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Special Issue "Counteracting Drug Resistant Mechanisms in Cancer"

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

Deadline for manuscript submissions: closed (15 January 2018)

Special Issue Editor

Guest Editor
Prof. Dr. M. Helena Vasconcelos

FFUP – Faculdade de Farmácia da Universidade do Porto, Porto 4050-313, Potugal; I3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal
Website | E-Mail
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

Special Issue Information

Dear Colleagues,

Drug resistance is a major obstacle to the successful treatment of cancer patients. The intratumor genetic heterogeneity and tumor dynamics, together with the presence of cancer stem cells, make it a very difficult problem to overcome. This Special Issue of Molecules aims to collect review and research articles on novel approaches for counteracting drug resistant mechanisms in cancer. Topics may include: i) novel compounds or small molecules designed to inhibit targets known to be responsible for chemoresistance (e.g. drug-efflux pumps or antiapoptotic proteins), ii) natural compounds that circumvent drug resistance, iii) molecules that target cancer stem cells, iv) antimiRs or siRNAs designed to inhibit targets responsible for chemoresistance, or v) drug delivery approaches to improve drug response.

Prof. Dr. M. Helena Vasconcelos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer
  • drug resistance
  • multidrug resistance
  • chemoresistance
  • chemosensitisation
  • drug-efflux pumps
  • ATP-binding cassette (ABC) transporters
  • cell death
  • apoptosis; autophagy
  • p53
  • mutations
  • DNA repair
  • tumour-microenvironment interactions
  • EMT
  • cancer stem cells
  • natural products
  • small molecules
  • siRNAs
  • microRNAs
  • antimiRs
  • drug delivery
  • nanotechnology
  • liposomes
  • extracellular vesicles

Published Papers (7 papers)

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Research

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Open AccessArticle New and Old Genes Associated with Primary and Established Responses to Paclitaxel Treatment in Ovarian Cancer Cell Lines
Molecules 2018, 23(4), 891; doi:10.3390/molecules23040891
Received: 12 March 2018 / Revised: 4 April 2018 / Accepted: 10 April 2018 / Published: 12 April 2018
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Abstract
Development of drug resistance is the main reason for low chemotherapy effectiveness in treating ovarian cancer. Paclitaxel (PAC) is a chemotherapeutic drug used in the treatment of this cancer. We analysed the development of PAC resistance in two ovarian cancer cell lines. Exposure
[...] Read more.
Development of drug resistance is the main reason for low chemotherapy effectiveness in treating ovarian cancer. Paclitaxel (PAC) is a chemotherapeutic drug used in the treatment of this cancer. We analysed the development of PAC resistance in two ovarian cancer cell lines. Exposure of drug-sensitive cell lines (A2780 and W1) to PAC was used to determine the primary response. An established response was determined in PAC-resistant sublines of the A2780 and W1 cell lines. qRT-PCR was performed to measure the expression levels of specific genes. We observed decreased expression of the PCDH9, NSBP1, MCTP1 and SEMA3A genes in the PAC-resistant cell lines. Short-term exposure to PAC led to increased expression of the MDR1 and BCRP genes in the A2780 and W1 cell lines. In the A2780 cell line, we also observed increased expression of the C4orf18 gene and decreased expression of the PCDH9 and SEMA3A genes after PAC treatment. In the W1 cell line, short-term treatment with PAC upregulated the expression of the ALDH1A1 gene, a marker of Cancer stem cells (CSCs). Our results suggest that downregulation of the PCDH9, NSBP1, MCTP1 and SEMA3A genes and upregulation of the MDR1, BCRP, C4orf18 and ALDH1A1 genes may be related to PAC resistance. Full article
(This article belongs to the Special Issue Counteracting Drug Resistant Mechanisms in Cancer)
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Open AccessArticle A Novel Receptor Tyrosine Kinase Switch Promotes Gastrointestinal Stromal Tumor Drug Resistance
