scholarly journals Organoselenium Compounds as Novel Adjuvants of Chemotherapy Drugs—A Promising Approach to Fight Cancer Drug Resistance

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 336 ◽  
Author(s):  
Gabriella Spengler ◽  
Márió Gajdács ◽  
Małgorzata Marć ◽  
Enrique Domínguez-Álvarez ◽  
Carmen Sanmartín
Keyword(s):  
Drug Interactions ◽  
Efflux Pump ◽  
Alkylating Agents ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Cancer Drug ◽  
Organoselenium Compounds ◽  
Public Health Burden ◽  
Chemotherapy Drugs

Malignant diseases present a serious public health burden and their treatment with traditional chemotherapy cannot be considered an all-round solution, due to toxic side effects. Selenium compounds (Se-compounds) have received substantial attention in medicinal chemistry, especially in experimental chemotherapy, both as cytotoxic agents and adjuvants in chemotherapy. A checkerboard microplate method was applied to study the drug interactions of Se-compounds and clinically relevant chemotherapeutic drugs against the multidrug-resistant (MDR) subtype of mouse t-lymphoma cells overexpressing the ABCB1 transporter. Se-compounds showed synergistic interactions with chemotherapeutic agents targeting the topoisomerase enzymes or the microtubule apparatus. The ketone-containing selenoesters showed synergism at lower concentrations (1.25 µM). Most of the tested compounds interacted antagonistically with alkylating agents and verapamil. A thiophene-containing Se-compound showed synergism with all tested drugs, except cisplatin. While the exact mechanism of drug interactions is yet unknown, the potency of the selenocompounds as efflux pump inhibitors or the potentiation of their efficacy as reactive oxygen species modulators may play a role in their complementary activity against the tested MDR lymphoma cell line.

Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1528-1536 ◽  
Author(s):  
RJ Arceci ◽  
K Stieglitz ◽  
BE Bierer
Keyword(s):  
Efflux Pump ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Drug ◽  
Cytotoxic Agents ◽  
Cross Resistance ◽  
Clinical Role ◽  
Reversal Agents ◽  
P Glycoprotein ◽  
Mdr Reversal

Abstract The multidrug-resistant (MDR) phenotype is characterized in vitro by the resistance displayed by cell lines to a broad spectrum of natural product cytotoxic agents. This high level of cross-resistance is due to the increased expression of a membrane glycoprotein termed P- glycoprotein. Encoded in humans by the mdr1 gene, P-glycoprotein functions as an energy-dependent efflux pump of these cytotoxic agents. In this report, we demonstrate that the newly characterized immunosuppressant FK506 and its structural analogue, rapamycin, are capable of functioning as MDR reversal agents. FK506 and rapamycin increase both intracellular, cytotoxic drug (daunomycin) accumulation, and the cytotoxicity of chemotherapeutic agents in multidrug-resistant cells. The increase in cytotoxic drug accumulation is observed at concentrations of FK506 and rapamycin 1,000-fold greater than the concentrations required for FK506 and rapamycin to inhibit T-lymphocyte activation and similar to those shown to be effective for other MDR reversal agents such as cyclosporine A (CsA) and verapamil. The effect of FK506 or rapamycin on both intracellular accumulation and cytotoxicity of daunomycin is additive. This is supported by the ability of FK506 and rapamycin to directly compete the binding of the photoaffinity analogue 125I-iodoaryl azidoprazosin to the P- glycoprotein. The data demonstrate that FK506 and rapamycin represent a new class of structurally distinct molecules that can function as MDR reversal agents and suggest a previously unidentified, potential clinical role for these compounds.

scholarly journals Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1528-1536
Author(s):  
RJ Arceci ◽  
K Stieglitz ◽  
BE Bierer
Keyword(s):  
Efflux Pump ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Drug ◽  
Cytotoxic Agents ◽  
Cross Resistance ◽  
Clinical Role ◽  
Reversal Agents ◽  
P Glycoprotein ◽  
Mdr Reversal

