scholarly journals 5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1839
Author(s):  
Omolbanin Shahraki ◽  
Mehdi Khoshneviszadeh ◽  
Mojtaba Dehghani ◽  
Maryam Mohabbati ◽  
Marjan Tavakkoli ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Therapeutic Potential ◽  
Uterine Sarcoma ◽  
Glycoprotein P ◽  
Hek 293 ◽  
Reversal Agents ◽  
Flow Cytometric Method ◽  
Flow Cytometric ◽  
Induced Apoptosis ◽  
Cancerous Cells

Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason of chemotherapy failure in many patients and is often related to overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of modulation of the activity of these transporters might be effective in overcoming MDR. In this study, a new set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole moiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of these 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human uterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the most potent compounds in induction of apoptosis and alterations of cell cycle was examined in these cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was evaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental non-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds A1 and A2 with 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties, respectively, and their tetrahydroquinoline counterparts B1 and B2 significantly blocked P-gp efflux, induced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However, only A2 and B2 compounds were relatively selective against cancer and MDR cells as compared to non-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline and 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in drug resistant cancers.

Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 988-994 ◽  
Author(s):  
Michael L. Linenberger ◽  
Tom Hong ◽  
David Flowers ◽  
Eric L. Sievers ◽  
Ted A. Gooley ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Annexin V ◽  
Poor Response ◽  
Surface Expression ◽  
Gemtuzumab Ozogamicin ◽  
Drug Induced ◽  
Reversal Agents ◽  
Clinical Resistance ◽  
Induced Apoptosis

Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of P-glycoprotein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is effective monotherapy for CD33+ relapsed AML. However, the contribution of Pgp to gemtuzumab ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72% or 52%, respectively, exhibited CSA-sensitive dye efflux compared with 29% (P = .003) or 24% (P < .001) among samples from responders. In vitro gemtuzumab ozogamicin–induced apoptosis was also evaluated using an annexin V–based assay. Low levels of drug-induced apoptosis were associated with CSA-sensitive dye efflux, whereas higher levels correlated strongly with achievement of remission and marrow blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA. Together, these findings indicate that Pgp plays a role in clinical resistance to gemtuzumab ozogamicin and suggest that treatment trials combining gemtuzumab ozogamicin with MDR reversal agents are warranted.

Design, synthesis and biological evaluation of novel triazole-core reversal agents against P-glycoprotein-mediated multidrug resistance

RSC Advances ◽  
2016 ◽  
Vol 6 (31) ◽  
pp. 25819-25828 ◽  
Author(s):  
Bo Zhang ◽  
Tianxiao Zhao ◽  
Jie Zhou ◽  
Qianqian Qiu ◽  
Yuxuan Dai ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Click Chemistry ◽  
Biological Evaluation ◽  
Glycoprotein P ◽  
Design Synthesis ◽  
Reversal Agents ◽  
P Glycoprotein ◽  
Synthesis And Biological Evaluation

We designed and synthesized a novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors bearing a triazolphenethyl–tetrahydroisoquinoline scaffold through click chemistry.

Therapeutic Potential of Endophytic Compounds: A Special Reference to Drug Transporter Inhibitors

2019 ◽  
Vol 19 (10) ◽  
pp. 754-783 ◽  
Author(s):  
Khusbu Singh ◽  
Gaurav Raj Dwivedi ◽  
A. Swaroop Sanket ◽  
Sanghamitra Pati
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Therapeutic Potential ◽  
Drug Transporters ◽  
Chemotherapeutic Agents ◽  
Chemical Diversity ◽  
Drug Transporter ◽  
Reversal Agents ◽  
Resistance Reversal ◽  
Novel Drug

From the discovery to the golden age of antibiotics (miracle), millions of lives have been saved. The era of negligence towards chemotherapeutic agents gave birth to drug resistance. Among all the regulators of drug resistance, drug transporters are considered to be the key regulators for multidrug resistance. These transporters are prevalent from prokaryotes to eukaryotes. Endophytes are one of the unexplored wealths of nature. Endophytes are a model mutualistic partner of plants. They are the reservoir of novel therapeutics. The present review deals with endophytes as novel drug resistance reversal agents by inhibiting the drug transporters across the genera. This review also focuses on drug transporters, and mutualistic chemical diversity, exploring drug transporter modulating potential of endophytes.

