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14 pages, 2281 KiB

Open AccessArticle

Anti-Multiple Myeloma Potential of Secondary Metabolites from Hibiscus sabdariffa—Part 2

by Alessio Malacrida, Valeria Cavalloro, Emanuela Martino, Giosuè Costa, Francesca Alessandra Ambrosio, Stefano Alcaro, Roberta Rigolio, Arianna Cassetti, Mariarosaria Miloso and Simona Collina

Molecules 2021, 26(21), 6596; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216596 - 31 Oct 2021

Cited by 11 | Viewed by 1739

Abstract

Multiple Myeloma (MM) is an aggressive tumor causing millions of deaths every year and currently available therapies are often unsuccessful or correlated with severe side effects. In our previous work we demonstrated that the Hibiscus sabdariffa hydroalcoholic extract inhibits the growth of the [...] Read more.

Multiple Myeloma (MM) is an aggressive tumor causing millions of deaths every year and currently available therapies are often unsuccessful or correlated with severe side effects. In our previous work we demonstrated that the Hibiscus sabdariffa hydroalcoholic extract inhibits the growth of the MM cell line and we isolated two metabolites responsible for the activity: Hib-ester and Hib-carbaldehyde. Herein we report their interaction with proteasome, one of the main targets in the fight against MM. The molecular modelling study outlined a good interaction of both compounds with the target and these results prompted us to investigate their potential to inhibit proteasome. Metabolites were then isolated from the calyces and an extract with a high content of Hib-ester and Hib-carbaldehyde was prepared. An anticancer profile was drawn, evaluating apoptosis, autophagy and proteasome inhibition, with the anticancer properties being mainly attributed to the Hib-ester and Hib-carbaldehyde, while the proteasome inhibition of the extract could also be ascribed to the presence of anthocyanins, a class of secondary metabolites already known for their proteasome inhibitory activity. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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11 pages, 3852 KiB

Open AccessArticle

The Selectivity for Tumor Cells of Nuclear-Directed Cytotoxic RNases Is Mediated by the Nuclear/Cytoplasmic Distribution of p27^KIP1

by Glòria García-Galindo, Jessica Castro, Jesús Matés, Marlon Bravo, Marc Ribó, Maria Vilanova and Antoni Benito

Molecules 2021, 26(5), 1319; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26051319 - 02 Mar 2021

Cited by 2 | Viewed by 1668

Abstract

Although single targeted anti-cancer drugs are envisaged as safer treatments because they do not affect normal cells, cancer is a very complex disease to be eradicated with a single targeted drug. Alternatively, multi-targeted drugs may be more effective and the tumor cells may [...] Read more.

Although single targeted anti-cancer drugs are envisaged as safer treatments because they do not affect normal cells, cancer is a very complex disease to be eradicated with a single targeted drug. Alternatively, multi-targeted drugs may be more effective and the tumor cells may be less prone to develop drug resistance although these drugs may be less specific for cancer cells. We have previously developed a new strategy to endow human pancreatic ribonuclease with antitumor action by introducing in its sequence a non-classical nuclear localization signal. These engineered proteins cleave multiple species of nuclear RNA promoting apoptosis of tumor cells. Interestingly, these enzymes, on ovarian cancer cells, affect the expression of multiple genes implicated in metabolic and signaling pathways that are critic for the development of cancer. Since most of these targeted pathways are not highly relevant for non-proliferating cells, we envisioned the possibility that nuclear directed-ribonucleases were specific for tumor cells. Here, we show that these enzymes are much more cytotoxic for tumor cells in vitro. Although the mechanism of selectivity of NLSPE5 is not fully understood, herein we show that p27^KIP1 displays an important role on the higher resistance of non-tumor cells to these ribonucleases. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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17 pages, 4797 KiB

Open AccessArticle

Identification of Phytochemical-Based β-Catenin Nuclear Localization Inhibitor in NSCLC: Differential Targeting Population from Member of Isothiocyanates

by Win Sen Heng and Shiau-Chuen Cheah

Molecules 2021, 26(2), 399; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020399 - 13 Jan 2021

Cited by 8 | Viewed by 2180

Abstract

Decades of research has convinced us that phytochemical compounds contained within the plant products are the real deal, and they provide benefits such as health maintenance an d cure to illnesses. One of the deadliest noncommunicable diseases today is lung cancer, hence its [...] Read more.

