Molecular mechanisms of drug resistance and its reversal in cancer

Yandım, Melis Kartal; Adan-Gokbulut, A.; Baran, Yusuf

doi:10.3109/07388551.2015.1015957

Cited by 280 publications

(199 citation statements)

References 105 publications

(102 reference statements)

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“…Therefore, cancer drug resistance is a major impediment in medical oncology often resulting in a failure of the treatment. An acquired resistance to an anti-cancer drug or/and multiple drugs (which could be structurally and functionally different) could additionally result in cross-resistance to multiple drugs [6]. Clinically, drug resistance can exist prior to therapy or can be the consequence of cancer therapy [7] since Darwinian selection is also applicable in the clonal selection of tumor cells [8].…”

Section: Need Of New Strategies To Overcome Drug Resistancementioning

confidence: 99%

Targeting Intracellular Calcium Signaling ([Ca2+]i) to Overcome Acquired Multidrug Resistance of Cancer Cells: A Mini-Overview

Büsselberg

Florea

2017

Cancers

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Cancer is a main public health problem all over the world. It affects millions of humans no matter their age, gender, education, or social status. Although chemotherapy is the main strategy for the treatment of cancer, a major problem limiting its success is the intrinsic or acquired drug resistance. Therefore, cancer drug resistance is a major impediment in medical oncology resulting in a failure of a successful cancer treatment. This mini-overview focuses on the interdependent relationship between intracellular calcium ([Ca2+]i) signaling and multidrug resistance of cancer cells, acquired upon treatment of tumors with anticancer drugs. We propose that [Ca2+]i signaling modulates gene expression of multidrug resistant (MDR) genes which in turn can be modulated by epigenetic factors which in turn leads to modified protein expression in drug resistant tumor cells. A precise knowledge of these mechanisms will help to develop new therapeutic strategies for drug resistant tumors and will improve current chemotherapy.

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Section: Need Of New Strategies To Overcome Drug Resistancementioning

confidence: 99%

Targeting Intracellular Calcium Signaling ([Ca2+]i) to Overcome Acquired Multidrug Resistance of Cancer Cells: A Mini-Overview

Büsselberg

Florea

2017

Cancers

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“…The results show that a significant phenotype is only commensurate with co-loss of p53 binding, and therefore unlikely to occur in cancers that retain p53 function. Peptidic drugs may therefore prove robust antagonists in oncology applications, where clinical resistance is of fundamental importance to the treatment outcome [48, 49]. …”

Section: Introductionmentioning

confidence: 99%

Avoiding drug resistance through extended drug target interfaces: a case for stapled peptides

Wei

Chee

Yurlova³

et al. 2016

Oncotarget

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Cancer drugs often fail due to the emergence of clinical resistance. This can manifest through mutations in target proteins that selectively exclude drug binding whilst retaining aberrant function. A priori knowledge of resistance-inducing mutations is therefore important for both drug design and clinical surveillance. Stapled peptides represent a novel class of antagonists capable of inhibiting therapeutically relevant protein-protein interactions. Here, we address the important question of potential resistance to stapled peptide inhibitors. HDM2 is the critical negative regulator of p53, and is often overexpressed in cancers that retain wild-type p53 function. Interrogation of a large collection of randomly mutated HDM2 proteins failed to identify point mutations that could selectively abrogate binding by a stapled peptide inhibitor (PM2). In contrast, the same interrogation methodology has previously uncovered point mutations that selectively inhibit binding by Nutlin, the prototypical small molecule inhibitor of HDM2. Our results demonstrate both the high level of structural p53 mimicry employed by PM2 to engage HDM2, and the potential resilience of stapled peptide antagonists to mutations in target proteins. This inherent feature could reduce clinical resistance should this class of drugs enter the clinic.

