scholarly journals S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation

2021 ◽  
Vol 22 (17) ◽  
pp. 9286
Author(s):  
Laura Mosca ◽  
Martina Pagano ◽  
Luigi Borzacchiello ◽  
Luigi Mele ◽  
Annapina Russo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Defense Mechanism ◽  
Multiple Drug Resistance ◽  
Nutritional Supplement ◽  
Multi Drug Resistance ◽  
Multiple Drug ◽  
Cell Defense ◽  
P Glycoprotein

Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.

scholarly journals Chemosensitizing multiple drug resistance of human carcinoma by bicyclol involves attenuated P-glycoprotein, GST-P and Bcl-2

2006 ◽  
Vol 5 (5) ◽  
pp. 536-543 ◽  
Author(s):  
Bing Zhu ◽  
Geng Tao Liu ◽  
Yong Mei Zhao ◽  
Ruo Su Wu ◽  
Samuel J Strada
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
Human Carcinoma ◽  
P Glycoprotein

scholarly journals Ubiquitous Conjugative Mega-Plasmids of Acinetobacter Species and Their Role in Horizontal Transfer of Multi-Drug Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Sofia Mindlin ◽  
Olga Maslova ◽  
Alexey Beletsky ◽  
Varvara Nurmukanova ◽  
Zhiyong Zong ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Antibiotic Resistance Genes ◽  
Multi Drug Resistance ◽  
Clear Correlation ◽  
Multiple Drug ◽  
Special Role ◽  
Acinetobacter Species ◽  
Group Iii

Conjugative mega-plasmids play a special role in adaptation since they carry a huge number of accessory genes, often allowing the host to develop in new niches. In addition, due to conjugation they are able to effectively spread themselves and participate in the transfer of small mobilizable plasmids. In this work, we present a detailed characterization of a recently discovered family of multiple-drug resistance mega-plasmids of Acinetobacter species, termed group III-4a. We describe the structure of the plasmid backbone region, identify the rep gene and the origin of plasmid replication, and show that plasmids from this group are able not only to move between different Acinetobacter species but also to efficiently mobilize small plasmids containing different mob genes. Furthermore, we show that the population of natural Acinetobacter strains contains a significant number of mega-plasmids and reveal a clear correlation between the living conditions of Acinetobacter strains and the structure of their mega-plasmids. In particular, comparison of the plasmids from environmental and clinical strains shows that the genes for resistance to heavy metals were eliminated in the latter, with the simultaneous accumulation of antibiotic resistance genes by incorporation of transposons and integrons carrying these genes. The results demonstrate that this group of mega-plasmids plays a key role in the dissemination of multi-drug resistance among Acinetobacter species.

scholarly journals 3,3′-Diindolylmethane Promotes Gastric Cancer Progression via β-TrCP-Mediated NF-κB Activation in Gastric Cancer-Derived MSCs

2021 ◽  
Vol 11 ◽  
Author(s):  
Hui Shi ◽  
Yaoxiang Sun ◽  
Hongru Ruan ◽  
Cheng Ji ◽  
Jiahui Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Multiple Drug Resistance ◽  
Cancer Drug ◽  
Multiple Drug ◽  
High Morbidity ◽  
Related Factors ◽  
Anti Cancer

Gastric cancer is a malignant tumor characterized by high morbidity and invasion. Surgery combined with chemo-radiotherapy is the most common treatment for gastric cancer, while multiple drug resistance always results in treatment failure. Once the anti-tumor drugs enter the tumor foci, tumor cells as well as those found in the microenvironment are affected. However, the effects of drugs on tumor microenvironment (TME) are easily overlooked. In this study, we investigated the effects of the anti-cancer drug 3,3’-diindolylmethane (DIM) on gastric cancer-derived mesenchymal stem cells (GC-MSCs) and their subsequent impact on cancer progression. Surprisingly, we found that the therapeutic concentration of DIM upregulated the expression level of tumor-related factors such as CCL-2, IL-6, and IL-8 in GC-MSCs. The conditioned medium of DIM-treated GC-MSCs promoted the proliferation, invasion, and migration of gastric cancer cells in vitro and tumor growth in vivo. Mechanistically, DIM enhanced the expression of β-TrCP, an E3 ubiquitin ligase leading to IκBα degradation and NF-κB activation in GC-MSCs. The β-TrCP knockdown partially eliminated positive results caused by DIM. Our results showed that the therapeutic dosage of DIM induced cell death in cancer cells, while enhancing MSC paracrine functions in the stroma to offset the original DIM effect on cancer cells. These findings provide a new mechanism of anti-cancer drug resistance and remind us to adjust the chemotherapeutic scheme by combining the anti-cancer drug with an appropriate signaling pathway inhibitor to block the side effects of drug on targeted TME cells.