Molecules 2017, 22(12), 2152; doi:10.3390/molecules22122152
Received: 21 September 2017 / Revised: 27 November 2017 / Accepted: 1 December 2017 / Published: 5 December 2017
Cited by 1 | PDF Full-text (6977 KB) | HTML Full-text | XML Full-text
Abstract
The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs
[...] Read more.
The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc. We established and characterized the IM-resistant GIST T-1 cell line (GIST T-1R) lacking secondary c-KIT mutations typical for the IM-resistant phenotype. The resistance to IM in GIST T-1R cells was due to RTK switch (loss of c-KIT/gain of FGFR2α). Indeed, we have found that FGFR inhibition reduced cellular viability, induced apoptosis and affected the growth kinetics of the IM-resistant GISTs in vitro. In contrast, IM-naive GIST T-1 parental cells were not susceptible to FGFR inhibition. Importantly, inhibition of FGF-signaling restored the susceptibility to IM in IM-resistant GISTs. Additionally, IM-resistant GISTs were less susceptible to certain chemotherapeutic agents as compared to parental IM-sensitive GIST cells. The chemoresistance in GIST T-1R cells is not due to overexpression of ABC-related transporter proteins and might be the result of upregulation of DNA damage signaling and repair (DDR) genes involved in DNA double-strand break (DSB) repair pathways (e.g., XRCC3, Rad51, etc.). Taken together, the established GIST T-1R cell subline might be used for in vitro and in vivo studies to examine the efficacy and prospective use of FGFR inhibitors for patients with IM-resistant, un-resectable and metastatic forms of GISTs with the type of RTK switch indicated above. Full article
(This article belongs to the Special Issue Counteracting Drug Resistant Mechanisms in Cancer)
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Open AccessArticle New and Old Genes Associated with Primary and Established Responses to Cisplatin and Topotecan Treatment in Ovarian Cancer Cell Lines
Molecules 2017, 22(10), 1717; doi:10.3390/molecules22101717
Received: 19 September 2017 / Revised: 29 September 2017 / Accepted: 6 October 2017 / Published: 13 October 2017
Cited by 1 | PDF Full-text (3059 KB) | HTML Full-text | XML Full-text
Abstract
Low efficiency of chemotherapy in ovarian cancer results from the development of drug resistance. Cisplatin (CIS) and topotecan (TOP) are drugs used in chemotherapy of this cancer. We analyzed the development of CIS and TOP resistance in ovarian cancer cell lines. Incubation of
[...] Read more.
Low efficiency of chemotherapy in ovarian cancer results from the development of drug resistance. Cisplatin (CIS) and topotecan (TOP) are drugs used in chemotherapy of this cancer. We analyzed the development of CIS and TOP resistance in ovarian cancer cell lines. Incubation of drug sensitive cell lines (W1 and A2780) with cytostatic drugs was used to determine the primary response to CIS and TOP. Quantitative polymerase chain reaction (Q-PCR) was performed to measure the expression levels of the genes. We observed decreased expression of the MCTP1 gene in all resistant cell lines. We observed overexpression of the S100A3 and HERC5 genes in TOP-resistant cell lines. Increased expression of the S100A3 gene was also observed in CIS-resistant A2780 sublines. Overexpression of the C4orf18 gene was observed in CIS- and TOP-resistant A2780 sublines. A short time of exposure to CIS led to increased expression of the ABCC2 gene in the W1 and A2780 cell lines and increased expression of the C4orf18 gene in the A2780 cell line. A short time of exposure to TOP led to increased expression of the S100A3 and HERC5 genes in both sensitive cell lines, increased expression of the C4orf18 gene in the A2780 cell line and downregulation of the MCTP1 gene in the W1 cell line. Our results suggest that changes in expression of the MCTP1, S100A3 and C4orf18 genes may be related to both CIS and TOP resistance. Increased expression of the HERC5 gene seems to be important only in TOP resistance. Full article
(This article belongs to the Special Issue Counteracting Drug Resistant Mechanisms in Cancer)
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Review

