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New Approaches to Counteract Drug Resistance in Cancer

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (10 July 2016) | Viewed by 86007

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Dr. M. Helena Vasconcelos

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Guest Editor

1. FFUP – Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, Potugal
2. i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
Interests: cancer drug resistance; cancer multidrug resistance; intercellular transfer of drug resistance mediated by Extracellular Vesicles (EVs); new approaches to overcome drug resistance; drug-efflux pumps; escape from apoptosis; autophagy; metabolic alterations associated with drug resistance; tumour-microenvironment interactions; cancer stem cells; microRNAs; biomarkers of minimal residual disease and of drug resistance
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Dear Colleagues,

Drug resistance in cancer, either intrinsic or acquired, is a major impediment to the success of cancer treatment. This clinical problem has proven very difficult to resolve, due to several factors, such as intratumor heterogeneity and tumor dynamics, together with the presence of cancer stem cells in tumors and the intercellular transfer of drug resistance mediated by extracellular vesicles (such as exosomes or microvesicles). This Special Issue of Molecules intends to collect state-of-the-art original research and review articles on new approaches to counteract drug resistance in cancer, which may include but are not exclusively limited to articles on: novel compounds or small molecules designed for drug targets responsible for drug resistance, compounds isolated from natural products with chemosensitizing effects, new RNAi therapeutics, based on antimiRs or siRNAs, designed towards targets responsible for drug resistance, or innovative drug delivery approaches to improve response to therapy. Articles on the development of new methods to detect resistance to antitumor drugs will also be considered.

Dr. Helena Vasconcelos
Guest Editor

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Keywords

Cancer
drug resistance
multidrug resistance
chemoresistance
chemosensitisation
drug-efflux pumps
ATP-binding cassette (ABC) transporters
Apoptosis
Autophagy
p53
mutations
DNA repair
tumor-microenvironment interactions
cancer stem cells
natural products
small molecules
synthesized compounds
RNAi
siRNAs
microRNAs
antimiRs
drug delivery

Published Papers (10 papers)

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Editorial

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152 KiB

Open AccessEditorial

Special Issue: New Approaches to Counteract Drug Resistance in Cancer

by M. Helena Vasconcelos

Molecules 2017, 22(1), 6; https://doi.org/10.3390/molecules22010006 - 23 Dec 2016

Cited by 2 | Viewed by 3859

Abstract

Drug resistance is amajor impediment to the successful treatment of cancer patients[...] Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

Research

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2324 KiB

Open AccessArticle

Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells

by Xiao-Yu Zhang, Yun-Kai Zhang, Yi-Jun Wang, Pranav Gupta, Leli Zeng, Megan Xu, Xiu-Qi Wang, Dong-Hua Yang and Zhe-Sheng Chen

Molecules 2016, 21(9), 1236; https://doi.org/10.3390/molecules21091236 - 15 Sep 2016

Cited by 39 | Viewed by 8311

Abstract

In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [³H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 µM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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3556 KiB

Open AccessArticle

Prenylated Chalcone 2 Acts as an Antimitotic Agent and Enhances the Chemosensitivity of Tumor Cells to Paclitaxel

by Joana Fonseca, Sandra Marques, Patrícia M. A. Silva, Pedro Brandão, Honorina Cidade, Madalena M. Pinto and Hassan Bousbaa

Molecules 2016, 21(8), 982; https://doi.org/10.3390/molecules21080982 - 29 Jul 2016

