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A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (23 July 2019) | Viewed by 51929

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Special Issue Editor

Dr. Nuno Vale

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Guest Editor

Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Interests: drug repurposing; drug metabolism; drug delivery; peptides; prodrugs; ADME in pharmacology; pharmacokinetic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

One possible way to overcome or delay the development of drug resistance is to treat patients with combinations of different drugs, probably because the combination treatment approach works by different molecular mechanisms. For cancer, the other approach is based on the treatment of patients with drugs that block the particular resistance mechanism that tumors have developed, and in a second step, using other drugs to improve intrinsic resistance.

I believe that we need to work on developing a new generation of drug combinations to strike a balance between increased efficacy and decreased toxicity. This Special Issue on Multidrug Combinations, will consider publications on several topics, including:

Combining cancer drugs
Precision medicine
Drug–drug interactions
Drug repurposing in drug combinations
Peptide as a drug in biomedicine
Drug metabolism
Alteration in the tumor microenvironment
High-throughput screening
Keeping cancer drugs inside cells
Epigenetic alteration and drug resistance/combination

Biomolecules is an open access journal and therefore all manuscripts will be published as soon as they are accepted and will be accessible online free of charge to all readers. The article processing charge is 650 CHF per published manuscript. The deadline for submissions is 15 November 2018.

Prof. Nuno Vale
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 submissions that pass pre-check are 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. Biomolecules 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 2700 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

Combining cancer drugs
Precision medicine
Drug–drug interactions
Drug repurposing in drug combinations
Peptide as a drug in biomedicine
Drug metabolism
Alteration in the tumor microenvironment
High-throughput screening
Keeping cancer drugs inside cells
Epigenetic alteration and drug resistance/combination

Published Papers (10 papers)

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Editorial

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3 pages, 199 KiB

Open AccessEditorial

Editorial on the Special Issue: “Multidrug Combinations”

by Nuno Vale

Biomolecules 2022, 12(6), 812; https://doi.org/10.3390/biom12060812 - 09 Jun 2022

Viewed by 1150

Abstract

Biological organisms are composed of complex subsystems that interact dynamically at different levels, with functions that are complemented to avoid system malfunctions [...] Full article

(This article belongs to the Special Issue Multidrug Combinations)

Research

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12 pages, 1207 KiB

Open AccessArticle

Combination of Gemcitabine with Cell-Penetrating Peptides: A Pharmacokinetic Approach Using in Silico Tools

by Abigail Ferreira, Rui Lapa and Nuno Vale

Biomolecules 2019, 9(11), 693; https://doi.org/10.3390/biom9110693 - 04 Nov 2019

Cited by 11 | Viewed by 2889

Abstract

Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first line treatment for pancreatic cancer. Our group has previously developed novel conjugates of gemcitabine with cell-penetrating peptides (CPP), and here we report some preliminary data regarding the pharmacokinetics of gemcitabine, two gemcitabine-CPP conjugates and respective CPP gathered from GastroPlus™, and analyze these results considering our previous evaluation of gemcitabine release and conjugates’ bioactivity. Additionally, seeking to shed some light on the relation between the penetration ability of CPP and their physicochemical properties, chemical descriptors for the 20 natural amino acids were calculated, a new principal property scale (z-scale) was created and CPP prediction models were developed, establishing quantitative structure-activity relationships (QSAR). The z-scores of the peptides conjugated with gemcitabine are presented and analyzed with the aforementioned data. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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11 pages, 2993 KiB

Open AccessArticle

Carbidopa Alters Tryptophan Metabolism in Breast Cancer and Melanoma Cells Leading to the Formation of Indole-3-Acetonitrile, a Pro-Proliferative Metabolite

by Diana Duarte, Filipa Amaro, Isabel Silva, Dany Silva, Paula Fresco, José C. Oliveira, Henrique Reguengo, Jorge Gonçalves and Nuno Vale

Biomolecules 2019, 9(9), 409; https://doi.org/10.3390/biom9090409 - 24 Aug 2019

Cited by 7 | Viewed by 3392

Abstract

Carbidopa is used for the treatment of Parkinson’s disease (PD) as an inhibitor of DOPA decarboxylase, and PD patients taking carbidopa have a lower incidence of various tumors, except for breast cancer and melanoma. Recently, it was shown that carbidopa inhibits tryptophan-2,3-dioxygenase (TDO) and kynureninase enzymes. In the present study, the effect of carbidopa on the viability and metabolic profile of breast cancer MCF-7 and melanoma A375 cells was investigated. Carbidopa was not effective in inhibiting MCF-7 and A375 proliferation. Liquid chromatography and mass spectrometry revealed a new compound, identified as indole-3-acetonitrile (IAN), which promoted a concentration-dependent increase in the viability of both cell lines. The results suggest that treatment with carbidopa may alter tryptophan (Trp) metabolism in breast cancer and melanoma leading to the formation of a pro-proliferative Trp metabolite, which may contribute to its failure in reducing breast cancers and melanoma incidence in PD patients taking carbidopa. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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14 pages, 1946 KiB