scholarly journals Assessment of the Potential of CDK2 Inhibitor NU6140 to Influence the Expression of Pluripotency Markers NANOG, OCT4, and SOX2 in 2102Ep and H9 Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Ade Kallas ◽  
Martin Pook ◽  
Annika Trei ◽  
Toivo Maimets
Keyword(s):  
Cell Cycle Progression ◽  
Single Cells ◽  
Embryonic Stem ◽  
Embryoid Bodies ◽  
Flow Cytometric Method ◽  
Histone 3 ◽  
Flow Cytometric ◽  
M Phase ◽  
Induced Apoptosis ◽  
Hes Cells

As cyclin-dependent kinases (CDKs) regulate cell cycle progression and RNA transcription, CDKs are attractive targets for creating cancer cell treatments. In this study we investigated the effects of the small molecular agent NU6140 (inhibits CDK2 and cyclin A interaction) on human embryonic stem (hES) cells and embryonal carcinoma-derived (hEC) cells via the expression of transcription factors responsible for pluripotency. A multiparameter flow cytometric method was used to follow changes in the expression of NANOG, OCT4, and SOX2 together in single cells. Both hES and hEC cells responded to NU6140 treatment by induced apoptosis and a decreased expression of NANOG, OCT4, and SOX2 in surviving cells. A higher sensitivity to NU6140 application in hES than hEC cells was detected. NU6140 treatment arrested hES and hEC cells in the G2 phase and inhibited entry into the M phase as evidenced by no significant increase in histone 3 phosphorylation. When embryoid bodies (EBs) formed from NU6104 treated hES cells were compared to EBs from untreated hES cells differences in ectodermal, endodermal, and mesodermal lineages were found. The results of this study highlight the importance of CDK2 activity in maintaining pluripotency of hES and hEC cells and in differentiation of hES cells.

scholarly journals Inhibitors of N-glycosylation as a potential tool for analysis of the mechanism of action and cellular localisation of glycoprotein P.

2012 ◽  
Vol 59 (4) ◽  
Author(s):  
Karolina Wojtowicz ◽  
Witold Szaflarski ◽  
Radosław Januchowski ◽  
Piotr Zawierucha ◽  
Michał Nowicki ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Membrane Protein ◽  
Mechanism Of Action ◽  
Therapeutic Potential ◽  
Basic Knowledge ◽  
Glycoprotein P ◽  
Intracellular Location ◽  
Cellular Localisation ◽  
Modified Proteins ◽  
Potential Tool

Multidrug resistance has for many years attracted attention of numerous investigators. Attempts have also been made to increase efficiency of anti-neoplastic therapy. For this reason, most of efforts have been devoted to analysing proteins engaged in the mechanism of multidrug resistance such as the N-glycosylated membrane protein glycoprotein P. Interestingly, glycosylation probably plays a significant role in the intracellular location and activity of modified proteins. Inhibitors of glycosylation have been demonstrated to alter the activity of glycoprotein P in various ways, depending on the cell line examined. These inhibitors markedly reduce multidrug resistance of cancer cells, thus promoting success of anti-neoplastic therapy. Here, we review the basic knowledge on N-glycosylation inhibitors, their effect on glycoprotein P and their therapeutic potential.

scholarly journals Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 458
Author(s):  
Sabesan Yoganathan ◽  
Anushan Alagaratnam ◽  
Nikita Acharekar ◽  
Jing Kong
Keyword(s):  
Multidrug Resistance ◽  
Small Molecules ◽  
Anticancer Drugs ◽  
Abc Transporters ◽  
Ellagic Acid ◽  
Therapeutic Potential ◽  
Anticancer Activities ◽  
Glycoprotein P ◽  
Major Mechanism ◽  
Anticancer Properties

Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. The primary function of ABC transporters is to regulate the transport of endogenous and exogenous small molecules across the membrane barrier in various tissues. P-gp and similar efflux pumps are associated with MDR because of their overexpression in many cancer types. One of the intensively studied approaches to overcome this mode of MDR involves development of small molecules to modulate P-gp activity. This strategy improves the sensitivity of cancer cells to anticancer drugs that are otherwise ineffective. Although multiple generations of P-gp inhibitors have been identified to date, reported compounds have demonstrated low clinical efficacy and adverse effects. More recently, natural polyphenols have emerged as a promising class of compounds to address P-gp linked MDR. This review highlights the chemical structure and anticancer activities of selected members of a structurally unique class of ‘biaryl’ polyphenols. The discussion focuses on the anticancer properties of ellagic acid, ellagic acid derivatives, and schisandrins. Research reports regarding their inherent anticancer activities and their ability to sensitize MDR cell lines towards conventional anticancer drugs are highlighted here. Additionally, a brief discussion about the axial chirality (i.e., atropisomerism) that may be introduced into these natural products for medicinal chemistry studies is also provided.

