Multienzyme-mediated stable and transient multidrug resistance and collateral sensitivity induced by xenobiotics

1997 ◽  
Vol 40 (3) ◽  
pp. 215-224 ◽  
Author(s):  
Ganaganur K. Rekha ◽  
N. E. Sladek
Keyword(s):  
Multidrug Resistance ◽  
Collateral Sensitivity

scholarly journals Selective Cytotoxicity of Piperine over Multidrug Resistance Leukemic Cells

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 934
Author(s):  
Julia Quarti ◽  
Daianne N. M. Torres ◽  
Erika Ferreira ◽  
Raphael S. Vidal ◽  
Fabiana Casanova ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Black Pepper ◽  
Leukemic Cells ◽  
Glycoprotein P ◽  
Cytotoxic Effects ◽  
Collateral Sensitivity ◽  
Main Challenge ◽  
Independent Mechanism ◽  
High Level ◽  
Parp 1

Multidrug resistance (MDR) is the main challenge in the treatment of chronic myeloid leukemia (CML), and P-glycoprotein (P-gp) overexpression is an important mechanism involved in this resistance process. However, some compounds can selectively affect MDR cells, inducing collateral sensitivity (CS), which may be dependent on P-gp. The aim of this study was to investigate the effect of piperine, a phytochemical from black pepper, on CS induction in CML MDR cells, and the mechanisms involved. The results indicate that piperine induced CS, being more cytotoxic to K562-derived MDR cells (Lucena-1 and FEPS) than to K562, the parental CML cell. CS was confirmed by analysis of cell metabolic activity and viability, cell morphology and apoptosis. P-gp was partially required for CS induction. To investigate a P-gp independent mechanism, we analyzed the possibility that poly (ADP-ribose) polymerase-1 (PARP-1) could be involved in piperine cytotoxic effects. It was previously shown that only MDR FEPS cells present a high level of 24 kDa fragment of PARP-1, which could protect these cells against cell death. In the present study, piperine was able to decrease the 24 kDa fragment of PARP-1 in MDR FEPS cells. We conclude that piperine targets selectively MDR cells, inducing CS, through a mechanism that might be dependent or not on P-gp.

scholarly journals Collateral sensitivity as a strategy against cancer multidrug resistance

2012 ◽  
Vol 15 (1-2) ◽  
pp. 98-105 ◽  
Author(s):  
Kristen M. Pluchino ◽  
Matthew D. Hall ◽  
Andrew S. Goldsborough ◽  
Richard Callaghan ◽  
Michael M. Gottesman
Keyword(s):  
Multidrug Resistance ◽  
Collateral Sensitivity

scholarly journals Exploring the Monoterpene Indole Alkaloid Scaffold for Reversing P-Glycoprotein-Mediated Multidrug Resistance in Cancer

2021 ◽  
Vol 14 (9) ◽  
pp. 862
Author(s):  
David S. P. Cardoso ◽  
Nikoletta Szemerédi ◽  
Gabriella Spengler ◽  
Silva Mulhovo ◽  
Daniel J. V. A. dos Santos ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cell Model ◽  
Indole Alkaloid ◽  
2D Nmr ◽  
Qsar Model ◽  
Collateral Sensitivity ◽  
P Glycoprotein ◽  
In Silico Studies ◽  
T Lymphoma ◽  
Drug Receptor

Dregamine (1), a major monoterpene indole alkaloid isolated from Tabernaemontana elegans, was submitted to chemical transformation of the ketone function, yielding 19 azines (3–21) and 11 semicarbazones (22–32) bearing aliphatic or aromatic substituents. Their structures were assigned mainly by 1D and 2D NMR (COSY, HMQC, and HMBC) experiments. Compounds 3–32 were evaluated as multidrug resistance (MDR) reversers through functional and chemosensitivity assays in a human ABCB1-transfected mouse T-lymphoma cell model, overexpressing P-glycoprotein. A significant increase of P-gp inhibitory activity was observed for most derivatives, mainly those containing azine moieties with aromatic substituents. Compounds with trimethoxyphenyl (17) or naphthyl motifs (18, 19) were among the most active, exhibiting strong inhibition at 0.2 µM. Moreover, most of the derivatives showed selective antiproliferative effects toward resistant cells, having a collateral sensitivity effect. In drug combination assays, all compounds showed to interact synergistically with doxorubicin. Selected compounds (12, 17, 18, 20, and 29) were evaluated in the ATPase activity assay, in which all compounds but 12 behaved as inhibitors. To gather further insights on drug–receptor interactions, in silico studies were also addressed. A QSAR model allowed us to deduce that compounds bearing bulky and lipophilic substituents were stronger P-gp inhibitors.