Open AccessArticle

Study of the Combination of Self-Activating Photodynamic Therapy and Chemotherapy for Cancer Treatment

by Luís Pinto da Silva, Carla M. Magalhães, Ara Núñez-Montenegro, Paulo J.O. Ferreira, Diana Duarte, José E. Rodríguez-Borges, Nuno Vale and Joaquim C.G. Esteves da Silva

Biomolecules 2019, 9(8), 384; https://doi.org/10.3390/biom9080384 - 20 Aug 2019

Cited by 30 | Viewed by 4263

Abstract

Cancer is a very challenging disease to treat, both in terms of treatment efficiency and side-effects. To overcome these problems, there have been extensive studies regarding the possibility of improving treatment by employing combination therapy, and by exploring therapeutic modalities with reduced side-effects (such as photodynamic therapy (PDT)). Herein, this work has two aims: (i) to develop self-activating photosensitizers for use in light-free photodynamic therapy, which would eliminate light-related restrictions that this therapy currently possesses; (ii) to assess their co-treatment potential when combined with reference chemotherapeutic agents (Tamoxifen and Metformin). We synthesized three new photosensitizers capable of self-activation and singlet oxygen production via a chemiluminescent reaction involving only a cancer marker and without requiring a light source. Cytotoxicity assays demonstrated the cytotoxic activity of all photosensitizers for prostate and breast tumor cell lines. Analysis of co-treatment effects revealed significant improvements for breast cancer, producing better results for all combinations than just for the individual photosensitizers and even Tamoxifen. By its turn, co-treatment for prostate cancer only presented better results for one combination than for just the isolated photosensitizers and Metformin. Nevertheless, it should be noted that the cytotoxicity of the isolated photosensitizers in prostate tumor cells was already very appreciable. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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11 pages, 702 KiB

Open AccessArticle

In Vitro Interactions of Moroccan Propolis Phytochemical’s on Human Tumor Cell Lines and Anti-Inflammatory Properties

by Soraia I. Falcão, Ricardo C. Calhelha, Soumaya Touzani, Badiaâ Lyoussi, Isabel C. F. R. Ferreira and Miguel Vilas-Boas

Biomolecules 2019, 9(8), 315; https://doi.org/10.3390/biom9080315 - 29 Jul 2019

Cited by 16 | Viewed by 3519

Abstract

Propolis is a resin manufactured by bees through the mixture of plant exudates and waxes with secreted substances from their metabolism, resulting in a complex mixture of natural substances of which quality depends on the phytogeographic and climatic conditions around the hive. The present study investigated the contribution of phenolic compounds to the cytotoxic and anti-inflammatory activities of propolis. The phenolic composition was evaluated by liquid chromatography with diode-array detection coupled to electrospray ionization tandem mass spectrometry (LC/DAD/ESI-MSⁿ) analysis after phenolic extraction. The cytotoxicity of the extracts was checked using human tumor cell lines (MCF7- breast adenocarcinoma, NCI-H460- non-small cell lung carcinoma, HeLa- cervical carcinoma, HepG2- hepatocellular carcinoma, and MM127- malignant melanoma), as well as non-tumor cells (a porcine liver primary culture-PLP2). The anti-inflammatory activity was assessed using the murine macrophage (RAW 264.7) cell line. The results showed a composition rich in phenolic acids, such as caffeic and p-coumaric acid, as well as flavonoids, such as pinocembrin, pinobanksin, and pinobanksin-3-O-butyrate. Samples MP2 from Sefrou and MP3 from Moulay Yaâcoub presented a high concentration in phenolic compounds, while MP1 and MP4 from Boulemane and Immouzzer Mermoucha, respectively, showed similar composition with low bioactivity. The higher concentration of phenolic compound derivatives, which seems to be the most cytotoxic phenolic class, can explain the pronounced antitumor and anti-inflammatory activity observed for sample MP2. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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20 pages, 7743 KiB

