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New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 March 2020) | Viewed by 54482

Special Issue Editors

Dr. Carlos Martínez-Campa

E-Mail Website
Guest Editor
Department of Physiology and Pharmacology, University of Cantabria, Santander, Spain
Interests: melatonin; breast cancer; chemotherapy; radiotherapy; apoptosis; angiogenesis; gene expression
Special Issues, Collections and Topics in MDPI journals
Dr. Carolina Alonso-González

E-Mail Website
Guest Editor
Department of Physiology and Pharmacology, University of Cantabria, 39011 Santander, Spain
Interests: melatonin and mammary cancer

Special Issue Information

Dear Colleagues,

Cancer is a group of diseases characterized by abnormal growth and proliferation of cells which, in most cases, forms a tumor. Primary tumor growth is often accompanied by angiogenesis, progression, and metastasis. Some cancers are hormone-independent, whilst others are responsive to hormones (principally, sexual hormones in breast, prostate, and ovary cancers). For both hormone-dependent and independent cancers, the effectiveness of cytotoxic drugs is limited, and their use is often accompanied by severe adverse effects, leading to the continuous search for “next-generation” compounds and/or delivery strategies. Over the past two decades, great effort has been made to develop new effective therapies. In the case of hormone-dependent cancers, hormone antagonists, inhibitors, and analogues are currently used. In addition, emerging knowledge about the molecular mechanisms involved in the generation and progression of tumors has led to the design of promising therapies against specific molecular targets. The combination of hormonal analogues, classic or new-generation cytotoxic drugs, and targeted therapies (small RNAs, monoclonal antibodies) with new forms of drug delivery will hopefully have future successful application in cancer treatment.

This Special Issue “New strategies in cancer pharmacotherapy: Development of hormonal antineoplastic drugs, cytotoxic drugs and targeted therapies” will include reviews and original research on advances in cancer treatment. Novel insights into the development and assay of new compounds either alone or in combination are of particular interest for this issue.

Dr. Carlos Martínez-Campa
Dr. Carolina Alonso-González
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 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 treatment
  • hormone analogues
  • targeted therapy
  • chemotherapy
  • cytotoxic drugs
  • signaling pathways
  • gene expresión
  • angiogénesis
  • metastasis

Published Papers (15 papers)

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Editorial

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4 pages, 192 KiB  
Editorial
Editorial for the Special Issue “New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies”
by Carlos Martínez-Campa and Carolina Alonso-González
Int. J. Mol. Sci. 2020, 21(11), 4081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114081 - 08 Jun 2020
Cited by 2 | Viewed by 1606
Abstract
The Special Issue entitled “New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies” was conceived with the idea of compiling information on the latest advances in the treatment of both hormone-dependent and hormone-independent cancers [...] Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)