Cited by 15 | Viewed by 6251

Abstract

We previously reported that prenylated chalcone 2 (PC2), the O-prenyl derivative (2) of 2′-hydroxy-3,4,4′,5,6′-pentamethoxychalcone (1), induced cytotoxicity of tumor cells via disruption of p53-MDM2 interaction. However, the cellular changes through which PC2 exerts its cytotoxic activity and its antitumor potential, remain to be addressed. In the present work, we aimed to (i) characterize the effect of PC2 on mitotic progression and the underlying mechanism; and to (ii) explore this information to evaluate its ability to sensitize tumor cells to paclitaxel in a combination regimen. PC2 was able to arrest breast adenocarcinoma MCF-7 and non-small cell lung cancer NCI-H460 cells in mitosis. All mitosis-arrested cells showed collapsed mitotic spindles with randomly distributed chromosomes, and activated spindle assembly checkpoint. Live-cell imaging revealed that the compound induced a prolonged delay (up to 14 h) in mitosis, culminating in massive cell death by blebbing. Importantly, PC2 in combination with paclitaxel enhanced the effect on cell growth inhibition as determined by cell viability and proliferation assays. Our findings demonstrate that the cytotoxicity induced by PC2 is mediated through antimitotic activity as a result of mitotic spindle damage. The enhancement effects of PC2 on chemosensitivity of cancer cells to paclitaxel encourage further validation of the clinical potential of this combination. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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5530 KiB

Open AccessArticle

The Effects and Mechanisms of Periplaneta americana Extract Reversal of Multi-Drug Resistance in BEL-7402/5-FU Cells

by Falu Yuan, Junyong Liu, Tingting Qiao, Ting Li, Qi Shen and Fang Peng

Molecules 2016, 21(7), 852; https://doi.org/10.3390/molecules21070852 - 28 Jun 2016

Cited by 12 | Viewed by 6002

Abstract

The present study reports the reversing effects of extracts from P. americana on multidrug resistance of BEL-7402/5-FU cells, as well as a preliminary investigation on their mechanism of action. A methylthiazolyl tetrazolium (MTT) method was applied to determine the multidrug resistance of BEL-7402/5-FU, while an intracellular drug accumulation assay was used to evaluate the effects of a column chromatography extract (PACC) and defatted extract (PADF) from P. americana on reversing multi-drug resistance. BEL-7402/5-FU reflected high resistance to 5-FU; PACC and PADF could promote drug accumulation in BEL-7402/5-FU cells, among which PADF was more effective than PACC. Moreover, results from the immunocytochemical method showed that PACC and PADF could downregulate the expression of drug resistance-associated proteins (P-gp, MRP, LRP); PACC and PADF had no effects on the expression of multidrug resistance-associated enzymes (GST-π), but PACC could increase the expression of multidrug resistance-associated enzymes (PKC). Results of real-time fluorescence quantitative PCR revealed that PACC and PADF were able to markedly inhibit the expression of multidrug resistance-associated genes (MDR1, LRP and MRP1); PACC presented a significant impact on the gene expression of multidrug resistance-associated enzymes, which increased the gene expression of GST-π and PKC. However, PADF had little impact on the expression of multidrug resistance-associated enzymes. These results demonstrated that PACC and PADF extracted from P. americana could effectively reverse MDR in BEL-7402/5-FU cells, whose mechanism was to inhibit the expression of P-gp, MRP, and LRP, and that PADF was more effective in the reversal of MDR than did PACC. In addition, some of extracts from P. americana altered (sometimes increasing) the expression of multidrug resistance-associated enzymes. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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8681 KiB

Open AccessArticle

Resistance to DNA Damaging Agents Produced Invasive Phenotype of Rat Glioma Cells—Characterization of a New in Vivo Model

by Sonja Stojković, Ana Podolski-Renić, Jelena Dinić, Željko Pavković, Jose M. Ayuso, Luis J. Fernández, Ignacio Ochoa, Victor M. Pérez-García, Vesna Pešić and Milica Pešić

Molecules 2016, 21(7), 843; https://doi.org/10.3390/molecules21070843 - 27 Jun 2016

