluorescence in a dose-dependent manner and demonstrated an uptake pattern similar to that seen with DNR and verapamil. Similar results were obtained in the vincristine- resistant human myeloid leukemia cell line HL-60/RV+. Cellular retention of DNR was also measured in both cell lines and results suggested that continuous exposure of the cells to Tmx resulted in higher intracellular DNR content compared with cells resuspended in fresh medium. No effect of Tmx or verapamil was observed in the drug- sensitive parent cell lines CEM or HL-60. Clonogenic experiments were then performed to determine whether Tmx was itself inhibitory to cell growth or whether Tmx potentiated DNR cytotoxicity. Tmx 10 mumol/L did not significantly inhibit either CEM-VBL or HL-60/RV+ cells after a 3- hour exposure followed by culture in methylcellulose. Tmx 50 mumol/L was significantly more inhibitory in both cell lines. However, cells that had been incubated with DNR and Tmx 10 mumol/L demonstrated a marked increment in growth inhibition compared with cells that had been incubated with DNR alone or Tmx 10 mumol/L alone. Based on the data presented here, we suggest that clinical testing of Tmx and DNR be pursued in the setting where MDR may play a role.

Imatinib Is a Substrate for Various Multidrug Resistance Proteins

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4249-4249
Author(s):  
Krzysztof Czyzewski ◽  
Jan Styczynski
Keyword(s):  
Multidrug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Cell Line ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Resistant Cell ◽  
Multidrug Resistance Proteins ◽  
Resistance Proteins ◽  
Imatinib Resistant ◽  
Ic50 Value

Abstract An increasing resistance to imatinib is an emerging problem in patients with chronic myeloid leukemia. The aim of the study was assessing possible mechanisms of cellular drug resistance in imatinib-resistant derivates of chronic myeloid leukemia K-562 cell line. A parental K-562 and its imatinib-resistant derivate cell lines were used. Cell lines were tested for cytotoxicity of imatinib, cytarabine, busulfan and etoposide. Multidrug resistance proteins expression, rhodamine retention and daunorubicin accumulation were measured for each cell line. Imatinib was cytotoxic to all tested groups of cells. Exposition of K-562 cell line to low concentrations of imatinib caused an increase of IC50 value of imatinib, while exposition of K-562 cell line to higher concentrations of imatinib decreased IC50 value of imatinib. There was a high correlation between PGP, MRP1 and LRP expression and IC50 for imatinib and etoposide. All tested cell lines were highly resistant to cytarabine. Rhodamine retention alone and in the presence of cyclosporine was the lowest in imatinib-resistant K-562R-0.1 cell line, what suggest high PGP activity in this cell line. Daunorubicin accumulation was the highest in parental K-562 cell line and it decreased in imatinib-resistant cell lines, which were characterized by high PGP, MRP1 and LRP expression. These data suggest that imatinib is a substrate for multidrug resistance proteins, and an increased expression of PGP, MRP1 and LRP play a role in resistance to imatinib in chronic myeloid leukemia.

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