Research

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19 pages, 5795 KiB  
Article
Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment
by Anne-Kathrin Noack, Henrike Lucas, Petr Chytil, Tomáš Etrych, Karsten Mäder and Thomas Mueller
Int. J. Mol. Sci. 2020, 21(17), 6029; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176029 - 21 Aug 2020
Cited by 3 | Viewed by 2349
Abstract
Stimulus-sensitive polymer drug conjugates based on high molecular weight N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers carrying doxorubicin via a pH-dependent cleavable bond (pHPMA-Dox) were previously shown to be able to overcome multi-drug resistance. Nevertheless, a tumor type dependent differential response was observed. Although an improved [...] Read more.
Stimulus-sensitive polymer drug conjugates based on high molecular weight N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers carrying doxorubicin via a pH-dependent cleavable bond (pHPMA-Dox) were previously shown to be able to overcome multi-drug resistance. Nevertheless, a tumor type dependent differential response was observed. Although an improved and more selective tumor accumulation of pHPMA-Dox is generally achieved due to the enhanced permeability and retention (EPR) effect, little is known about the fate of these conjugates upon entering the tumor tissue, which could explain the different responses. In this study, we compared in vitro and in vivo accumulation and Dox-activation of pHPMA-Dox in three cancer cell line models (1411HP, A2780cis, HT29) and derived xenograft tumors using a near-infrared fluorescence-labeled pHPMA-Dox conjugate. Firstly, cytotoxicity assays using different pH conditions proved a stepwise, pH-dependent increase in cytotoxic activity and revealed comparable sensitivity among the cell lines. Using multispectral fluorescence microscopy, we were able to track the distribution of drug and polymeric carrier simultaneously on cellular and histological levels. Microscopic analyses of cell monolayers confirmed the assumed mechanism of cell internalization of the whole conjugate followed by intracellular cleavage and nuclear accumulation of Dox in all three cell lines. In contrast, intratumoral distribution and drug release in xenograft tumors were completely different and were associated with different tissue substructures and microenvironments analyzed by Azan- and Hypoxisense®-staining. In 1411HP tumors, large vessels and less hypoxic/acidic microenvironments were associated with a pattern resulting from consistent tissue distribution and cellular uptake as whole conjugate followed by intracellular drug release. In A2780cis tumors, an inconsistent pattern of distribution partly resulting from premature drug release was associated with a more hypoxic/acidic microenvironment, compacted tumor tissue with compressed vessels and specific pre-damaged tissue structures. A completely different distribution pattern was observed in HT29 tumors, resulting from high accumulation of polymer in abundant fibrotic structures, with small embedded vessels featuring this tumor type together with pronounced premature drug release due to the strongly hypoxic/acidic microenvironment. In conclusion, the pattern of intratumoral distribution and drug release strongly depends on the tumor substructure and microenvironment and may result in different degrees of therapeutic efficacy. This reflects the pronounced heterogeneity observed in the clinical application of nanomedicines and can be exploited for the future design of such conjugates. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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17 pages, 2904 KiB  
Article
Ring-Substituted 1-Hydroxynaphthalene-2-Carboxanilides Inhibit Proliferation and Trigger Mitochondria-Mediated Apoptosis
by Tereza Kauerová, Tomáš Goněc, Josef Jampílek, Susanne Hafner, Ann-Kathrin Gaiser, Tatiana Syrovets, Radek Fedr, Karel Souček and Peter Kollar
Int. J. Mol. Sci. 2020, 21(10), 3416; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103416 - 12 May 2020
Cited by 8 | Viewed by 2692
Abstract
Ring-substituted 1-hydroxynaphthalene-2-carboxanilides were previously investigated for their antimycobacterial properties. In our study, we have shown their antiproliferative and cell death-inducing effects in cancer cell lines. Cell proliferation and viability were assessed by WST-1 assay and a dye exclusion test, respectively. Cell cycle distribution, [...] Read more.
Ring-substituted 1-hydroxynaphthalene-2-carboxanilides were previously investigated for their antimycobacterial properties. In our study, we have shown their antiproliferative and cell death-inducing effects in cancer cell lines. Cell proliferation and viability were assessed by WST-1 assay and a dye exclusion test, respectively. Cell cycle distribution, phosphatidylserine externalization, levels of reactive oxygen or nitrogen species (RONS), mitochondrial membrane depolarization, and release of cytochrome c were estimated by flow cytometry. Levels of regulatory proteins were determined by Western blotting. Our data suggest that the ability to inhibit the proliferation of THP-1 or MCF-7 cells might be referred to meta- or para-substituted derivatives with electron-withdrawing groups -F, -Br, or -CF3 at anilide moiety. This effect was accompanied by accumulation of cells in G1 phase. Compound 10 also induced apoptosis in THP-1 cells in association with a loss of mitochondrial membrane potential and production of mitochondrial superoxide. Our study provides a new insight into the action of salicylanilide derivatives, hydroxynaphthalene carboxamides, in cancer cells. Thus, their structure merits further investigation as a model moiety of new small-molecule compounds with potential anticancer properties. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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16 pages, 4225 KiB  