Decades of research has convinced us that phytochemical compounds contained within the plant products are the real deal, and they provide benefits such as health maintenance an d cure to illnesses. One of the deadliest noncommunicable diseases today is lung cancer, hence its disease management still deserves attention. Wnt/β-catenin pathway activation conferring cancer stem cell (CSC) activities to non-small cell lung carcinomas (NSCLCs) may explain why the disease is still difficult to cure. In the present study, we assessed several representatives of phytochemical categories consisting of alkaloids, chalcones and isothiocyanates for their inhibitory activity to nuclear localization of β-catenin—an important event for Wnt/β-catenin pathway activation, in lung cancer cell lines. Real-time cell analyzer confirmed that evodiamine (EVO), chelidonine (CHE), isoliquiritigenin (ISO), licochalcone-A (LICO), benzyl isothiocyanate (BI) and phenethylisothiocyanate (PI) exhibited anti-proliferative activities and cytotoxicities to adenocarcinoma cell line SK-LU-1 and human lung CSC primary cell line (HLCSC). Immunofluorescence assay identified that CHE, ISO, LICO, BI and PI were capable of reducing the number of cells harboring β-catenin within the nuclei of these cells. We extended the characterizations of BI and PI in Wnt-dependent squamous cell carcinoma cell line NCI-H1703 on several CSC functions and found that BI was better at inhibiting soft agar colony formation as an output of self-renewal ability, whereas PI was more effective in inhibiting the growth of multicellular tumor spheroid model mimicking micrometastases. Both however were not able to inhibit migration and invasion of NCI-H1703. In conclusion, BI could potentially be used as a safer alternative to target undifferentiated CSCs as adjuvant therapy, whereas PI could be used as chemotherapy to remove bulk tumor. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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10 pages, 2076 KiB

Open AccessArticle

Combinatorial Therapeutic Effect of Inhibitors of Aldehyde Dehydrogenase and Mitochondrial Complex I, and the Chemotherapeutic Drug, Temozolomide against Glioblastoma Tumorspheres

by Hun Ho Park, Junseong Park, Hye Joung Cho, Jin-Kyoung Shim, Ju Hyung Moon, Eui Hyun Kim, Jong Hee Chang, Soo Youl Kim and Seok-Gu Kang

Molecules 2021, 26(2), 282; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020282 - 08 Jan 2021

Cited by 7 | Viewed by 2413

Abstract

Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects [...] Read more.

Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects of dual inhibition of tumor bioenergetics by combination of gossypol, an aldehyde dehydrogenase inhibitor, and phenformin, a biguanide compound that depletes oxidative phosphorylation, with the chemotherapeutic drug, temozolomide (TMZ), to block proliferation, stemness, and invasiveness of GBM tumorspheres (TSs). Combination therapy with gossypol, phenformin, and TMZ induced a significant reduction in ATP levels, cell viability, stemness, and invasiveness compared to TMZ monotherapy and dual therapy with gossypol and phenformin. Analysis of differentially expressed genes revealed up-regulation of genes involved in programmed cell death, autophagy, and protein metabolism and down-regulation of those associated with cell metabolism, cycle, and adhesion. Combination of TMZ with dual inhibitors of tumor bioenergetics may, therefore, present an effective strategy against GBM by enhancing therapeutic effects through multiple mechanisms of action. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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15 pages, 2460 KiB

Open AccessArticle

The Anticancer Peptide CIGB-552 Exerts Anti-Inflammatory and Anti-Angiogenic Effects through COMMD1

by Hellen Daghero, Julio Raúl Fernández Massó, Soledad Astrada, Maribel Guerra Vallespí and Mariela Bollati-Fogolín

Molecules 2021, 26(1), 152; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26010152 - 31 Dec 2020

Cited by 5 | Viewed by 2881

Abstract

CIGB-552 is a synthetic anti-tumor peptide capable of reducing tumor size and increasing the lifespan of tumor-bearing mice. Part of its anti-cancer effects consists of inducing apoptosis, modulating NF-kB signaling pathway, and the angiogenesis process. Although one of its major mediators, the COMMD1 [...] Read more.

CIGB-552 is a synthetic anti-tumor peptide capable of reducing tumor size and increasing the lifespan of tumor-bearing mice. Part of its anti-cancer effects consists of inducing apoptosis, modulating NF-kB signaling pathway, and the angiogenesis process. Although one of its major mediators, the COMMD1 protein, has been identified, the mechanism by which CIGB-552 exerts such effects remains elusive. In the present study, we show the role of COMMD1 in CIGB-552 mechanism of action by generating the COMMD1 knock-out from the human lung cancer cell line NCI-H460. A microarray was performed to analyze both wild-type and KO cell lines with regard to CIGB-552 treatment. Additionally, different signaling pathways were studied in both cell lines to validate the results. Furthermore, the interaction between CIGB-552 and COMMD1 was analyzed by confocal microscopy. By signaling pathway analysis we found that genes involved in cell proliferation and apoptosis, oncogenic transformation, angiogenesis and inflammatory response are potentially regulated by the treatment with CIGB-552. We then demonstrated that CIGB-552 is capable of modulating NF-kB in both 2D and 3D cell culture models. Finally, we show that the ability of CIGB-552 to negatively modulate NF-kB and HIF-1 pathways is impaired in the COMMD1 knock-out NCI-H460 cell line, confirming that COMMD1 is essential for the peptide mechanism of action. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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15 pages, 3464 KiB