Anticancer natural products with collateral sensitivity: a review

2021 ◽  
Vol 21 ◽  
Author(s):  
Jiajun Qian ◽  
Jiahua Cui ◽  
Shaoshun Li ◽  
Jun Chen ◽  
Jinping Jia
Keyword(s):  
Natural Products ◽  
Multidrug Resistance ◽  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Structural Features ◽  
Parental Cell ◽  
Drug Resistant ◽  
Drug Candidates ◽  
Collateral Sensitivity ◽  
Working Mechanisms

Background: Multidrug resistance (MDR) is the resistance of cancer cells against a variety of currently used antineoplastic agents with diverse structural scaffolds and different anticancer mechanisms. It has been recognized as one of the major impediments to successful treatment of cancer, leading to the metastasis and relapse of the malignant diseases. Introduction: Collateral sensitivity (CS) is the characteristics of certain chemicals to kill the drug-resistant sublines selectively over the parental cell lines from which the resistant cells were generated. The research and development of new drug candidates with collateral sensitivity will be an efficient approach to conquer multidrug resistance in cancer. We aims to provide an update in the discovery of natural products with collateral sensitivity. Results and conclusion: The review focused on the characterized anticancer natural products and their derivatives with collateral sensitivity, their working mechanisms and related structural activity relationships, with the emphasis on recently identified CS compounds. According to their structural features, these MDR-targeting compounds were mainly classified into the following categories: flavonoids, terpenoids, stilbenes, alkaloids and quinones. The exploration of molecular mechanisms of collateral sensitivity and structural features of anticancer agents with collateral sensitivity provided an effective approach for the clinic treatment of MDR in cancer.

scholarly journals Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review

Pathogens ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 522
Author(s):  
András Fodor ◽  
Birhan Addisie Abate ◽  
Péter Deák ◽  
László Fodor ◽  
Ervin Gyenge ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Antimicrobial Peptides ◽  
Resistance Genes ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Mobility Patterns ◽  
Collateral Sensitivity ◽  
Resistance Evolution ◽  
Antimicrobial Peptide Resistance

Antibiotic poly-resistance (multidrug-, extreme-, and pan-drug resistance) is controlled by adaptive evolution. Darwinian and Lamarckian interpretations of resistance evolution are discussed. Arguments for, and against, pessimistic forecasts on a fatal “post-antibiotic era” are evaluated. In commensal niches, the appearance of a new antibiotic resistance often reduces fitness, but compensatory mutations may counteract this tendency. The appearance of new antibiotic resistance is frequently accompanied by a collateral sensitivity to other resistances. Organisms with an expanding open pan-genome, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, can withstand an increased number of resistances by exploiting their evolutionary plasticity and disseminating clonally or poly-clonally. Multidrug-resistant pathogen clones can become predominant under antibiotic stress conditions but, under the influence of negative frequency-dependent selection, are prevented from rising to dominance in a population in a commensal niche. Antimicrobial peptides have a great potential to combat multidrug resistance, since antibiotic-resistant bacteria have shown a high frequency of collateral sensitivity to antimicrobial peptides. In addition, the mobility patterns of antibiotic resistance, and antimicrobial peptide resistance, genes are completely different. The integron trade in commensal niches is fortunately limited by the species-specificity of resistance genes. Hence, we theorize that the suggested post-antibiotic era has not yet come, and indeed might never come.

scholarly journals Corrigendum to: Limited evolutionary conservation of multidrug resistance and collateral sensitivity

2021 ◽  
Author(s):  
Gábor Apjok ◽  
Gábor Boross ◽  
Ákos Nyerges ◽  
Gergely Fekete ◽  
Viktória Lázár ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Evolutionary Conservation ◽  
Collateral Sensitivity

scholarly journals Multiple drug resistance in Candida albicans.