Article
The Effect of 3′-Hydroxy-3,4,5,4′-Tetramethoxy -stilbene, the Metabolite of the Resveratrol Analogue DMU-212, on the Motility and Proliferation of Ovarian Cancer Cells
by Andrzej Nowicki, Paulina Skupin-Mrugalska, Malgorzata Jozkowiak, Marcin Wierzchowski, Marcin Rucinski, Piotr Ramlau, Violetta Krajka-Kuzniak, Jadwiga Jodynis-Liebert and Hanna Piotrowska-Kempisty
Int. J. Mol. Sci. 2020, 21(3), 1100; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031100 - 07 Feb 2020
Cited by 8 | Viewed by 2875
Abstract
Targeting tumor cell motility and proliferation is an extremely important challenge in the prevention of metastasis and improving the effectiveness of cancer treatment. We recently published data revealing that DMU-214, the metabolite of firmly cytotoxic resveratrol analogue DMU-212, exerted significantly higher biological activity [...] Read more.
Targeting tumor cell motility and proliferation is an extremely important challenge in the prevention of metastasis and improving the effectiveness of cancer treatment. We recently published data revealing that DMU-214, the metabolite of firmly cytotoxic resveratrol analogue DMU-212, exerted significantly higher biological activity than the parent compound in ovarian cancer cells. The aim of the present study was to assess the molecular mechanism of the potential anti-migration and anti-proliferative effect of DMU-214 in ovarian cancer cell line SKOV-3. We showed that DMU-214 reduced the migratory capacity of SKOV-3 cells. The microarray analysis indicated ontology groups of genes involved in processes of negative regulation of cell motility and proliferation. Furthermore, we found DMU-214 triggered changes in expression of several migration- and proliferation-related genes (SMAD7, THBS1, IGFBP3, KLF4, Il6, ILA, SOX4, IL15, SRF, RGCC, GPR56) and proteins (GPR56, RGCC, SRF, SMAD7, THBS1), which have been shown to interact to each other to reduce cell proliferation and motility. Our study showed for the first time that DMU-214 displayed anti-migratory and anti-proliferative activity in SKOV-3 ovarian cancer cells. On the basis of whole transcriptome analysis of these cells, we provide new insight into the role of DMU-214 in inhibition of processes related to metastasis. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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11 pages, 3080 KiB  
Article
The Amuvatinib Derivative, N-(2H-1,3-Benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, Inhibits Mitochondria and Kills Tumor Cells under Glucose Starvation
by Ran Marciano, Hila Ben David, Barak Akabayov and Barak Rotblat
Int. J. Mol. Sci. 2020, 21(3), 1041; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031041 - 04 Feb 2020
Cited by 3 | Viewed by 2794
Abstract
Glucose levels inside solid tumors are low as compared with normal surrounding tissue, forcing tumor cells to reprogram their metabolism to adapt to such low glucose conditions. Unlike normal tissue, tumor cells experience glucose starvation, making the targeting of pathways supporting survival during [...] Read more.
Glucose levels inside solid tumors are low as compared with normal surrounding tissue, forcing tumor cells to reprogram their metabolism to adapt to such low glucose conditions. Unlike normal tissue, tumor cells experience glucose starvation, making the targeting of pathways supporting survival during glucose starvation an interesting therapeutic strategy in oncology. Using high-throughput screening, we previously identified small molecules that selectively kill cells exposed to glucose starvation. One of the identified compounds was the kinase inhibitor amuvatinib. To identify new molecules with potential antineoplastic activity, we procured 12 amuvatinib derivatives and tested their selective toxicity towards glucose-starved tumor cells. One of the amuvatinib derivatives, N-(2H-1,3-benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, termed compound 6, was found to be efficacious in tumor cells experiencing glucose starvation. In line with the known dependence of glucose-starved cells on the mitochondria, compound 6 inhibits mitochondrial membrane potential. These findings support the concept that tumor cells are dependent on mitochondria under glucose starvation, and bring forth compound 6 as a new molecule with potential antitumor activity for the treatment of glucose-starved tumors. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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17 pages, 2951 KiB  
Article
The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma
by Verena Boschert, Nicola Klenk, Alexander Abt, Sudha Janaki Raman, Markus Fischer, Roman C. Brands, Axel Seher, Christian Linz, Urs D. A. Müller-Richter, Thorsten Bischler and Stefan Hartmann
Int. J. Mol. Sci. 2020, 21(2), 471; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020471 - 11 Jan 2020
Cited by 18 | Viewed by 3307
Abstract
Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Methigh-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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20 pages, 2884 KiB  
Article
Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment
by Ewelina Dratkiewicz, Aleksandra Simiczyjew, Katarzyna Pietraszek-Gremplewicz, Justyna Mazurkiewicz and Dorota Nowak