Open AccessArticle

The Antiasthma Medication Ciclesonide Suppresses Breast Cancer Stem Cells through Inhibition of the Glucocorticoid Receptor Signaling-Dependent YAP Pathway

by Su-Lim Kim, Hack Sun Choi, Ji-Hyang Kim and Dong-Sun Lee

Molecules 2020, 25(24), 6028; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25246028 - 19 Dec 2020

Cited by 9 | Viewed by 2436

Abstract

Ciclesonide is an FDA-approved glucocorticoid used to treat asthma and allergic rhinitis. However, whether it has anticancer and anti-cancer stem cell (CSC) effects is unknown. This study focused on investigating the effect of ciclesonide on breast cancer and CSCs and determining its underlying [...] Read more.

Ciclesonide is an FDA-approved glucocorticoid used to treat asthma and allergic rhinitis. However, whether it has anticancer and anti-cancer stem cell (CSC) effects is unknown. This study focused on investigating the effect of ciclesonide on breast cancer and CSCs and determining its underlying mechanism. Here, we showed that ciclesonide inhibits breast cancer and CSC formation. Similar glucocorticoids—dexamethasone and prednisone—did not inhibit CSC formation. Ciclesonide-induced glucocorticoid receptor (GR) degradation was dependent on ubiquitination. We showed via GR small interfering RNA (siRNA) that GR plays an important role in CSC formation. We showed via western blot and immunofluorescence assays that ciclesonide reduces the nuclear level of GR. The GR antagonist RU-486 also inhibited CSC formation. Ciclesonide reduced the protein level of the Hippo transducer Yes-associated protein (YAP). GR siRNA induced a decrease in YAP protein expression and inhibited mammosphere formation. The YAP inhibitor verteporfin inhibited CSC formation and transcription of the connective tissue growth factor and cysteine-rich protein 61 genes. The GR/YAP1 pathway regulated breast CSC formation. We showed that the GR/YAP signaling pathway regulates breast CSC formation and revealed a new approach for targeting GR and YAP to inhibit CSC formation. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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11 pages, 2011 KiB

Open AccessArticle

Virtual Screening and In Vitro Evaluation of PD-L1 Dimer Stabilizers for Uncoupling PD-1/PD-L1 Interaction from Natural Products

by Jrhau Lung, Ming-Szu Hung, Yu-Ching Lin, Chien-Hui Hung, Chih-Cheng Chen, Kuan-Der Lee and Ying Huang Tsai

Molecules 2020, 25(22), 5293; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25225293 - 13 Nov 2020

Cited by 10 | Viewed by 2671

Abstract

Genetic mutations accumulated overtime could generate many growth and survival advantages for cancer cells, but these mutations also mark cancer cells as targets to be eliminated by the immune system. To evade immune surveillance, cancer cells adopted different intrinsic molecules to suppress immune [...] Read more.

Genetic mutations accumulated overtime could generate many growth and survival advantages for cancer cells, but these mutations also mark cancer cells as targets to be eliminated by the immune system. To evade immune surveillance, cancer cells adopted different intrinsic molecules to suppress immune response. PD-L1 is frequently overexpressed in many cancer cells, and its engagement with PD-1 on T cells diminishes the extent of cytotoxicity from the immune system. To resume immunity for fighting cancer, several therapeutic antibodies disrupting the PD-1/PD-L1 interaction have been introduced in clinical practice. However, their immunogenicity, low tissue penetrance, and high production costs rendered these antibodies beneficial to only a limited number of patients. PD-L1 dimer formation shields the interaction interface for PD-1 binding; hence, screening for small molecule compounds stabilizing the PD-L1 dimer may make immune therapy more effective and widely affordable. In the current study, 111 candidates were selected from over 180,000 natural compound structures through virtual screening, contact fingerprint analysis, and pharmacological property prediction. Twenty-two representative candidates were further evaluated in vitro. Two compounds were found capable of inhibiting the PD-1/PD-L1 interaction and promoting PD-L1 dimer formation. Further structure optimization and clinical development of these lead inhibitors will eventually lead to more effective and affordable immunotherapeutic drugs for cancer patients. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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13 pages, 9486 KiB

Open AccessArticle

Enhancement of Phthalocyanine Mediated Photodynamic Therapy by Catechin on Lung Cancer Cells

by Giftson J. Senapathy, Blassan P. George and Heidi Abrahamse

Molecules 2020, 25(21), 4874; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25214874 - 22 Oct 2020

Cited by 20 | Viewed by 2465

Abstract

Worldwide, lung cancer remains one of the leading cancers with increasing mortality rates. Though chemotherapy for lung cancer is effective, it is always accompanied by unavoidable and grave side effects. Photodynamic therapy (PDT), using novel photosensitizers, is an advanced treatment method with relatively [...] Read more.