Open AccessArticle

The Main Metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) Are Not Major Contributors to FAC Toxicity in H9c2 Cardiac Differentiated Cells

by Ana Reis-Mendes, Félix Carvalho, Fernando Remião, Emília Sousa, Maria de Lourdes Bastos and Vera Marisa Costa

Biomolecules 2019, 9(3), 98; https://doi.org/10.3390/biom9030098 - 11 Mar 2019

Cited by 11 | Viewed by 5687

Abstract

In the clinical practice, the combination of 5-fluorouracil (5-FU) + Adriamycin (also known as doxorubicin, DOX) + cyclophosphamide (CYA) (known as FAC) is used to treat breast cancer. The FAC therapy, however, carries some serious risks, namely potential cardiotoxic effects, although the mechanisms are still unclear. In the present study, the role of the main metabolites regarding FAC-induced cardiotoxicity was assessed at clinical relevant concentrations. Seven-day differentiated H9c2 cells were exposed for 48 h to the main metabolites of FAC, namely the metabolite of 5-FU, α-fluoro-β-alanine (FBAL, 50 or 100 μM), of DOX, doxorubicinol (DOXOL, 0.2 or 1 μM), and of CYA, acrolein (ACRO, 1 or 10 μM), as well as to their combination. The parent drugs (5-FU 50 μM, DOX 1 μM, and CYA 50 μM) were also tested isolated or in combination with the metabolites. Putative cytotoxicity was evaluated through phase contrast microscopy, Hoechst staining, membrane mitochondrial potential, and by two cytotoxicity assays: the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and the neutral red (NR) lysosomal incorporation. The metabolite DOXOL was more toxic than FBAL and ACRO in the MTT and NR assays. When in combination, neither FBAL nor ACRO increased DOXOL-induced cytotoxicity. No nuclear condensation was observed for any of the tested combinations; however, a significant mitochondrial potential depolarization after FBAL 100 μM + DOXOL 1 μM + ACRO 10 μM or FBAL 100 μM + DOXOL 1 μM exposure was seen at 48 h. When tested alone DOX 1 μM was more cytotoxic than all the parent drugs and metabolites in both the cytotoxicity assays performed. These results demonstrated that DOXOL was the most toxic of all the metabolites tested; nonetheless, the metabolites do not seem to be the major contributors to FAC-induced cardiotoxicity in this cardiac model. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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19 pages, 6748 KiB

Open AccessArticle

Combination Anthelmintic/Antioxidant Activity Against Schistosoma Mansoni

by Maria João Gouveia, Paul J. Brindley, Gabriel Rinaldi, Fátima Gärtner, José Manuel Correia da Costa and Nuno Vale

Biomolecules 2019, 9(2), 54; https://doi.org/10.3390/biom9020054 - 05 Feb 2019

Cited by 10 | Viewed by 4528

Abstract

Schistosomiasis is a major neglected tropical disease. Treatment for schistosomiasis with praziquantel (PZQ), which is effective against the parasite, by itself is not capable to counteract infection-associated disease lesions including hepatic fibrosis. There is a pressing need for novel therapies. Due to their biological properties, antioxidant biomolecules might be useful in treating and reverting associated pathological sequelae. Here, we investigated a novel therapy approach based on a combination of anthelmintic drugs with antioxidant biomolecules. We used a host-parasite model involving Bioamphalaria glabrata and newly transformed schistosomula (NTS) of Schistosoma mansoni. For in vitro drug screening assays, was selected several antioxidants and evaluated not only antischistosomal activity but also ability to enhance activity of the anthelmintic drugs praziquantel (PZQ) and artesunate (AS). The morphological alterations induced by compounds alone/combined were assessed on daily basis using an inverted and automated microscope to quantify NTS viability by a fluorometric-based method. The findings indicated that not only do some antioxidants improve antischistosomal activity of the two anthelmintics, but they exhibit activity per se, leading to high mortality of NTS post-exposure. The combination index (CI) of PZQ + Mel (CI = 0.80), PZQ + Resv (CI = 0.74), AS + Resv (CI = 0.34), AS + NAC (CI = 0.89), VDT + Flav (CI = 1.03) and VDT + Resv (CI = 1.06) reveal that they display moderate to strong synergism. The combination of compounds with discrete mechanisms of action might provide a valuable adjunct to contribution for treatment of schistosomiasis-associated disease. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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20 pages, 5761 KiB

Open AccessArticle

Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells

by Maria Pereira-Oliveira, Ana Reis-Mendes, Félix Carvalho, Fernando Remião, Maria de Lourdes Bastos and Vera Marisa Costa