The multidrug-resistant (MDR) phenotype is characterized in vitro by the resistance displayed by cell lines to a broad spectrum of natural product cytotoxic agents. This high level of cross-resistance is due to the increased expression of a membrane glycoprotein termed P- glycoprotein. Encoded in humans by the mdr1 gene, P-glycoprotein functions as an energy-dependent efflux pump of these cytotoxic agents. In this report, we demonstrate that the newly characterized immunosuppressant FK506 and its structural analogue, rapamycin, are capable of functioning as MDR reversal agents. FK506 and rapamycin increase both intracellular, cytotoxic drug (daunomycin) accumulation, and the cytotoxicity of chemotherapeutic agents in multidrug-resistant cells. The increase in cytotoxic drug accumulation is observed at concentrations of FK506 and rapamycin 1,000-fold greater than the concentrations required for FK506 and rapamycin to inhibit T-lymphocyte activation and similar to those shown to be effective for other MDR reversal agents such as cyclosporine A (CsA) and verapamil. The effect of FK506 or rapamycin on both intracellular accumulation and cytotoxicity of daunomycin is additive. This is supported by the ability of FK506 and rapamycin to directly compete the binding of the photoaffinity analogue 125I-iodoaryl azidoprazosin to the P- glycoprotein. The data demonstrate that FK506 and rapamycin represent a new class of structurally distinct molecules that can function as MDR reversal agents and suggest a previously unidentified, potential clinical role for these compounds.

scholarly journals Comprehensive Analysis of Chemotherapeutic Agents THAT Induce Infectious Neutropenia

2021 ◽  
Vol 14 (7) ◽  
pp. 681
Author(s):  
Mashiro Okunaka ◽  
Daisuke Kano ◽  
Reiko Matsui ◽  
Toshikatsu Kawasaki ◽  
Yoshihiro Uesawa
Keyword(s):  
Chemotherapy Regimen ◽  
Alkylating Agents ◽  
Univariate Analysis ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Chemotherapeutic Agents ◽  
Comprehensive Analysis ◽  
Cytotoxic Agents ◽  
Underweight Patients ◽  
Using Data

Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of clinical trials have currently highlighted the risk of CIN with each chemotherapy regimen, only a few ones have comprehensively examined the risk associated with all chemotherapeutic agents. Therefore, this study aimed to investigate the risk factors and characteristics of CIN caused by each neoplastic agent using data from the large voluntary reporting Food and Drug Administration Adverse Event Reporting System database. Initially, univariate analysis showed that an age ≥ 65 years, the female sex, and treatment with chemotherapeutic agents were factors that caused CIN. Then, cluster and component analyses showed that cytotoxic agents (i.e., alkylating agents, antimetabolic agents, antineoplastic antibiotics, platinating agents, and plant-derived alkaloids) were associated with infection following neutropenia. This comprehensive analysis comparing CIN risk suggests that elderly or underweight patients treated with cytotoxic drugs require particularly careful monitoring.

scholarly journals Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

2020 ◽  
Vol 13 (11) ◽  
pp. 358
Author(s):  
Paloma Begines ◽  
Lucía Sevilla-Horrillo ◽  
Adrián Puerta ◽  
Rebecca Puckett ◽  
Samuel Bayort ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tumour Cell ◽  
Efflux Pump ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Therapeutic Approaches ◽  
Vast Number ◽  
Antiproliferative Agents ◽  
Multifactorial Diseases ◽  
Tumour Cell Lines

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI50 = 0.88‒2.0 µM) and selectivity towards tumour cell lines (selectivity index: 14‒32); moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents.

scholarly journals Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids

2015 ◽  
Vol 3 (4) ◽  
pp. 245-260 ◽  
Author(s):  
Christa P. Bénit ◽  
Charles J. Vecht
Keyword(s):  
Drug Metabolism ◽  
Tyrosine Kinase ◽  
Drug Interactions ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Large Individual ◽  
Pharmacokinetic Studies ◽  
Chemotherapeutic Drugs

Abstract Patients with cancer commonly experience seizures. Combined therapy with anticonvulsant drugs (AEDs) and chemotherapeutic drugs or tyrosine kinase inhibitors carries inherent risks on drug-drug interactions (DDIs). In this review, pharmacokinetic studies of AEDs with chemotherapeutic drugs, tyrosine kinase inhibitors, and glucocorticoids are discussed, including data on maximum tolerated dose, drug clearance, elimination half-life, and organ exposure. Enzyme-inducing AEDs (EIAEDs) cause about a 2-fold to 3-fold faster clearance of concurrent chemotherapeutic drugs metabolized along the same pathway, including cyclophosphamide, irinotecan, paclitaxel, and teniposide, and up to 4-fold faster clearance with the tyrosine kinase inhibitors crizotinib, dasatinib, imatinib, and lapatinib. The use of tyrosine kinase inhibitors, particularly imatinib and crizotinib, may lead to enzyme inhibition of concurrent therapy. Many of the newer generation AEDs do not induce or inhibit drug metabolism, but they can alter enzyme activity by other drugs including AEDs, chemotherapeutics and tyrosine kinase inhibitors. Glucocorticoids can both induce and undergo metabolic change. Quantitative data on changes in drug metabolism help to apply the appropriate dose regimens. Because the large individual variability in metabolic activity increases the risks for undertreatment and/or toxicity, we advocate routine plasma drug monitoring. There are insufficient data available on the effects of tyrosine kinase inhibitors on AED metabolism.