Worldwide, lung cancer remains one of the leading cancers with increasing mortality rates. Though chemotherapy for lung cancer is effective, it is always accompanied by unavoidable and grave side effects. Photodynamic therapy (PDT), using novel photosensitizers, is an advanced treatment method with relatively few side effects. Plant products are emerging as potent photosensitizers (PSs). The dose-dependent effect of Catechin (CA) (20–100 µM) on cellular morphological changes, cell viability, cytotoxicity, proliferation, DNA damage and apoptosis were studied on A549 adenocarcinoma alveolar basal epithelial cells. The effect of CA, along with Zinc phthalocyanine PS at 680 nm and 5 J/cm² fluency was also studied. As the doses of CA increased, the results showed a pattern of increased cytotoxicity, accompanied by decreased cell viability and proliferation in A549 cells. Also, at 52 µM (IC₅₀), CA in combination with PS significantly increased the cytotoxicity, DNA damage, and apoptosis, as compared to control and PS alone, treated cells in PDT experiments. These findings leave a possible thread that CA can be used in the application of phyto-photodynamic therapy of cancer in future. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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15 pages, 2307 KiB

Open AccessArticle

Synthesis of Novel Chalcone-Based Phenothiazine Derivatives as Antioxidant and Anticancer Agents

by Nourah A. Al Zahrani, Reda M. El-Shishtawy, Mahmoud M. Elaasser and Abdullah M. Asiri

Molecules 2020, 25(19), 4566; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25194566 - 06 Oct 2020

Cited by 43 | Viewed by 4355

Abstract

Based on reported results for the potential medicinal impact of phenothiazine core, as well as the chalcone skeleton that is widely present in many natural products, together with their reported bioactivities, the present work was aimed at combining both moieties in one molecular [...] Read more.

Based on reported results for the potential medicinal impact of phenothiazine core, as well as the chalcone skeleton that is widely present in many natural products, together with their reported bioactivities, the present work was aimed at combining both moieties in one molecular skeleton and to synthesize and characterize a novel series of chalone-based phenothiazine derivatives. For this purpose, 2-acetylphenothiazine was N-alkylated, followed by the Claisen-Schmidt reaction to produce the chalcones with good yield. Antioxidant activity, as evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, was assessed to determine if their antioxidant potential was comparable with ascorbic acid, and attributable to the phenothiazine core. Screening anticancer activities of the synthesized chalone-based phenothiazine derivatives against human breast cancer cell line MCF-7 cells, and human hepatocellular carcinoma HepG-2 cells, compared with standard drugs cisplatin and doxorubicin, was evaluated. The results revealed that compounds 4a, 4b, 4d, 4h, 4j, 4k, 4m, 4o, and 4p were good against human hepatocellular carcinoma HepG-2 cells, and among these compounds 4b and 4k were the most effective compounds, with IC₅₀ values of 7.14 μg/mL and 7.6 1 μg/mL, respectively. On the other hand, compounds 4a, 4b, 4k, and 4m were good against human breast cancer cell line MCF-7 cells and, among these compounds, 4k and 4b were the most effective compounds, with IC₅₀ values of 12 μg/mL and 13. 8 μg/mL, respectively. The overall results suggest that these compounds could, potentially, be further modified for the formation of more potent antioxidant and anticancer agents. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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15 pages, 3435 KiB

Open AccessFeature PaperArticle

Indole Derivative Interacts with Estrogen Receptor Beta and Inhibits Human Ovarian Cancer Cell Growth

by Laura Verardi, Jessica Fiori, Vincenza Andrisano, Alessandra Locatelli, Rita Morigi, Marina Naldi, Carlo Bertucci, Elena Strocchi, Carla Boga, Gabriele Micheletti and Natalia Calonghi

Molecules 2020, 25(19), 4438; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25194438 - 27 Sep 2020

Cited by 8 | Viewed by 2320

Abstract

Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step [...] Read more.

Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re-expression by genetic engineering, as well as the use of targeted ERβ therapies, still constitute an important therapeutic approach. 3-{[2-chloro-1-(4-chlorobenzyl)-5-methoxy-6-methyl-1H-indol-3-yl]methylene}-5-hydroxy-6-methyl-1,3-dihydro-2H-indol-2-one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and liquid chromatography mass spectrometry were exploited to localize and quantify compound 3 in cells. Molecular docking was used to prove compound 3 binding to ERβ. Mass spectrometry-based approaches were used to analyze histone post-translational modifications. Finally, gene expression analyses revealed a set of genes regulated by the ERβ/3 complex, namely CCND1, MYC, CDKN2A, and ESR2, providing possible molecular mechanisms that underline the observed antiproliferative effects. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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17 pages, 5186 KiB

Open AccessFeature PaperArticle

Novel Anticancer NHC*-Gold(I) Complexes Inspired by Lepidiline A

by Danielle Curran, Helge Müller-Bunz, Sofia I. Bär, Rainer Schobert, Xiangming Zhu and Matthias Tacke

Molecules 2020, 25(15), 3474; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153474 - 30 Jul 2020

Cited by 13 | Viewed by 3309

Abstract

N-Heterocyclic carbene gold(I) complexes derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) represent a promising class of anticancer drugs. Complexes of the type NHC*-Au-L (L = Br⁻, I⁻, C≡C-R) and [NHC*-Au-L]⁺ (L = NHC*, PPh₃) have been synthesised. The [...] Read more.

N-Heterocyclic carbene gold(I) complexes derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) represent a promising class of anticancer drugs. Complexes of the type NHC*-Au-L (L = Br⁻, I⁻, C≡C-R) and [NHC*-Au-L]⁺ (L = NHC*, PPh₃) have been synthesised. The X-ray crystal structures of all gold(I) complexes are presented; aurophilic interactions were observed in five of the complexes. The anticancer activity was assessed via MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-based proliferation assays against the human colon carcinoma cell line HCT-116^wt and the multidrug-resistant human breast carcinoma cell line MCF-7^topo. Most complexes showed good cytotoxicity with IC₅₀ values in the low micromolar range, while excellent sub-micromolar activity was observed for 2c, 3a and 3b. Generally, the activity of the ligands studied was as follows: carbene > phosphine > alkyne > halide, with an exception for the highly active iodido derivative 2c. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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21 pages, 6456 KiB

Open AccessArticle

Synthesis, Characterization, Photoluminescence, Molecular Docking and Bioactivity of Zinc (II) Compounds Based on Different Substituents

by Rongping Liu, Hao Yan, Jinzhang Jiang, Jiahe Li, Xing Liang, Dengfeng Yang, Lixia Pan, Tisan Xie and Zhen Ma

Molecules 2020, 25(15), 3459; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153459 - 29 Jul 2020

Cited by 11 | Viewed by 2563

Abstract

Six new zinc(II) complexes were prepared by the reaction of ZnBr₂ or ZnI₂ with 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine compounds, bearing p-methylsulfonyl (L¹), p-methoxy (L²) and p-methyl (L³), which were characterized by elemental analysis, FT-IR, NMR [...] Read more.

Six new zinc(II) complexes were prepared by the reaction of ZnBr₂ or ZnI₂ with 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine compounds, bearing p-methylsulfonyl (L¹), p-methoxy (L²) and p-methyl (L³), which were characterized by elemental analysis, FT-IR, NMR and single crystal X-ray diffraction. The antiproliferative properties against Eca-109, A549 and Bel-7402 cell lines and the cytotoxicity test on RAW-264.7 of these compounds were monitored using a CCK-8 assay, and the studies indicate that the complexes show higher antiproliferative activities than cisplatin. The interactions of these complexes with CT-DNA and proteins (BSA) were studied by UV-Vis, circular dichroism (CD) and fluorescent spectroscopy, respectively. The results indicate that the interaction of these zinc(II) complexes with CT-DNA is achieved through intercalative binding, and their strong binding affinity to BSA is fulfilled through a static quenching mechanism. The simulation of the complexes with the CT-DNA fragment and BSA was studied by using molecular docking software. It further validates that the complexes interact with DNA through intercalative binding mode and that they have a strong interaction with BSA. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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13 pages, 3738 KiB

Open AccessArticle

The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma

by Cheng-Chan Yu, Sung-Ying Huang, Shu-Fang Chang, Kuan-Fu Liao and Sheng-Chun Chiu

Molecules 2020, 25(10), 2454; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25102454 - 25 May 2020

Cited by 12 | Viewed by 3509

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines (n = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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18 pages, 2628 KiB

Open AccessArticle

Differential Proliferation Effect of the Newly Synthesized Valine, Tyrosine and Tryptophan–Naphthoquinones in Immortal and Tumorigenic Cervical Cell Lines

by Sergio Córdova-Rivas, Jorge Gustavo Araujo-Huitrado, Ernesto Rivera-Avalos, Ismailia L. Escalante-García, Sergio M. Durón-Torres, Yamilé López-Hernández, Hiram Hernández-López, Lluvia López, Denisse de Loera and Jesús Adrián López

Molecules 2020, 25(9), 2058; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25092058 - 28 Apr 2020

Cited by 8 | Viewed by 2865

Abstract

We previously showed that microwave assisted synthesis is the best method for the synthesis of naphthoquinone amino acid and chloride-naphthoquinone amino acid derivatives by a complete evaluation of reaction conditions such as stoichiometry, bases, and pH influence. Following the same strategy, we synthesized [...] Read more.