Int. J. Mol. Sci. 2020, 21(1), 113; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010113 - 23 Dec 2019
Cited by 34 | Viewed by 4384
Abstract
Constitutively active mutated BRAF kinase occurs in more than 40% of patients suffering from melanoma. To block its activity, a specific inhibitor, vemurafenib, is applied as a therapy. Unfortunately, patients develop resistance to this drug rather quickly. Previously, we demonstrated that pairs of [...] Read more.
Constitutively active mutated BRAF kinase occurs in more than 40% of patients suffering from melanoma. To block its activity, a specific inhibitor, vemurafenib, is applied as a therapy. Unfortunately, patients develop resistance to this drug rather quickly. Previously, we demonstrated that pairs of inhibitors directed against EGFR (epidermal growth factor receptor) and MET (hepatocyte growth factor receptor) trigger a synergistic cytotoxic effect in human melanoma cells, and decrease their invasive abilities. In this study, we aimed to generate and characterize melanoma cells resistant to vemurafenib treatment, and then to evaluate the effectiveness of a previously developed therapy in this model. We showed that melanoma cells resistant to the BRAF inhibitor are characterized by a lower proliferation rate and they acquire a spindle-like shape. Using Western Blot, we also noticed increased levels of EGFR, MET, and selected markers of cancer stem cells in generated cell lines. Resistant cells also exhibited increased invasive abilities and elevated proteolytic activity, observed using scratch wound assays and gelatin zymography. Moreover, combination therapy reduced their viability, as measured with a colorimetric cytotoxicity test, and decreased invasiveness. The obtained results validate the application of combination therapy directed against EGFR and MET in melanoma cells resistant to treatment with inhibitors of mutated BRAF. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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15 pages, 4573 KiB  
Article
Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment
by Hui-I Yu, Hui-Ching Shen, Shu-Hsin Chen, Yun-Ping Lim, Hsiang-Hsun Chuang, Tsai-Sung Tai, Fang-Ping Kung, Chieh-Hsiang Lu, Chia-Yi Hou and Ying-Ray Lee
Int. J. Mol. Sci. 2019, 20(21), 5315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215315 - 25 Oct 2019
Cited by 20 | Viewed by 2956
Abstract
Aloperine, an alkaloid isolated from Sophora alopecuroides, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, [...] Read more.
Aloperine, an alkaloid isolated from Sophora alopecuroides, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, including multiple myeloma; colon, breast, and prostate cancers; and osteosarcoma. Cell cycle arrest, apoptosis induction, and tumorigenesis suppression have been demonstrated following aloperine treatment. In a previous study, we demonstrated antitumor effects of aloperine on human thyroid cancer cells through anti-tumorigenesis and caspase-dependent apoptosis induction via the Akt signaling pathway. In the present study, we demonstrated the modulation of the autophagy mechanism following the incubation of multidrug-resistant papillary and anaplastic human thyroid cancer cells with aloperine; we also illustrate the underlying mechanisms, including AMPK, Erk, JNK, p38, and Akt signaling pathways. Further investigation revealed the involvement of the Akt signaling pathway in aloperine-modulated autophagy in human thyroid cancer cells. These results indicate a previously unappreciated function of aloperine in autophagy modulation in human thyroid cancer cells. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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24 pages, 7194 KiB  
Article
Mixed-Generation PAMAM G3-G0 Megamer as a Drug Delivery System for Nimesulide: Antitumor Activity of the Conjugate Against Human Squamous Carcinoma and Glioblastoma Cells
by Magdalena Zaręba, Przemysław Sareło, Marta Kopaczyńska, Agata Białońska, Łukasz Uram, Małgorzata Walczak, David Aebisher and Stanisław Wołowiec
Int. J. Mol. Sci. 2019, 20(20), 4998; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20204998 - 09 Oct 2019
Cited by 12 | Viewed by 3597
Abstract
Polyhydroxylated dendrimer was synthesized from poly(amidoamine) (PAMAM) dendrimer generation 3 by addition of glycidol (G3gl). G3gl megamer was further modified by binding PAMAM G0 dendrimers by activation of G3gl with p-nitrophenylchloroformate, followed by the addition of excess [...] Read more.
Polyhydroxylated dendrimer was synthesized from poly(amidoamine) (PAMAM) dendrimer generation 3 by addition of glycidol (G3gl). G3gl megamer was further modified by binding PAMAM G0 dendrimers by activation of G3gl with p-nitrophenylchloroformate, followed by the addition of excess PAMAM G0 and purification using dialysis. The maximum G0 binding capacity of G3gl was 12 in the case when G0 was equipped with two covalently attached nimesulide equivalents. Nimesulide (N) was converted into N-(p-nitrophenyl) carbonate derivative and fully characterized using X-ray crystallography and spectral methods. Nimesulide was then attached to G0 via a urea bond to yield G02N. The mixed generation G3gl–G02N megamer was characterized using 1H NMR spectroscopy, and its molecular weight was estimated to be 22.4 kDa. The AFM image of G3gl–G02N deposited on mica demonstrated aggregation of nimesulide-covered megamer. The height of the deposited megamer was 8.5 nm. The megameric conjugate with nimesulide was tested in vitro on three human cell lines: squamous cell carcinoma (SCC-15) and glioblastoma (U-118 MG) overexpressing cyclooxygenase-2 (COX-2), and normal skin fibroblasts (BJ). The conjugate efficiently penetrated into all cells and was more cytotoxic against SCC-15 than against BJ. Moreover, the conjugate produced a strong and selective antiproliferative effect on both cancer cell lines (IC50 < 7.5 µM). Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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13 pages, 1819 KiB  