Cited by 9 | Viewed by 6225

Abstract

Chemoresistance and invasion properties are severe limitations to efficient glioma therapy. Therefore, development of glioma in vivo models that more accurately resemble the situation observed in patients emerges. Previously, we established RC6 rat glioma cell line resistant to DNA damaging agents including antiglioma approved therapies such as 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ). Herein, we evaluated the invasiveness of RC6 cells in vitro and in a new orthotopic animal model. For comparison, we used C6 cells from which RC6 cells originated. Differences in cell growth properties were assessed by real-time cell analyzer. Cells’ invasive potential in vitro was studied in fluorescently labeled gelatin and by formation of multicellular spheroids in hydrogel. For animal studies, fluorescently labeled cells were inoculated into adult male Wistar rat brains. Consecutive coronal and sagittal brain sections were analyzed 10 and 25 days post-inoculation, while rats’ behavior was recorded during three days in the open field test starting from 25th day post-inoculation. We demonstrated that development of chemoresistance induced invasive phenotype of RC6 cells with significant behavioral impediments implying usefulness of orthotopic RC6 glioma allograft in preclinical studies for the examination of new approaches to counteract both chemoresistance and invasion of glioma cells. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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3454 KiB

Open AccessArticle

Antitumor Effect of the Mannich Base(1,3-bis-((3-Hydroxynaphthalen-2-yl)phenylmethyl)urea) on Hepatocellular Carcinoma

by Vadanasundari Vedarethinam, Karthik Dhanaraj, Soundharrajan Ilavenil, Mariadhas Valan Arasu, Ki Choon Choi, Naif Abdullah Al-Dhabi, Srigopalram Srisesharam, Kyung Dong Lee, Da Hye Kim, Tamilvenvendan Dhanapal, Ravikumar Sivanesan, Han Sung Choi and Young Ock Kim

Molecules 2016, 21(5), 632; https://doi.org/10.3390/molecules21050632 - 14 May 2016

Cited by 9 | Viewed by 5222

Abstract

The present study was designed to evaluate the antitumor effects of the synthetic Mannich base 1,3-bis-((3-hydroxynaphthalen-2-yl)phenylmethyl)urea (1,3-BPMU) against HEP-G2 hepatoma cells and diethylnitrosamine (DEN)-induced hepatocarcinoma (HCC) in albino rats. In vitro analysis results revealed that 1,3-BPMU showed significant cytotoxicity and cell growth inhibition in HEP-G2 hepatoma cells in a concentration-dependent manner. Furthermore, flow cytometry results indicated that 1,3-BPMU enhanced early and late apoptosis. The maximum apoptosis was exhibited at a concentration of 100 μg/mL of 1,3-BPMU. In in vivo analysis, DEN treatment increased the content of nucleic acids, LPO and the activities of AST, ALT, ALP, LDH, γGT and 5’NT with decreased antioxidant activity as compared to control rats. However, 1,3-BPMU treatment to DEN-induced rats decreased the content of nucleic acids, LPO and the activities of AST, ALT, ALP, LDH, γGT and 5’NT and increased the activities of SOD, CAT, GPx, GST and GR (p < 0.05). Furthermore, 1,3-BPMU enhanced the apoptosis via upregulation of caspase-3 and caspase-9 and the downregulation of Bcl-2 and Bcl-XL mRNA expression as compared to DEN-induced rats. Histological and ultrastructural investigation showed that 1,3-BPMU treatment renovated the internal architecture of the liver in DEN-induced rats. In this study, the molecular and pre-clinical results obtained by treatment of DEN-induced rats with 1,3-BPMU suggested that 1,3-BPMU might be considered as an antitumor compound in the future. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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2866 KiB

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The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells

by Deep Pokharel, Matthew P. Padula, Jamie F. Lu, Ritu Jaiswal, Steven P. Djordjevic and Mary Bebawy

Molecules 2016, 21(3), 290; https://doi.org/10.3390/molecules21030290 - 01 Mar 2016

