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Special Issue "Anticancer Drug Discovery and Development"

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

Deadline for manuscript submissions: 30 September 2020.

Special Issue Editors

Dr. Bartosz Tylkowski
Website
Guest Editor
Eurecat, Centre Tecnològic de Catalunya, tarragona, Spain
Interests: Encapsulation technology for medical and consumer goods applications
Special Issues and Collections in MDPI journals
Prof. Dr. Anna Bajek
Website
Guest Editor
Ludwik Rydygier Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
Interests: anticancer therapy, personalized oncology, new drug development, microbiome, immunotherapy, cancer microenvironment, cancer cells culture, cancer stem cells, ILCs
Prof. Dr. Krzysztof Roszkowski
Website
Guest Editor
Department of Oncology, Collegium Medicum Nicolaus Copernicus University Bydgoszcz, PL
Interests: molecular markers of the effectiveness of oncological treatment; epigenetic factors affecting clinical decisions
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a serious problem that presents a huge threat to human health. Global cancer statistics have predicted that the number of cancer cases will constantly increase. During the last few years, there has been continued progress in anticancer drug development. New agents ranging from small molecules to engineered antibodies and immune modulators have been approved for cancer treatment. However, many of these drugs still cause serious adverse side effects. Targeting drugs specifically to cancer cells can minimize the toxic effects on normal, healthy cells.

This Special Issue on “Anticancer drugs discovery and development” aims to be an open forum where researchers may share their experiences and findings in this promising field. It is focused on the discovery and development of new therapeutic agents for cancer, using the newest techniques of biotechnology, pharmacology, and genetic engineering. Contributions to this issue, in the form of both original research and review articles, may cover all aspects of new anticancer approaches, including three-dimensional tumor models, nanotechnology, bio-printing, and molecular imaging.

Dr. Bartosz Tylkowski
Prof. Dr. Anna Bajek
Prof. Dr. Krzysztof Roszkowski
Guest Editors

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 semimonthly 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 2000 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

  • Anticancer therapy
  • Drug development
  • Personalized cancer treatment
  • nanotechnology
  • 3D tumor models
  • Drug resistance in cancer
  • Molecular imaging

Published Papers (11 papers)