We previously showed that microwave assisted synthesis is the best method for the synthesis of naphthoquinone amino acid and chloride-naphthoquinone amino acid derivatives by a complete evaluation of reaction conditions such as stoichiometry, bases, and pH influence. Following the same strategy, we synthesized chloride and non-chloride tyrosine, valine, and tryptophan-naphthoquinones achieving 85–95%, 80–92%, and 91–95% yields, respectively. The cyclic voltammetry profiles showed that both series of naphthoquinone amino acid derivatives mainly display one redox reaction process. Overall, chloride naphthoquinone amino acid derivatives exhibited redox potential values (E_1/2) more positive than non-chloride compounds. The six newly synthesized compounds were tested in HPV positive and negative as well as in immortal and tumorigenic cell lines to observe the effects in different cellular context simulating precancerous and cancerous status. A dose-response was achieved to determine the IC50 of six newly synthesized compounds in SiHa (Tumorigenic and HPV16 positive), CaLo (Tumorigenic and HPV18 positive), C33-A (Tumorigenic and HPV negative) and HaCaT (Keratinocytes immortal HPV negative) cell lines. Non-chloride tryptophan-naphthoquinone (3c) and chloride tyrosine-naphthoquine (4a) effects were more potent in tumorigenic SiHa, CaLo, and C33-A cells with respect to non-tumorigenic HaCaT cells. Interestingly, there seems to be a differential effect in non-chloride and chloride naphthoquinone amino acid derivatives in tumorigenic versus non tumorigenic cells. Considering all naphthoquinone amino acid derivatives that our group synthesized, it seems that hydrophobic and aromatic amino acids have the greatest effect on cell proliferation inhibition. These results show promising compounds for cervical cancer treatment. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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12 pages, 3486 KiB

Open AccessArticle

Cytotoxic Activities and Molecular Mechanisms of the Beauvericin and Beauvericin G₁ Microbial Products against Melanoma Cells

by Haet Nim Lim, Jun-Pil Jang, Hee Jeong Shin, Jae-Hyuk Jang, Jong Seog Ahn and Hye Jin Jung

Molecules 2020, 25(8), 1974; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25081974 - 23 Apr 2020

Cited by 6 | Viewed by 2256

Abstract

Melanoma is the most serious type of skin cancer and remains highly drug-resistant. Therefore, the discovery of novel effective agents against melanoma is in high demand. Herein, we investigated the cytotoxic activities in melanoma cells and underlying molecular mechanisms of beauvericin (BEA) and [...] Read more.

Melanoma is the most serious type of skin cancer and remains highly drug-resistant. Therefore, the discovery of novel effective agents against melanoma is in high demand. Herein, we investigated the cytotoxic activities in melanoma cells and underlying molecular mechanisms of beauvericin (BEA) and its analogue beauvericin G₁ (BEA G₁), which are cyclohexadepsipeptides isolated from fungi. BEA and BEA G₁ significantly suppressed the growth, clonogenicity, migration, and invasion of A375SM human melanoma cells and promoted caspase-dependent apoptosis through upregulation of death receptors, as well as modulation of pro- and anti-apoptotic Bcl-2 family members. Furthermore, the effects of BEA and BEA G₁ were associated with the suppression of multiple molecular targets that play crucial roles in melanoma oncogenesis, including ERK, JNK, p38, NF-κB, STAT3, and MITF. Notably, the cytotoxic efficacy of BEA G₁ against A375SM cells was stronger than that of BEA. These findings suggest that BEA and BEA G₁ can be further investigated as potent cytotoxic natural compounds for the suppression of melanoma progression. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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19 pages, 2289 KiB

Open AccessArticle

A Higher Frequency Administration of the Nontoxic Cycloartane-Type Triterpene Argentatin A Improved Its Anti-Tumor Activity

by Zaira Tavarez-Santamaría, Nadia J. Jacobo-Herrera, Leticia Rocha-Zavaleta, Alejandro Zentella-Dehesa, Beatriz del Carmen Couder-García and Mariano Martínez-Vázquez

Molecules 2020, 25(8), 1780; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25081780 - 14 Apr 2020

Cited by 12 | Viewed by 2551

Abstract

Parthenium argentatum (Gray), commonly known as guayule, has been used to obtain natural rubber since the beginning of the 20th century. Additionally, the so called “resin” is a waste product derived from the industrial process. The cycloartane-type triterpene Argentatin A (AA) is one [...] Read more.