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“…The ability of P-gp to actively remove drugs used for chemotherapy, including DB, results in a low intracellular concentration of these drugs and therefore treatment failure (14,38). The effect of resveratrol was studied in human colorectal cancer HCT116 cell lines that were sensitive or resistant to oxaliplatin (39).…”

Section: Discussionmentioning

confidence: 99%

“…MDR is defined as the insensitivity to therapeutic substances that are not associated by structure or mechanism of action (15,16). The classical mechanism of MDR is associated with the overexpression of the ATP binding cassette subfamily B member 1 (ABCB1) gene enco ding P-glycoprotein (P-gp), which contributes to the reduction of the effective drug concentration in the cell by transporting the drug out of the cell (14,15,(17)(18)(19)(20). In addition to the classical MDR mechanism associated with overexpression of P-gp, there are atypical mechanisms (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

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Expression of genes and proteins of multidrug resistance in gastric cancer cells treated with resveratrol

et al. 2018

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Abstract. Multidrug resistance (MDR) is a notable problem in the use of chemotherapy. Therefore, studies aimed at identifying substances capable of overcoming resistance of cancer cells are required. Examples of these compounds are polyphenols, including resveratrol, that exert a range of various biological activities. The aim of the present study was to demonstrate the effect of 3,5,4'-trihydroxy-trans-stilbene (resveratrol) on the expression of ATP binding cassette subfamily B member 1, Annexin A1 (ANXA1) and thioredoxin (TXN) genes, and the proteins encoded by these genes, which are associated with MDR. The experiments were performed in human gastric cancer cell lines EPG85-257RDB (RDB) and EPG85-257RNOV (RNOV), which are resistant to daunorubicin and mitoxantrone, respectively, in addition to EPG85-257P (control), which is sensitive to cytostatic drugs. Cells were treated with 30 or 50 µM resveratrol for 72 h and changes in the expression levels of the genes were analysed with the use of a reverse transcription-quantitative polymerase chain reaction. The cellular levels of P-glycoprotein (P-gp), ANXA1 and TXN were evaluated using immunofluorescence and western blot analysis. Resveratrol in both concentrations has been shown to have a statistically significant influence on expression of the mentioned genes, compared with untreated cells. In RDB cells, resveratrol reduced the expression level of all analyzed genes, compared with untreated cells. Similar results at the protein level were obtained for P-gp and TXN. In turn, in the RNOV cell line, resveratrol reduced TXN expression at mRNA and protein levels, compared with untreated cells. The results of the present study indicate that resveratrol may reduce the resistance of cancer cells by affecting the expression of a number of the genes and proteins associated with MDR. IntroductionResveratrol belongs to the stilbenoid group of polyphenols, possessing two phenol rings linked to each other by an ethylene bridge (1). In 1940, resveratrol was isolated from the root of Veratrum grandiflorum (1,2). A primary dietary source of resveratrol is red wine, as a very high resveratrol concentration is present in the skin of red grapes (50-100 µg/g) (3). In natural conditions, resveratrol is synthesized by plants in response to external environmental factors, including ultraviolet radiation and heavy metals (3,4). Resveratrol is identified in two isomeric forms, cis and trans-resveratrol ( Fig. 1) (5,6).The trans form is dominant in terms of its prevalence and biological activity (7). The hydrophobic nature of resveratrol considerably contributes to its limited bioavailability (8).Owing to the varied biological activity of resveratrol, it has been the subject of numerous studies aimed at revealing its health-enhancing properties, and its use in prevention and treatment of many diseases (1,3,5,9). The results of in vitro and in vivo studies have proved that resveratrol exhibits anticancer activity at all three stages of the oncogenic process: initiation, promotion and progr...

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Molecular mechanisms of drug resistance and its reversal in cancer

Cited by 280 publications

References 105 publications

Targeting Intracellular Calcium Signaling ([Ca2+]i) to Overcome Acquired Multidrug Resistance of Cancer Cells: A Mini-Overview

Targeting Intracellular Calcium Signaling ([Ca2+]i) to Overcome Acquired Multidrug Resistance of Cancer Cells: A Mini-Overview

Avoiding drug resistance through extended drug target interfaces: a case for stapled peptides

Expression of genes and proteins of multidrug resistance in gastric cancer cells treated with resveratrol

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