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Research

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Open AccessArticle
The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer
Molecules 2020, 25(13), 3045; https://doi.org/10.3390/molecules25133045 - 03 Jul 2020
Abstract
Background: Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids—piperlongumine (PL), sanguinarine (SAN) and their combination—on the [...] Read more.
Background: Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids—piperlongumine (PL), sanguinarine (SAN) and their combination—on the basic life processes of the A549 cell line was considered reasonable. Methods: The aim was achieved by analyzing the cytotoxic effects of PL and SAN and their combination in the ratio of 4:1 on the induction of cell death, changes in the distribution of cell cycle phases, reorganization of cytoskeleton and metastatic potential of A549 cells. The versatility of the applied concentration ratio was evaluated in terms of other cancer cell lines: MCF-7, H1299 and HepG2. Results: The results obtained from the MTT assay indicated that the interaction between the alkaloids depends on the concentration and type of cells. Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells. The combined effects of PL and SAN increased apoptosis and favored metastasis inhibition. Conclusion: Selected alkaloids exhibit a cytotoxic effect on A549 cells. In turn, treatment with the combination of PL and SAN in a 4:1 ratio indicates a synergistic effect and is associated with an increase in the level of reactive oxygen species (ROS). Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
Open AccessArticle
Sesquiterpene Lactones from Calea pinnatifida: Absolute Configuration and Structural Requirements for Antitumor Activity
Molecules 2020, 25(13), 3005; https://doi.org/10.3390/molecules25133005 - 30 Jun 2020
Abstract
This work describes the chromatographic fractionation of the aerial parts of Calea pinnatifida and the structural characterization and determination of the absolute configuration of the isolated compounds as well as their antitumor potential. The HPLC fractionation of the CH2Cl2 phase [...] Read more.
This work describes the chromatographic fractionation of the aerial parts of Calea pinnatifida and the structural characterization and determination of the absolute configuration of the isolated compounds as well as their antitumor potential. The HPLC fractionation of the CH2Cl2 phase of the MeOH extract from the leaves of C. pinnatifida led to the isolation of two related sesquiterpene lactones (STLs): calein C (1) and calealactone B (2). Additionally, during the purification process, a derivative of calein C (3) was formed as a product of the Michael addition of MeOH. The structures of Compounds 13 were established based on spectroscopic and spectrometric data, while the absolute stereochemistry was established by vibrational circular dichroism. In order to evaluate the effect of the conjugated double bonds on the cytotoxic activity of STLs, Compounds 13 were tested against anaplastic (KTC-2) and papillary (TPC-1) thyroid carcinoma cells. Calein C was the most active of the STLs, and displayed activity against both KTC-2 and TPC-1. On the other hand, the calein C derivative (3) was the least cytotoxic of all the compounds tested. These results are promising and suggest the importance of studying sesquiterpene lactones isolated from C. pinnatifida in terms of antitumor activity, especially considering the effects of α,β-unsaturated carbonyl systems. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Open AccessArticle
Tumoricidal Potential of Novel Amino-1,10-phenanthroline Derived Imine Ligands: Chemical Preparation, Structure, and Biological Investigations
Molecules 2020, 25(12), 2865; https://doi.org/10.3390/molecules25122865 - 22 Jun 2020
Abstract
Herein we report the synthesis and structural elucidation of two novel imine-based ligands, 2-(1,10-phenanthrolin-5-yl)imino)methyl)-5-bromophenol (PIB) and N-(1,10-phenanthrolin-5-yl)-1-(thiophen-3-yl)methanimine (PTM) ligands. An in vitro cytotoxicity assay of the synthesized molecules was carried out against breast, cervical, colorectal, and prostate cancer cell lines as well [...] Read more.
Herein we report the synthesis and structural elucidation of two novel imine-based ligands, 2-(1,10-phenanthrolin-5-yl)imino)methyl)-5-bromophenol (PIB) and N-(1,10-phenanthrolin-5-yl)-1-(thiophen-3-yl)methanimine (PTM) ligands. An in vitro cytotoxicity assay of the synthesized molecules was carried out against breast, cervical, colorectal, and prostate cancer cell lines as well as immortalized human keratinocytes. The observations indicated that both the molecules possesses dose-dependent selective cytotoxicity of cancer cells with no detrimental effect on the normal cell lines. Furthermore, the detailed computational analysis of newly synthetized ligands (PIB and PTM) has been conducted in order to identify their most important parts from the perspective of local reactivity. The IC50 values of PIB treatment on MCF-7, HeLa, HCT-116 and PC-3 were 15.10, 16.25, 17.88, 17.55 and 23.86 micromoles, respectively. Meanwhile, the IC50 values of PTM on MCF-7, HeLa, HCT-116, PC-3 and HaCat were observed to be 14.82, 15.03, 17.88, 17.28 and 21.22 micromoles, respectively. For computational