Jump to: Research

Open AccessReview Interplay between P-Glycoprotein Expression and Resistance to Endoplasmic Reticulum Stressors
Molecules 2018, 23(2), 337; doi:10.3390/molecules23020337
Received: 13 January 2018 / Revised: 30 January 2018 / Accepted: 1 February 2018 / Published: 6 February 2018
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Abstract
Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)—a drug efflux pump (ABCB1 member of the ABC transporter gene family)—is frequently observed to be a molecular cause of MDR. The drug-efflux
[...] Read more.
Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)—a drug efflux pump (ABCB1 member of the ABC transporter gene family)—is frequently observed to be a molecular cause of MDR. The drug-efflux activity of P-gp is considered as the underlying mechanism of drug resistance against P-gp substrates and results in failure of cancer chemotherapy. Several pathological impulses such as shortages of oxygen and glucose supply, alterations of calcium storage mechanisms and/or processes of protein N-glycosylation in the endoplasmic reticulum (ER) leads to ER stress (ERS), characterized by elevation of unfolded protein cell content and activation of the unfolded protein response (UPR). UPR is responsible for modification of protein folding pathways, removal of misfolded proteins by ER associated protein degradation (ERAD) and inhibition of proteosynthesis. However, sustained ERS may result in UPR-mediated cell death. Neoplastic cells could escape from the death pathway induced by ERS by switching UPR into pro survival mechanisms instead of apoptosis. Here, we aimed to present state of the art information about consequences of P-gp expression on mechanisms associated with ERS development and regulation of the ERAD system, particularly focused on advances in ERS-associated therapy of drug resistant malignancies. Full article
(This article belongs to the Special Issue Counteracting Drug Resistant Mechanisms in Cancer)
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Open AccessReview Cell Migration Related to MDR—Another Impediment to Effective Chemotherapy?
Molecules 2018, 23(2), 331; doi:10.3390/molecules23020331
Received: 8 January 2018 / Revised: 29 January 2018 / Accepted: 1 February 2018 / Published: 5 February 2018
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Abstract
Multidrug resistance, mediated by members of the ATP-binding cassette (ABC) proteins superfamily, has become one of the biggest obstacles in conquering tumour progression. If the chemotherapy outcome is considered successful, when the primary tumour volume is decreased or completely abolished, modulation of ABC
[...] Read more.
Multidrug resistance, mediated by members of the ATP-binding cassette (ABC) proteins superfamily, has become one of the biggest obstacles in conquering tumour progression. If the chemotherapy outcome is considered successful, when the primary tumour volume is decreased or completely abolished, modulation of ABC proteins activity is one of the best methods to overcome drug resistance. However, if a positive outcome is represented by no metastasis or, at least, elongation of remission-free time, then the positive effect of ABC proteins inhibition should be compared with the several side effects it causes, which may inflict cancer progression and decrease overall patient health. Clinical trials conducted thus far have shown that the tested ABC modulators add limited or no benefits to cancer patients, as some of them are merely toxic and others induce unwanted drug–drug interactions. Moreover, the inhibition of certain ABC members has been recently indicated as potentially responsible for increased fibroblasts migration. A better understanding of the complex role of ABC proteins in relation to cancer progression may offer novel strategies in cancer therapy. Full article
(This article belongs to the Special Issue Counteracting Drug Resistant Mechanisms in Cancer)
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Open AccessFeature PaperReview Towards Comprehension of the ABCB1/P-Glycoprotein Role in Chronic Myeloid Leukemia
Molecules 2018, 23(1), 119; doi:10.3390/molecules23010119
Received: 21 November 2017 / Revised: 25 December 2017 / Accepted: 5 January 2018 / Published: 7 January 2018
Cited by 1 | PDF Full-text (845 KB) | HTML Full-text | XML Full-text
Abstract
Abstract: The introduction of imatinib (IM), a BCR-ABL1 tyrosine kinase inhibitor (TKI), has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML). However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to
[...] Read more.
Abstract: The introduction of imatinib (IM), a BCR-ABL1 tyrosine kinase inhibitor (TKI), has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML). However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs—dasatinib, nilotinib, and bosutinib—and the third-generation TKI—ponatinib. The mechanisms of resistance to TKIs may be BCR-ABL1-dependent and/or BCR-ABL1-independent. Although the role of efflux pump P-glycoprotein (Pgp), codified by the ABCB1 gene, is unquestionable in drug resistance of many neoplasms, a longstanding question exists about whether Pgp has a firm implication in TKI resistance in the clinical scenario. The goal of this review is to offer an overview of ABCB1/Pgp expression/activity/polymorphisms in CML. Understanding how interactions, associations, or cooperation between Pgp and other molecules—such as inhibitor apoptosis proteins, microRNAs, or microvesicles—impact IM resistance risk may be critical in evaluating the response to TKIs in CML patients. In addition, new non-TKI compounds may be necessary in order to overcome the resistance mediated by Pgp in CML. Full article
(This article belongs to the Special Issue Counteracting Drug Resistant Mechanisms in Cancer)
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Open AccessReview PP2A as the Main Node of Therapeutic Strategies and Resistance Reversal in Triple-Negative Breast Cancer
Molecules 2017, 22(12), 2277; doi:10.3390/molecules22122277
Received: 3 November 2017 / Revised: 7 December 2017 / Accepted: 19 December 2017 / Published: 20 December 2017
PDF Full-text (1110 KB) | HTML Full-text | XML Full-text
Abstract
Triple negative breast cancer (TNBC), is defined as a type of tumor lacking the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The ER, PR and HER2 are usually the molecular therapeutic targets for breast
[...] Read more.
Triple negative breast cancer (TNBC), is defined as a type of tumor lacking the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The ER, PR and HER2 are usually the molecular therapeutic targets for breast cancers, but they are ineffective for TNBC because of their negative expressions, so chemotherapy is currently the main treatment strategy in TNBC. However, drug resistance remains a major impediment to TNBC chemotherapeutic treatment. Recently, the protein phosphatase 2A (PP2A) has been found to regulate the phosphorylation of some substrates involved in the relevant target of TNBC, such as cell cycle control, DNA damage responses, epidermal growth factor receptor, immune modulation and cell death resistance, which may be the effective therapeutic strategies or influence drug sensitivity to TNBCs. Furthermore, PP2A has also been found that could induce ER re-expression in ER-negative breast cancer cells, and which suggests PP2A could promote the sensitivity of tamoxifen to TNBCs as a resistance reversal agent. In this review, we will summarize the potential therapeutic value of PP2A as the main node in developing targeting agents, disrupting resistance or restoring drug sensitivity in TNBC. Full article
(This article belongs to the Special Issue Counteracting Drug Resistant Mechanisms in Cancer)
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