Biomolecules 2019, 9(1), 21; https://doi.org/10.3390/biom9010021 - 10 Jan 2019

Cited by 14 | Viewed by 6384

Abstract

Currently, a common therapeutic approach in cancer treatment encompasses a drug combination to attain an overall better efficacy. Unfortunately, it leads to a higher incidence of severe side effects, namely cardiotoxicity. This work aimed to assess the cytotoxicity of doxorubicin (DOX, also known as Adriamycin), 5-fluorouracil (5-FU), cyclophosphamide (CYA), and their combination (5-Fluorouracil + Adriamycin + Cyclophosphamide, FAC) in H9c2 cardiac cells, for a better understanding of the contribution of each drug to FAC-induced cardiotoxicity. Differentiated H9c2 cells were exposed to pharmacological relevant concentrations of DOX (0.13–5 μM), 5-FU (0.13–5 μM), CYA (0.13–5 μM) for 24 or 48 h. Cells were also exposed to FAC mixtures (0.2, 1 or 5 μM of each drug and 50 μM 5-FU + 1 μM DOX + 50 μM CYA). DOX was the most cytotoxic drug, followed by 5-FU and lastly CYA in both cytotoxicity assays (reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and neutral red (NR) uptake). Concerning the equimolar combination with 1 or 5 μM, FAC caused similar cytotoxicity to DOX alone. Even in the presence of higher concentrations of 5-FU and CYA (50 μM 5-FU + 1 μM DOX + 50 μM CYA), 1 μM DOX was still a determinant for the cardiotoxicity observed in the cytotoxicity assays, phase contrast morphological evaluation, and mitochondrial potential depolarization evaluation. To the best of our knowledge, this was the first in vitro work with this combination regimen, DOX being the most toxic drug and key to the toxicity of FAC. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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23 pages, 4561 KiB

Open AccessArticle

Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations

by Ana Correia, Dany Silva, Alexandra Correia, Manuel Vilanova, Fátima Gärtner and Nuno Vale

Biomolecules 2018, 8(4), 175; https://doi.org/10.3390/biom8040175 - 14 Dec 2018

Cited by 29 | Viewed by 5445

Abstract

Cancer is a disease that affects and kills millions of people worldwide. Breast cancer, especially, has a high incidence and mortality, and is challenging to treat. Due to its high impact on the health sector, oncological therapy is the subject of an intense and very expensive research. To improve this therapy and reduce its costs, strategies such as drug repurposing and drug combinations have been extensively studied. Drug repurposing means giving new usefulness to drugs which are approved for the therapy of various diseases, but, in this case, are not approved for cancer therapy. On the other hand, the purpose of combining drugs is that the response that is obtained is more advantageous than the response obtained by the single drugs. Using drugs with potential to be repurposed, combined with 5-fluorouracil, the aim of this project was to investigate whether this combination led to therapeutic benefits, comparing with the isolated drugs. We started with a screening of the most promising drugs, with verapamil and itraconazole being chosen. Several cellular viability studies, cell death and proliferation studies, mainly in MCF-7 cells (Michigan Cancer Foundation-7, human breast adenocarcinoma cells) were performed. Studies were also carried out to understand the effect of the drugs at the level of possible therapeutic resistance, evaluating the epithelial-mesenchymal transition. Combining all the results, the conclusion is that the combination of verapamil and itraconazole with 5-fluorouracil had benefits, mainly by decreasing cell viability and proliferation. Furthermore, the combination of itraconazole and 5-fluorouracil seemed to be the most effective, being an interesting focus in future studies. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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Review

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24 pages, 4138 KiB

Open AccessEditor’s ChoiceReview

Combination of Cell-Penetrating Peptides with Nanoparticles for Therapeutic Application: A Review

by Sara Silva, António J. Almeida and Nuno Vale

Biomolecules 2019, 9(1), 22; https://doi.org/10.3390/biom9010022 - 10 Jan 2019

Cited by 160 | Viewed by 13843

Abstract

Cell-penetrating peptides (CPPs), also known as protein translocation domains, membrane translocating sequences or Trojan peptides, are small molecules of 6 to 30 amino acid residues capable of penetrating biological barriers and cellular membranes. Furthermore, CPP have become an alternative strategy to overcome some of the current drug limitations and combat resistant strains since CPPs are capable of delivering different therapeutic molecules against a wide range of diseases. In this review, we address the recent conjugation of CPPs with nanoparticles, which constitutes a new class of delivery vectors with high pharmaceutical potential in a variety of diseases. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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