analysis, we have employed the combination of Density Functional Theory (DFT) calculations and MD simulations. DFT calculations provided us with information about structure and reactivity descriptors based on the electron distribution. Surfaces of molecular electrostatic potential (MEP) and averaged local ionization energy (ALIE) indicated the sites within studied molecules that are most reactive. These results indicated the importance of nitrogen atoms and OH group. Additionally, the values of bond dissociation for hydrogen abstraction showed that both molecules, especially the PTM, are stable toward the influence of autoxidation mechanism. On the other side, MD simulations gave us an insight how ligands interact with water molecules. Namely, the radial distribution functions (RDF) indicated that the hydrogen atom of the OH group in the case of the PIB has the most pronounced interactions with water. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Open AccessArticle
Antitumor Activity of New Olivacine Derivatives
Molecules 2020, 25(11), 2512; https://doi.org/10.3390/molecules25112512 - 28 May 2020
Abstract
Olivacine is an alkaloid-containing pyridocarbazole structure. It is isolated from the bark of the evergreen timber tree, Aspidosperma olivaceum. Its well-documented anticancer activity led to the synthesis of new derivatives, which are semisynthetic and fully synthetic pyridocarbazoles. This study aimed to evaluate the [...] Read more.
Olivacine is an alkaloid-containing pyridocarbazole structure. It is isolated from the bark of the evergreen timber tree, Aspidosperma olivaceum. Its well-documented anticancer activity led to the synthesis of new derivatives, which are semisynthetic and fully synthetic pyridocarbazoles. This study aimed to evaluate the potential antineoplastic activity of four newly synthesized olivacine derivatives. Multidrug resistance is a common phenomenon causing failure in the chemotherapy of many tumors. It is mainly related to increased function of P-glycoprotein, an efflux pump removing cytostatic out of the cells. The cell lines used in the study were colorectal carcinoma cell lines: LoVo (doxorubicin-sensitive) and LoVo/DX (doxorubicin-resistant). The NHDF cell line was used to assess cell viability. First, the cells were incubated with olivacine derivatives. In the next step, the following assays were performed: DCF-DA assay, MTT assay, rhodamine 123 assay, detection of apoptosis, proliferation inhibition-mitotic index. The tested compounds showed higher antineoplastic potential and lower toxicity than the reference compound ellipticine. The results indicate that the new olivacine derivatives are good candidates for future anticancer drugs. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Open AccessArticle
Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors
Molecules 2020, 25(9), 2220; https://doi.org/10.3390/molecules25092220 - 08 May 2020
Abstract
Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in [...] Read more.
Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in AML, which has a central role in the regulation of apoptosis and cell proliferation through client proteins including the growth factor receptors and cyclin dependent kinases. The objective of the first part of this study is to investigate the putative Hsp90 inhibition activity of three novel previously synthesized quinazolines, which showed HL60 cytotoxicity and VEGFR2 and EGFR kinases inhibition activities. Using surface plasmon resonance, compound 1 (HAA2020) showed better Hsp90 inhibition compared to 17-AAG, and a docking study revealed that it fits nicely into the ATPase site. The objective of the second part is to maximize the anti-leukemic activity of HAA2020, which was combined with each of the eleven standard inhibitors. The best resulting synergistic effect in HL60 cells was with the pan cyclin-dependent kinases (CDK) inhibitor dinaciclib, using an MTT assay. Furthermore, the inhibiting effect of the Hsp90α gene by the combination of HAA2020 and dinaciclib was associated with increased caspase-7 and TNF-α, leading to apoptosis in HL60 cells. In addition, the combination upregulated p27 simultaneously with the inhibition of cyclinD3 and CDK2, leading to abolished HL60 proliferation and survival. The actions of HAA2020 propagated the apoptotic and cell cycle control properties of dinaciclib, showing the importance of co-targeting Hsp90 and CDK, which could lead to the better management of leukemia. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Open AccessArticle
A Tryptophan Metabolite, 8-Hydroxyquinaldic Acid, Exerts Antiproliferative and Anti-Migratory Effects on Colorectal Cancer Cells
Molecules 2020, 25(7), 1655; https://doi.org/10.3390/molecules25071655 - 03 Apr 2020
Cited by 1
Abstract
8-Hydroxyquinaldic acid, the end-metabolite of tryptophan, is well-known metal chelator; however, its role in humans, especially in cancer promotion and progression, has not been fully revealed. Importantly, 8-hydroxyquinaldic acid is the analog of kynurenic acid with evidenced antiproliferative activity towards various cancer cells. [...] Read more.