Article
Extracellular Albumin Covalently Sequesters Selenocompounds and Determines Cytotoxicity
by Wenyi Zheng, Roberto Boada, Rui He, Tingting Xiao, Fei Ye, Laura Simonelli, Manuel Valiente, Ying Zhao and Moustapha Hassan
Int. J. Mol. Sci. 2019, 20(19), 4734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194734 - 24 Sep 2019
Cited by 6 | Viewed by 3097
Abstract
Selenocompounds (SeCs) are well-known nutrients and promising candidates for cancer therapy; however, treatment efficacy is very heterogeneous and the mechanism of action is not fully understood. Several SeCs have been reported to have albumin-binding ability, which is an important factor in determining the [...] Read more.
Selenocompounds (SeCs) are well-known nutrients and promising candidates for cancer therapy; however, treatment efficacy is very heterogeneous and the mechanism of action is not fully understood. Several SeCs have been reported to have albumin-binding ability, which is an important factor in determining the treatment efficacy of drugs. In the present investigation, we hypothesized that extracellular albumin might orchestrate SeCs efficacy. Four SeCs representing distinct categories were selected to investigate their cytotoxicity, cellular uptake, and species transformation. Concomitant treatment of albumin greatly decreased cytotoxicity and cellular uptake of SeCs. Using both X-ray absorption spectroscopy and hyphenated mass spectrometry, we confirmed the formation of macromolecular conjugates between SeCs and albumin. Although the conjugate was still internalized, possibly via albumin scavenger receptors expressed on the cell surface, the uptake was strongly inhibited by excess albumin. In summary, the present investigation established the importance of extracellular albumin binding in determining SeCs cytotoxicity. Due to the fact that albumin content is higher in humans and animals than in cell cultures, and varies among many patient categories, our results are believed to have high translational impact and clinical implications. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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18 pages, 3347 KiB  
Article
Melatonin Modulation of Radiation and Chemotherapeutics-induced Changes on Differentiation of Breast Fibroblasts
by Alicia González-González, Enrique García Nieto, Alicia González, Cristina Sánchez-Fernández, Carolina Alonso-González, Javier Menéndez-Menéndez, José Gómez-Arozamena, Samuel Cos and Carlos Martínez-Campa
Int. J. Mol. Sci. 2019, 20(16), 3935; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20163935 - 13 Aug 2019
Cited by 18 | Viewed by 3463
Abstract
Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the effects of docetaxel, vinorelbine, and radiation on human breast fibroblasts and its modulation by melatonin. Docetaxel or vinorelbine inhibits proliferation and stimulates the differentiation of [...] Read more.
Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the effects of docetaxel, vinorelbine, and radiation on human breast fibroblasts and its modulation by melatonin. Docetaxel or vinorelbine inhibits proliferation and stimulates the differentiation of breast preadipocytes, by increasing C/EBPα and PPARγ expression and by downregulating tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and IL-11 expression. Radiation inhibits both proliferation and differentiation through the downregulation of C/EBPα and PPARγ and by stimulating TNFα expression. In addition, docetaxel and radiation decrease aromatase activity and expression by decreasing aromatase promoter II and cyclooxygenases 1 and 2 (COX-1 and COX-2) expression. Melatonin potentiates the stimulatory effect of docetaxel and vinorelbine on differentiation and their inhibitory effects on aromatase activity and expression, by increasing the stimulatory effect on C/EBPα and PPARγ expression and the downregulation of antiadipogenic cytokines and COX expression. Melatonin also counteracts the inhibitory effect of radiation on differentiation of preadipocytes, by increasing C/EBPα and PPARγ expression and by decreasing TNFα expression. Melatonin also potentiates the inhibitory effect exerted by radiation on aromatase activity and expression by increasing the downregulation of promoter II, and COX-1 and COX-2 expression. Our findings suggest that melatonin modulates regulatory effects induced by chemotherapeutic drugs or radiation on preadipocytes, which makes it a promising adjuvant for chemotherapy and radiotherapy sensibilization. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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18 pages, 3251 KiB  
Article
The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein
by Ying Shen, Yi-Ming Li, Jing-Jing Zhou, Zhan Zhou, Ying-Chun Xu, Wen-Bin Zhao and Shu-Qing Chen
Int. J. Mol. Sci. 2019, 20(16), 3912; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20163912 - 12 Aug 2019
Cited by 9 | Viewed by 4882
Abstract
Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T [...] Read more.
Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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Review