scholarly journals Reversal of Ovarian Cancer Cell Lines Multidrug Resistance Phenotype by the Association of Apiole with Chemotherapies

2020 ◽  
Vol 13 (10) ◽  
pp. 327
Author(s):  
Carolina Afonso de Lima ◽  
Ian Lucas de Souza Bueno ◽  
Stanley Nunes Siqueira Vasconcelos ◽  
Juliana Mozer Sciani ◽  
Ana Lúcia Tasca Gois Ruiz ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Calcium Channel ◽  
Efflux Pump ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Channel Blockers ◽  
Dependent Manner ◽  
Tumor Resistance ◽  
Concentration Dependent Manner ◽  
Chemotherapy Drugs

Multidrug resistance (MDR) is the main obstacle in anticancer therapy. The use of drug combinations to circumvent tumor resistance is a well-established principle in the clinic. Among the therapeutic targets, glycoprotein-P (P-gp), an energy-dependent transmembrane efflux pump responsible for modulating MDR, is highlighted. Many pharmacological studies report the ability of calcium channel blockers to reverse tumor resistance to chemotherapy drugs. Isolated for the first time from parsley, the phenylpropanoid apiole is described as a potent calcium channel inhibitor. Taking this into account, herein, the ability of apiole to potentiate the action of well-established chemotherapeutics in the clinic, as well as the compound’s relationship with the reversal of the resistance phenomenon by blocking P-gp, is reported. The association of apiole with both chemotherapeutic drugs doxorubicin and vincristine resulted in synergistic effect, in a concentration-dependent manner, as evaluated by the concentration reduction index. Molecular docking analysis demonstrated the affinity between apiole and the active site of P-gp, corroborating the inhibitory effect. Moreover, apiole demonstrated druglikeness, according to ADME analysis. In conclusion, apiole possibly blocks the active P-gp site, with strong binding energy, which, in turn, inhibits doxorubicin and vincristine efflux, increasing the antiproliferative response of these chemotherapeutic agents.

scholarly journals Wnt/β-catenin signaling as an emerging potential key pharmacological target in cholangiocarcinoma

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Guo-Feng Zhang ◽  
Ling Qiu ◽  
Shu-Li Yang ◽  
Jia-Cheng Wu ◽  
Tong-Jun Liu
Keyword(s):  
Signaling Pathways ◽  
Nuclear Translocation ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Regulatory Subunit ◽  
Wnt Ligands ◽  
Liver Kinase B1 ◽  
Gsk 3Β

Abstract Cholangiocarcinoma (CCA) is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts. The prognosis of CCA is generally poor due to its diagnosis at the late stages. The currently employed chemotherapeutic agents do not increase the survival rate in patients with unresectable CCA. Accordingly, there is a need to identify new therapeutic agents for the effective management of intra- and extra-hepatic CCA. Clinical as well as preclinical studies have suggested the key role of the activation of Wnt/β-catenin signaling pathway in the induction and progression of CCA. There is an up-regulation of different Wnt ligands including Wnt2, Wnt3, Wnt5, Wnt7 and Wnt10 along with redistribution of β-catenin (more expression in the nucleus and lesser on the cell surface due to nuclear translocation of β-catenin) in different types of malignant biliary tumors. Apart from the role of this pathway in the induction and progression of CCA, this pathway is also involved in inducing multidrug resistance by inducing the expression of P-glycoprotein efflux pump on the cancer cells. These deleterious effects of Wnt/β-catenin signaling are mediated in association with other signaling pathways involving microRNAs (miRNAs), PI3K/AKT/PTEN/GSK-3β, retinoic acid receptors (RARs), dickkopf-1 (DKK1), protein kinase A regulatory subunit 1 α (PRKAR1A/PKAI), (SLAP), liver kinase B1 (LKB1) and CXCR4. The selective inhibitors of Wnt/β-catenin signaling may be potentially employed to overcome multidrug-resistant, fatal CCA. The present review discusses the role of Wnt/β-catenin along with its relation with other signaling pathways in the induction and progression of CCA.

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