8-Hydroxyquinaldic acid, the end-metabolite of tryptophan, is well-known metal chelator; however, its role in humans, especially in cancer promotion and progression, has not been fully revealed. Importantly, 8-hydroxyquinaldic acid is the analog of kynurenic acid with evidenced antiproliferative activity towards various cancer cells. In this study, we revealed that 8-hydroxyquinaldic acid inhibited not only proliferation and mitochondrial activity in colon cancer HT-29 and LS-180 cells, but it also decreased DNA synthesis up to 90.9% for HT-29 cells and 76.1% for LS-180 cells. 8-Hydroxyquinaldic acid induced changes in protein expression of cell cycle regulators (CDK4, CDK6, cyclin D1, cyclin E) and CDKs inhibitors (p21 Waf1/Cip1, p27 Kip1), but the effect was dependent on the tested cell line. Moreover, 8-hydroxyquinaldic acid inhibited migration of colon cancer HT-29 and LS-180 cells and increased the expression of β-catenin and E-cadherin. Importantly, antiproliferative and anti-migratory concentrations of 8-hydroxyquinaldic acid were non-toxic in vitro and in vivo. We reported for the first time antiproliferative and anti-migratory activity of 8-hydroxyquinaldic acid against colon cancer HT-29 and LS-180 cells. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Open AccessArticle
Thermodynamic and Spectroscopic Studies of the Complexes Formed in Tartaric Acid and Lanthanide(III) Ions Binary Systems
Molecules 2020, 25(5), 1121; https://doi.org/10.3390/molecules25051121 - 03 Mar 2020
Abstract
Binary complexes of tartaric acid with lanthanide(III) ions were investigated. The studies have been performed in aqueous solution using the potentiometric method with computer analysis of the data for detection of the complexes set, determination of the stability constants of these compounds. The [...] Read more.
Binary complexes of tartaric acid with lanthanide(III) ions were investigated. The studies have been performed in aqueous solution using the potentiometric method with computer analysis of the data for detection of the complexes set, determination of the stability constants of these compounds. The mode of the coordination of complexes found was determined using spectroscopy, which shows: Infrared, circular dichroism, ultraviolet, visible as well as luminescence spectroscopy. The overall stability constants of the complexes as well as the equilibrium constants of the reaction were determined. Analysis of the equilibrium constants of the reactions and spectroscopic data allowed the effectiveness of the carboxyl groups in the process of complex formation. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Open AccessArticle
Conjugation of Aspergillus flavipes Taxol with Porphyrin Increases the Anticancer Activity of Taxol and Ameliorates Its Cytotoxic Effects
Molecules 2020, 25(2), 263; https://doi.org/10.3390/molecules25020263 - 09 Jan 2020
Cited by 1
Abstract
Taxol is one of the potential anticancer drugs; however, the yield of Taxol and its cytotoxicity are common challenges. Thus, manipulating the Taxol biosynthetic pathway from endophytic fungi, in addition to chemical modification with biocompatible polymers, is the challenge. Four fungal isolates, namely, [...] Read more.
Taxol is one of the potential anticancer drugs; however, the yield of Taxol and its cytotoxicity are common challenges. Thus, manipulating the Taxol biosynthetic pathway from endophytic fungi, in addition to chemical modification with biocompatible polymers, is the challenge. Four fungal isolates, namely, Aspergillus flavipes, A. terreus, A. flavus, and A. parasiticus, were selected from our previous study as potential Taxol producers, and their potency for Taxol production was evaluated in response to fluconazole and silver nitrate. A higher Taxol yield was reported in the cultures of A. flavipes (185 µg/L) and A. terreus (66 µg/L). With addition of fluconazole, the yield of Taxol was increased 1.8 and 1.2-fold for A. flavipes and A. terreus, respectively, confirming the inhibition of sterol biosynthesis and redirecting the geranyl phosphate pool to terpenoids synthesis. A significant inhibition of ergosterol biosynthesis by A. flavipes with addition of fluconazole was observed, correlating with the increase on Taxol yield. To increase the Taxol solubility and to reduce its cytotoxicity, Taxol was modified via chemical conjugation with porphyrin, and the degree of conjugation was checked from the Thin layer chromatography and UV spectral analysis. The antiproliferative activity of native and modified Taxol conjugates was evaluated; upon porphyrin conjugation, the activity of Taxol towards HepG2 was increased 1.5-fold, while its cytotoxicity to VERO cells was reduced 3-fold. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Open AccessArticle
Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy
Molecules 2019, 24(24), 4589; https://doi.org/10.3390/molecules24244589 - 15 Dec 2019
Cited by 8
Abstract
Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. [...] Read more.
Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2 in-complex with the selected compound. We found that binding of 6-N,6-N-dimethyl-9-(2-phenylethyl)purine-2,6-diamine stabilizes the structure of CDK2 and causes minimal conformational change. Finally, we suggest that the compound (PubChem ID 101874157) would be a promising scaffold to be further exploited as a potential inhibitor of CDK2 for therapeutic management of cancer after required validation. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Review