Parthenium argentatum (Gray), commonly known as guayule, has been used to obtain natural rubber since the beginning of the 20th century. Additionally, the so called “resin” is a waste product derived from the industrial process. The cycloartane-type triterpene Argentatin A (AA) is one of the main constituents of the industrial waste resin. In this study we evaluated the AA anticancer activity both in vitro and in vivo in the HCT116 colon cancer cells. The apoptosis promotion of AA was assessed by the annexin V/propidium iodide (PI) assay. The senescence was evaluated for SA-β-galactosidase, and PCNA was used as a marker of proliferation. Its antitumor activity was evaluated using a xenograft mouse model. The results indicated that AA-induced apoptosis in HCT-116 cells and was positively stained for SA-β-galactosidase. In the xenografted mice test, the administration of AA at the dose of 250 mg/kg three times a week for 21 days reduced tumor growth by 78.1%. A comparable tumor reduction was achieved with cisplatin at the dose of 2 mg/kg administered three times a week for 21 days. However, nude mice treated with AA did not lose weight, as they did remarkably when treated with cisplatin. Furthermore, the animals treated with AA showed similar blood profiles as the healthy control group. These data indicate the low toxicity of AA compared to that shown by cisplatin. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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9 pages, 2056 KiB

Open AccessArticle

New Selective Progesterone Receptor Modulators and Their Impact on the RANK/RANKL Complex Activity

by Katarzyna Błaszczak-Świątkiewicz

Molecules 2020, 25(6), 1321; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25061321 - 13 Mar 2020

Cited by 4 | Viewed by 2902

Abstract

Breast cancer depends on women’s age. Its chemotherapy and hormone therapy lead to the loss of bone density and disruption of the skeleton. The proteins RANK and RANKL play a pivotal role in the formation of osteoclasts. It is also well established that [...] Read more.

Breast cancer depends on women’s age. Its chemotherapy and hormone therapy lead to the loss of bone density and disruption of the skeleton. The proteins RANK and RANKL play a pivotal role in the formation of osteoclasts. It is also well established that the same proteins (RANK and RANKL) are the main molecules that play an important role in mammary stem cell biology. Mammary stem cells guarantee differentiation of the epithelial mammary cells, the growth of which is regulated by the progesterone-induced RANKL signaling pathway. The crosstalk between progesterone receptor, stimulated by progesterone and its analogues results in RANKL to RANK binding and activation of cell proliferation and subsequently unlimited expansion of the breast cancer cells. Therefore downstream regulation of this signaling pathway is desirable. To meet this need, a new class of selective estrogen receptor modulators (SPRMs) with anti- and mesoprogestin function were tested as potential anti-RANK agents. To establish the new feature of SPRMs, the impact of tested SPRMs on RANK-RANKL proteins interaction was tested. Furthermore, the cells proliferation upon RANKL stimulation, as well as NFkB and cyclin D1 expression, induced by tested SPRMs were analyzed. Conducted experiments proved NFkB expression inhibition as well as cyclin D1 expression limitation under asoprisnil and ulipristal treatment. The established paracrine anti-proliferative activity of antiprogestins together with competitive interaction with RANK make this class of compounds attractive for further study in order to deliver more evidence of their anti-RANK activity and potential application in the breast cancer therapy together with its accompanied osteoporosis. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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13 pages, 2129 KiB

Open AccessArticle

Anticancer Activities of Newly Synthesized Chiral Macrocyclic Heptapeptide Candidates

by Mohamed H. Abo-Ghalia, Gaber O. Moustafa, Abd El-Galil E. Amr, Ahmed M. Naglah, Elsayed A. Elsayed and Ahmed H. Bakheit

Molecules 2020, 25(5), 1253; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25051253 - 10 Mar 2020

Cited by 29 | Viewed by 3367

Abstract

As important cancer therapeutic agents, macrocyclic peptides have recently drawn great attention, mainly because they are synthetically accessible and have lower toxicity towards normal cells. In the present work, we synthesized newly macrocyclic pyridoheptapeptide derivatives. The synthesized derivatives were characterized using standard chemical [...] Read more.