scholarly journals The Effects of TiO2 Nanoparticles on Cisplatin Cytotoxicity in Cancer Cell Lines

2020 ◽  
Vol 21 (2) ◽  
pp. 605 ◽  
Author(s):  
Basma Salama ◽  
El-Said El-Sherbini ◽  
Gehad El-Sayed ◽  
Mohamed El-Adl ◽  
Koki Kanehira ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Hepg2 Cells ◽  
Titanium Dioxide Nanoparticles ◽  
Membrane Receptors ◽  
Multi Drug Resistance ◽  
A431 Cells ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Low Expression

There have been many studies on improving the efficacy of cisplatin and on identifying safe compounds that can overcome multi-drug resistance (MDR) acquired by cancer cells. Our previous research showed that polyethylene glycol-modified titanium dioxide nanoparticles (TiO2 PEG NPs) affect cell membrane receptors, resulting in their aggregation, altered localization and downregulation. TiO2 PEG NPs may affect P-glycoprotein (P-gp), a membrane efflux channel involved in MDR. In this study, we investigated the effect of TiO2 PEG NPs on cisplatin cytotoxicity. We used HepG2 cells, which highly express P-gp and A431 cells, which show low expression of P-gp. The results showed that 10 µg/mL 100 nm TiO2 PEG NPs increased intracellular cisplatin levels and cytotoxicity in HepG2 cells but not in A431 cells. TiO2 PEG NPs treatment decreased the expression level of P-gp in HepG2 cells. Our findings indicate that TiO2 PEG NPs enhance cisplatin cytotoxicity by down regulating P-gp and that TiO2 PEG NPs are promising candidates for inhibiting P-gp and reversing drug resistance acquired by cancer cells.

scholarly journals DNA-mediated transfer of multiple drug resistance and plasma membrane glycoprotein expression.

1982 ◽  
Vol 2 (8) ◽  
pp. 881-889 ◽  
Author(s):  
P G Debenham ◽  
N Kartner ◽  
L Siminovitch ◽  
J R Riordan ◽  
V Ling
Keyword(s):  
Drug Resistance ◽  
Plasma Membranes ◽  
Multiple Drug Resistance ◽  
Chinese Hamster ◽  
Surface Glycoprotein ◽  
Multiple Drug ◽  
Cell Surface Glycoprotein ◽  
Resistance Phenotype ◽  
P Glycoprotein ◽  
Wide Range

Colchicine-resistant Chinese hamster ovary (CHO) cell mutants whose resistance results from reduced drug permeability have been isolated previously in our laboratories. This reduced permeability affects a wide range of unrelated drugs, resulting in the mutants displaying a multiple drug resistance phenotype. A 170,000-dalton cell surface glycoprotein (P-glycoprotein) was identified, and its expression appears to correlate with the degree of resistance. In this study we were able to confer the multiple drug resistance phenotype on sensitive mouse L cells by DNA-mediated gene transfer of DNA obtained from the colchicine-resistant mutants. P-glycoprotein was detected in plasma membranes of these DNA transformants by staining with an antiserum raised against membranes of mutant CHO cells. These results are consistent with a causal relationship between P-glycoprotein expression and the multiple drug resistance phenotype.