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Open AccessReview
Use of Fluorescence In Situ Hybridization (FISH) in Diagnosis and Tailored Therapies in Solid Tumors
Molecules 2020, 25(8), 1864; https://doi.org/10.3390/molecules25081864 - 17 Apr 2020
Abstract
Fluorescence in situ hybridization (FISH) is a standard technique used in routine diagnostics of genetic aberrations. Thanks to simple FISH procedure is possible to recognize tumor-specific abnormality. Its applications are limited to designed probe type. Gene rearrangements e.g., ALK, ROS1 reflecting numerous [...] Read more.
Fluorescence in situ hybridization (FISH) is a standard technique used in routine diagnostics of genetic aberrations. Thanks to simple FISH procedure is possible to recognize tumor-specific abnormality. Its applications are limited to designed probe type. Gene rearrangements e.g., ALK, ROS1 reflecting numerous translocational partners, deletions of critical regions e.g., 1p and 19q, gene fusions e.g., COL1A1-PDGFB, genomic imbalances e.g., 6p, 6q, 11q and amplifications e.g., HER2 are targets in personalized oncology. Confirmation of genetic marker is frequently a direct indication to start specific, targeted treatment. In other cases, detected aberration helps pathologists to better distinguish soft tissue sarcomas, or to state a final diagnosis. Our main goal is to show that applying FISH to formalin-fixed paraffin-embedded tissue sample (FFPE) enables assessing genomic status in the population of cells deriving from a primary tumor or metastasis. Although many more sophisticated techniques are available, like Real-Time PCR or new generation sequencing, FISH remains a commonly used method in many genetic laboratories. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Open AccessReview
Encapsulation for Cancer Therapy
Molecules 2020, 25(7), 1605; https://doi.org/10.3390/molecules25071605 - 31 Mar 2020
Cited by 1
Abstract
The current rapid advancement of numerous nanotechnology tools is being employed in treatment of many terminal diseases such as cancer. Nanocapsules (NCs) containing an anti-cancer drug offer a very promising alternative to conventional treatments, mostly due to their targeted delivery and precise action, [...] Read more.
The current rapid advancement of numerous nanotechnology tools is being employed in treatment of many terminal diseases such as cancer. Nanocapsules (NCs) containing an anti-cancer drug offer a very promising alternative to conventional treatments, mostly due to their targeted delivery and precise action, and thereby they can be used in distinct applications: as biosensors or in medical imaging, allowing for cancer detection as well as agents/carriers in targeted drug delivery. The possibility of using different systems—inorganic nanoparticles, dendrimers, proteins, polymeric micelles, liposomes, carbon nanotubes (CNTs), quantum dots (QDs), biopolymeric nanoparticles and their combinations—offers multiple benefits to early cancer detection as well as controlled drug delivery to specific locations. This review focused on the key and recent progress in the encapsulation of anticancer drugs that include methods of preparation, drug loading and drug release mechanism on the presented nanosystems. Furthermore, the future directions in applications of various nanoparticles are highlighted. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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