Cited by 42 | Viewed by 7231

Abstract

Multidrug resistance (MDR) is often attributed to the over-expression of P-glycoprotein (P-gp), which prevents the accumulation of anticancer drugs within cells by virtue of its active drug efflux capacity. We have previously described the intercellular transfer of P-gp via extracellular vesicles (EVs) and proposed the involvement of a unique protein complex in regulating this process. In this paper, we investigate the role of these mediators in the regulation of P-gp functionality and hence the acquisition of MDR following cell to cell transfer. By sequentially silencing the FERM domain-binding proteins, Ezrin, Radixin and Moesin (ERM), as well as CD44, which we also report a selective packaging in breast cancer derived EVs, we have established a role for these proteins, in particular Radixin and CD44, in influencing the P-gp-mediated MDR in whole cells. We also report for the first time the role of ERM proteins in the vesicular transfer of functional P-gp. Specifically, we demonstrate that intercellular membrane insertion is dependent on Ezrin and Moesin, whilst P-gp functionality is governed by the integrity of all ERM proteins in the recipient cell. This study identifies these candidate proteins as potential new therapeutic targets in circumventing MDR clinically. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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3020 KiB

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Alisol F 24 Acetate Enhances Chemosensitivity and Apoptosis of MCF-7/DOX Cells by Inhibiting P-Glycoprotein-Mediated Drug Efflux

by Guixiang Pan, Tingting Li, Qingqing Zeng, Xiaoming Wang and Yan Zhu

Molecules 2016, 21(2), 183; https://doi.org/10.3390/molecules21020183 - 04 Feb 2016

Cited by 19 | Viewed by 5243

Abstract

Multidrug resistance (MDR) is a prime reason for numerous failed oncotherapy approaches. In the present study, we investigated whether Alisol F 24 acetate (ALI) could reverse the MDR of MCF-7/DOX cells, a multidrug-resistant human breast cancer cell line. We found that ALI was a potent P-glycoprotein (P-gp) inhibitor, in the Caco-2-monolayer cell model. ALI showed a significant and concentration-dependent cytotoxic effect on MCF-7/DOX cells in combination with doxorubicin by increasing intracellular accumulation and inducing nuclear migration of doxorubicin. However, ALI had no such effect on MCF-7 cells. In addition, ALI also promoted doxorubicin-induced early apoptosis of MCF-7/DOX cells in a time-dependent manner. These results suggest that ALI can enhance chemosensitivity of doxorubicin and reinforce its anti-cancer effect by increasing its uptake, especially inducing its nuclear accumulation in MCF-7/DOX cells. Therefore, ALI could be developed as a potential MDR-reversing agent in cancer chemotherapy in further study. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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Review

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Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer

by Bowen Du and Joong Sup Shim

Molecules 2016, 21(7), 965; https://doi.org/10.3390/molecules21070965 - 22 Jul 2016

Cited by 558 | Viewed by 27072

Abstract

Epithelial–mesenchymal transition (EMT) is known to play an important role in cancer progression, metastasis and drug resistance. Although there are controversies surrounding the causal relationship between EMT and cancer metastasis, the role of EMT in cancer drug resistance has been increasingly recognized. Numerous EMT-related signaling pathways are involved in drug resistance in cancer cells. Cells undergoing EMT show a feature similar to cancer stem cells (CSCs), such as an increase in drug efflux pumps and anti-apoptotic effects. Therefore, targeting EMT has been considered a novel opportunity to overcome cancer drug resistance. This review describes the mechanism by which EMT contributes to drug resistance in cancer cells and summarizes new advances in research in EMT-associated drug resistance. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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8549 KiB

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Marine Natural Products as Models to Circumvent Multidrug Resistance

by Solida Long, Emília Sousa, Anake Kijjoa and Madalena M. M. Pinto

Molecules 2016, 21(7), 892; https://doi.org/10.3390/molecules21070892 - 08 Jul 2016

Cited by 37 | Viewed by 9742

Abstract

Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds. Full article

(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)

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