Design, Synthesis and Biological Evaluation of Dimethyl Cardamonin (DMC) Derivatives as P-glycoprotein-mediated Multidrug Resistance Reversal Agents

2020 ◽  
Vol 17 (10) ◽  
pp. 1270-1282
Author(s):  
Ximeng Shi ◽  
Yuyu Zhao ◽  
Licheng Zhou ◽  
Huanhuan Yin ◽  
Jianwen Liu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Biological Evaluation ◽  
Glycoprotein P ◽  
Design Synthesis ◽  
Reversal Agents ◽  
Protein Levels ◽  
P Glycoprotein ◽  
Resistance Reversal ◽  
Mcf 7

Background: P-glycoprotein (P-gp) has been regarded as an important factor in the multidrug resistance (MDR) of tumor cells within the last decade, which can be solved by inhibiting Pgp to reverse MDR. Thus, it is an effective strategy to develop inhibitor of P-gp. Objective: In this study, the synthesis of a series of derivatives had been carried out by bioisosterism design on the basis of Dimethyl Cardamonin (DMC). Subsequently, we evaluated their reversal activities as potential P-glycoprotein (P-gp)-mediated Multidrug Resistance (MDR) agents. Methods: Dimethyl cardamonin derivatives were synthesized from acetophenones and the corresponding benzaldehydes in the presence of 40% KOH by Claisen-Schmidt reaction. Their cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 was evaluated by Doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply. Results and Conclusion: The results showed that compounds B2, B4 and B6 had the potency of MDR reversers with little intrinsic cytotoxicity. Meanwhile, these compounds also demonstrated the capability to inhibit MCF-7 and MCF-7/DOX cells migration. Besides, the most compound B4 was selected for further study, which promoted the accumulation of DOX in MCF-7/DOX cells and inhibited the expressionof P-gp at protein levels. Conclusion: The above findings may provide new insights for the research and development of Pgp- mediated MDR reversal agents.

Induction of Apoptosis by Nano‐Synthesized Complexes of H2L and its Cu(II) Complex in Human Hepatocellular Carcinoma Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Thoria Diab ◽  
Tarek M. Mohamed ◽  
Alaa Hamed ◽  
Mohamed Gaber
Keyword(s):  
Cell Cycle ◽  
Metal Complexes ◽  
Hepg2 Cells ◽  
Therapeutic Potential ◽  
Free Ligand ◽  
Organometallic Complexes ◽  
Phase Cell ◽  
Sod Activity ◽  
Induced Apoptosis

Background: Chemotherapy is currently the most utilized treatment for cancer. Therapeutic potential of metal complexes in cancer therapy has attracted a lot of interest. The mechanisms of action of most organometallic complexes are poorly understood. Objective: This study was designed to explore the mechanisms governing the anti-proliferative effect of the free ligand N1,N6‐bis((2‐hydroxynaphthalin‐1‐yl)methinyl)) adipohydrazone (H2L) and its complexes of Mn(II), Co(II), Ni(II) and Cu(II). Methods: Cells were exposed to H2L or its metal complexes where cell viability determined by MTT assay. Cell cycle was analysed by flow cytometry. In addition, qRT-PCR was used to monitor the expression of Bax and Bcl-2. Moreover, molecular docking was carried out to find the potentiality of Cu(II) complex as an inhibitor of Adenosine Deaminase (ADA). ADA, Superoxide Dismutase (SOD) and reduced Glutathione (GSH) levels were measured in the most affected cancer cell line. Results: The obtained results demonstrated that H2L and its Cu(II) complex exhibited a strong cytotoxic activity compared to other complexes against HepG2 cells (IC50 = 4.14±0.036μM/ml and 3.2±0.02μM/ml), respectively. Both H2L and its Cu(II) complex induced G2/M phase cell cycle arrest in HepG2 cells. Additionally, they induced apoptosis in HepG2 cells via upregulation of Bax and downregulation of Bcl-2. Interestingly, the activity of ADA was decreased by 2.8 fold in HepG2 cells treated with Cu(II) complex compared to untreated cells. An increase of SOD activity and GSH level in HepG2 cells compared to control was observed. Conclusion: The results concluded that Cu(II) complex of H2L induced apoptosis in HepG2 cells. Further studies are needed to confirm its anti-cancer effect in vivo.

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