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12 pages, 247 KiB  
Review
Opportunities for Antibody Discovery Using Human Pluripotent Stem Cells: Conservation of Oncofetal Targets
by Heng Liang Tan and Andre Choo
Int. J. Mol. Sci. 2019, 20(22), 5752; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225752 - 15 Nov 2019
Cited by 4 | Viewed by 2797
Abstract
Pluripotent stem cells (PSCs) comprise both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The application of pluripotent stem cells is divided into four main areas, namely: (i) regenerative therapy, (ii) the study and understanding of developmental biology, (iii) drug screening [...] Read more.
Pluripotent stem cells (PSCs) comprise both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The application of pluripotent stem cells is divided into four main areas, namely: (i) regenerative therapy, (ii) the study and understanding of developmental biology, (iii) drug screening and toxicology and (iv) disease modeling. In this review, we describe a new opportunity for PSCs, the discovery of new biomarkers and generating antibodies against these biomarkers. PSCs are good sources of immunogen for raising monoclonal antibodies (mAbs) because of the conservation of oncofetal antigens between PSCs and cancer cells. Hence mAbs generated using PSCs can potentially be applied in two different fields. First, these mAbs can be used in regenerative cell therapy to characterize the PSCs. In addition, the mAbs can be used to separate or eliminate contaminating or residual undifferentiated PSCs from the differentiated cell product. This step is critical as undifferentiated PSCs can form teratomas in vivo. The mAbs generated against PSCs can also be used in the field of oncology. Here, novel targets can be identified and the mAbs developed as targeted therapy to kill the cancer cells. Conversely, as new and novel oncofetal biomarkers are discovered on PSCs, cancer mAbs that are already approved by the FDA can be repurposed for regenerative medicine, thus expediting the route to the clinics. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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17 pages, 454 KiB  
Review
Current Possibilities of Gynecologic Cancer Treatment with the Use of Immune Checkpoint Inhibitors
by Ewelina Grywalska, Małgorzata Sobstyl, Lechosław Putowski and Jacek Roliński
Int. J. Mol. Sci. 2019, 20(19), 4705; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194705 - 23 Sep 2019
Cited by 44 | Viewed by 4807
Abstract
Despite the ongoing progress in cancer research, the global cancer burden has increased to 18.1 million new cases and 9.6 million deaths in 2018. Gynecological cancers, such as ovarian, endometrial, and cervical cancers, considerably contribute to global cancer burden, leading to $5,862.6, $2,945.7, [...] Read more.
Despite the ongoing progress in cancer research, the global cancer burden has increased to 18.1 million new cases and 9.6 million deaths in 2018. Gynecological cancers, such as ovarian, endometrial, and cervical cancers, considerably contribute to global cancer burden, leading to $5,862.6, $2,945.7, and $1,543.9 million of annual costs of cancer care, respectively. Thus, the development of effective therapies against gynecological cancers is still a largely unmet medical need. One of the novel therapeutic approaches is to induce anti-cancer immunity by the inhibition of the immune checkpoint pathways using monoclonal antibodies. The molecular targets for monoclonal antibodies are cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1). The rationale for the use of immune checkpoint inhibitors in patients with gynecological cancers was based on the immunohistological studies showing high expression levels of PD-1 and PD-L1 in those cancers. Currently available immune checkpoint inhibitors include nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab. The efficacy and safety of these inhibitors, used as monotherapy and with combination with chemotherapy, is being currently evaluated in several clinical studies. As the results are promising, more clinical trials are being planned, which may lead to the development of efficient therapies for gynecological cancer patients. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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17 pages, 1800 KiB  
Review
Phenformin as an Anticancer Agent: Challenges and Prospects
by Mª Eugenia García Rubiño, Esmeralda Carrillo, Gloria Ruiz Alcalá, Alicia Domínguez-Martín, Juan A. Marchal and Houria Boulaiz
Int. J. Mol. Sci. 2019, 20(13), 3316; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133316 - 05 Jul 2019
Cited by 55 | Viewed by 7892
Abstract
Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop [...] Read more.
Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug. Full article
(This article belongs to the Special Issue New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies)
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