1995 ◽  
Vol 42 (4) ◽  
pp. 497-504 ◽  
Author(s):  
R Prasad ◽  
S K Murthy ◽  
V Gupta ◽  
R Prasad
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
Pleiotropic Drug Resistance ◽  
Multidrug Resistance Gene ◽  
Hydrophobic Region ◽  
Membrane Pump ◽  
Collateral Sensitivity ◽  
Sensitivity Pattern

By functional complementation of a PDR 5 (pleiotropic drug resistance) null mutant of S. cerevisiae, we have recently cloned and sequenced a multidrug resistance gene CDR 1 (Candida Drug Resistance). Transformation by CDR 1 of a PDR 5 disrupted host hypersensitive to cycloheximide and chloramphenicol resulted in resistance to these as well as other unrelated drugs. The nucleotide sequence of CDR 1 revealed that, like PDR 5, it encodes a putative membrane pump belonging to the ABC superfamily. CDR 1 encodes a protein of 169.9 kDa whose predicted structural organisation is characterised by two homologous halves, each comprising a hydrophobic region, with a set of six transmembrane stretches, preceded by a hydrophilic binding fold. We now have evidence to suggest that there are several PDR homologues present in C. albicans which display multidrug resistance and a collateral sensitivity pattern different from PDR 5 and CDR 1. The functions of such genes and their products in the overall physiology of C. albicans is not yet established.

scholarly journals Triterpenoids from Momordica balsamina with a Collateral Sensitivity Effect for Tackling Multidrug Resistance in Cancer Cells

Planta Medica ◽  
2018 ◽  
Vol 84 (18) ◽  
pp. 1372-1379 ◽  
Author(s):  
Cátia Ramalhete ◽  
Silva Mulhovo ◽  
Hermann Lage ◽  
Maria-José Ferreira
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Human Cancer ◽  
Multidrug Resistant ◽  
Antiproliferative Effects ◽  
Collateral Sensitivity ◽  
Pancreatic Cells ◽  
Colon Cancer Cell Lines ◽  
Ht 29

AbstractThe collateral sensitivity effect is among the most promising strategies for overcoming multidrug resistance in cancer. In this work, 28 cucurbitane-type triterpenoids (1–28), previously isolated from the African medicinal plant Momordica balsamina and its derivatives, were evaluated for their collateral sensitivity effect on three different human cancer entities, gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29), each with two different multidrug-resistant variants. One was selected for its resistance to daunorubicin (EPG85-257RDB, EPP85-181RDB, HT-29RDB) and the other was selected for its resistance to mitoxantrone (EPG85-257RNOV, EPP85-181RNOV, HT-29RNOV). On gastric cell lines, the best results were obtained for compounds 3 and 10, which exhibited a collateral sensitivity effect together with high antiproliferative activity. In turn, on colon cancer cell lines, the best multidrug resistance-selective antiproliferative effects were observed for derivatives 11, 13, and 15, which showed collateral sensitivity effects against both resistant variants. Compounds 11 and 3 were also the most selective against the multidrug resistance pancreatic cells lines. Some compounds, such 6, 10, 11 and 15, were previously found to be strong P-glycoprotein modulators, thus highlighting their potential as promising leads for overcoming multidrug resistance in cancer cells.

Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic

2005 ◽  
Vol 15 (Suppl 1) ◽  
pp. 12-17 ◽  
Author(s):  
M. A. Bookman
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Intracellular Transport ◽  
Recurrent Ovarian Cancer ◽  
Platinum Resistance ◽  
Synthetic Analog ◽  
Nucleoside Transporter ◽  
Collateral Sensitivity ◽  
Resistant Disease ◽  
Interstrand Cross Links

Gemcitabine (2′2′-difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2′ position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane-associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross-links, thereby leading to a G1 block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800–1250 mg/m2. dFdC is generally well tolerated, with the most frequently occurring dose-limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum-resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14–22% and a median duration of response of 4.0–10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated.

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