Flavonoids overcome drug resistance to cancer chemotherapy by epigenetically modulating multiple mechanisms

2021 ◽  
Vol 21 ◽  
Author(s):  
Kenneth K.W. To ◽  
William C.S. Cho
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Chemotherapy ◽  
Animal Studies ◽  
Multiple Drug Resistance ◽  
Resistance Mechanisms ◽  
Multiple Drug ◽  
Full Potential ◽  
Cancer Proliferation ◽  
Genes Encoding

Drug resistance is the major reason accounting for the treatment failure in cancer chemotherapy. Dysregulation of the epigenetic machineries is known to induce chemoresistance. It was reported that numerous genes encoding the key mediators in cancer proliferation, apoptosis, DNA repair, and drug efflux are dysregulated in resistant cancer cells by aberrant DNA methylation. The imbalance of various enzymes catalyzing histone post-translational modifications is also known to alter chromatin configuration and regulate multiple drug resistance genes. Alteration in miRNA signature in cancer cells also gives rise to chemoresistance. Flavonoids are a large group of naturally occurring polyphenolic compounds ubiquitously found in plants, fruits, vegetables and traditional herbs. There has been an increasing research interest in the health-promoting effects of flavonoids. Flavonoids were shown to directly kill or re-sensitize resistant cancer cells to conventional anticancer drugs by epigenetic mechanisms. In this review, we summarize the current findings about the circumvention of drug resistance by flavonoids through correcting the aberrant epigenetic regulation of multiple resistance mechanisms. More investigations including the evaluation of synergistic anticancer activity, dosing sequence effect, toxicity in normal cells, and animal studies, are warranted to establish the full potential of the combination of flavonoids with conventional chemotherapeutic drugs in the treatment of cancer with drug resistance.

DNA-mediated transfer of multiple drug resistance and plasma membrane glycoprotein expression

1982 ◽  
Vol 2 (8) ◽  
pp. 881-889
Author(s):  
P G Debenham ◽  
N Kartner ◽  
L Siminovitch ◽  
J R Riordan ◽  
V Ling
Keyword(s):  
Drug Resistance ◽  
Plasma Membranes ◽  
Multiple Drug Resistance ◽  
Chinese Hamster ◽  
Surface Glycoprotein ◽  
Multiple Drug ◽  
Cell Surface Glycoprotein ◽  
Resistance Phenotype ◽  
P Glycoprotein ◽  
Wide Range

Colchicine-resistant Chinese hamster ovary (CHO) cell mutants whose resistance results from reduced drug permeability have been isolated previously in our laboratories. This reduced permeability affects a wide range of unrelated drugs, resulting in the mutants displaying a multiple drug resistance phenotype. A 170,000-dalton cell surface glycoprotein (P-glycoprotein) was identified, and its expression appears to correlate with the degree of resistance. In this study we were able to confer the multiple drug resistance phenotype on sensitive mouse L cells by DNA-mediated gene transfer of DNA obtained from the colchicine-resistant mutants. P-glycoprotein was detected in plasma membranes of these DNA transformants by staining with an antiserum raised against membranes of mutant CHO cells. These results are consistent with a causal relationship between P-glycoprotein expression and the multiple drug resistance phenotype.

Co-amplification of double minute chromosomes, multiple drug resistance, and cell surface P-glycoprotein in DNA-mediated transformants of mouse cells

1984 ◽  
Vol 4 (3) ◽  
pp. 500-506
Author(s):  
S M Robertson ◽  
V Ling ◽  
C P Stanners
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Resistant Mutant ◽  
Genetic System ◽  
Cell Membrane Permeability ◽  
Multiple Drug ◽  
P Glycoprotein ◽  
Double Minute ◽  
Mouse Cells ◽  
Double Minute Chromosomes

A genetic system comprised of mammalian cell mutants which demonstrate concomitant resistance to a number of unrelated drugs has been described previously. The resistance is due to reduced cell membrane permeability and is correlated with the presence of large amounts of a plasma membrane glycoprotein termed P-glycoprotein. This system could represent a model for multiple drug resistance which develops in cancer patients treated with chemotherapeutic drugs. We demonstrate here that the multiple drug resistance phenotype can be transferred to mouse cells with DNA from a drug-resistant mutant and then amplified quantitatively by culture in media containing increasing concentrations of drug. The amount of P-glycoprotein was correlated directly with the degree of drug resistance in the transformants and amplified transformants. In addition, the drug resistance and expression of P-glycoprotein of the transformants were unstable and associated quantitatively with the number of double minute chromosomes. We suggest that the gene for multiple drug resistance and P-glycoprotein is contained in these extrachromosomal particles and is amplified by increases in double minute chromosome number. The potential use of this system for manipulation of mammalian genes in general is discussed.

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