As important cancer therapeutic agents, macrocyclic peptides have recently drawn great attention, mainly because they are synthetically accessible and have lower toxicity towards normal cells. In the present work, we synthesized newly macrocyclic pyridoheptapeptide derivatives. The synthesized derivatives were characterized using standard chemical and spectroscopic analytical techniques, and their anticancer activities against human breast and hepatocellular cancer cells were investigated. Results showed that compounds 1a and 1b were the most effective against hepatocellular (HepG2) and breast (MCF-7) cancer cell lines, respectively. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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21 pages, 6576 KiB

Open AccessArticle

Chiral Pyridine-3,5-bis- (L-phenylalaninyl-L-leucinyl) Schiff Base Peptides as Potential Anticancer Agents: Design, Synthesis, and Molecular Docking Studies Targeting Lactate Dehydrogenase-A

by Abd El-Galil E. Amr, Randa E. Abdel Mageid, Mohamed El-Naggar, Ahmed M. Naglah, Eman S. Nossier and Elsayed A. Elsayed

Molecules 2020, 25(5), 1096; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25051096 - 29 Feb 2020

Cited by 19 | Viewed by 2690

Abstract

A series of branched tetrapeptide Schiff bases 3–6 were designed and synthesized from corresponding tetrapeptide hydrazide 2 as a starting material.In vitroevaluation of the synthesized compounds 4–6 against breast MCF-7 carcinoma cells identified their excellent anticancer potency, with IC [...] Read more.

A series of branched tetrapeptide Schiff bases 3–6 were designed and synthesized from corresponding tetrapeptide hydrazide 2 as a starting material.In vitroevaluation of the synthesized compounds 4–6 against breast MCF-7 carcinoma cells identified their excellent anticancer potency, with IC₅₀ ranging from 8.12 ± 0.14 to 17.55 ± 0.27 μM in comparison with the references, cisplatin and milaplatin (IC₅₀= 13.34 ± 0.11and 18.43 ± 0.13 μM, respectively). Furthermore, all derivatives demonstrated promising activity upon evaluation of theirin vitroandin vivosuppression of p53 ubiquitination and inhibition assessment for LDHA kinase. Finally, molecular docking studies were performed to predict the possible binding features of the potent derivatives within the ATP pocket of LDHA in an attempt to get a lead for developing a more potent LDHA inhibitor with anti-proliferative potency. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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Review

Jump to: Research

27 pages, 4123 KiB

Open AccessReview

Recent Developments in Small-Molecule Ligands of Medicinal Relevance for Harnessing the Anticancer Potential of G-Quadruplexes

by Loukiani Savva and Savvas N. Georgiades

Molecules 2021, 26(4), 841; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26040841 - 05 Feb 2021

Cited by 36 | Viewed by 3296

Abstract

G-quadruplexes, a family of tetraplex helical nucleic acid topologies, have emerged in recent years as novel targets, with untapped potential for anticancer research. Their potential stems from the fact that G-quadruplexes occur in functionally-important regions of the human genome, such as the telomere [...] Read more.

G-quadruplexes, a family of tetraplex helical nucleic acid topologies, have emerged in recent years as novel targets, with untapped potential for anticancer research. Their potential stems from the fact that G-quadruplexes occur in functionally-important regions of the human genome, such as the telomere tandem sequences, several proto-oncogene promoters, other regulatory regions and sequences of DNA (e.g., rDNA), as well as in mRNAs encoding for proteins with roles in tumorigenesis. Modulation of G-quadruplexes, via interaction with high-affinity ligands, leads to their stabilization, with numerous observed anticancer effects. Despite the fact that only a few lead compounds for G-quadruplex modulation have progressed to clinical trials so far, recent advancements in the field now create conditions that foster further development of drug candidates. This review highlights biological processes through which G-quadruplexes can exert their anticancer effects and describes, via selected case studies, progress of the last few years on the development of efficient and drug-like G-quadruplex-targeted ligands, intended to harness the anticancer potential offered by G-quadruplexes. The review finally provides a critical discussion of perceived challenges and limitations that have previously hampered the progression of G-quadruplex-targeted lead compounds to clinical trials, concluding with an optimistic future outlook. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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17 pages, 1287 KiB

Open AccessReview

An Insight into the Anti-Angiogenic and Anti-Metastatic Effects of Oridonin: Current Knowledge and Future Potential

by Nurul Akmaryanti Abdullah, Nur Fariesha Md Hashim, Aula Ammar and Noraina Muhamad Zakuan

Molecules 2021, 26(4), 775; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26040775 - 03 Feb 2021

Cited by 20 | Viewed by 3126

Abstract

Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted [...] Read more.

Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted anti-cancer therapy is increasingly used with conventional therapy to improve patients’ outcomes in advanced and metastatic tumors. However, due to the complexity of cancer biology and metastasis, it is urgent to develop new agents and evaluate the anti-cancer efficacy of available treatments. Many phytochemicals from medicinal plants have been reported to possess anti-cancer properties. One such compound is known as oridonin, a bioactive component of Rabdosia rubescens. Several studies have demonstrated that oridonin inhibits angiogenesis in various types of cancer, including breast, pancreatic, lung, colon and skin cancer. Oridonin’s anti-cancer effects are mediated through the modulation of several signaling pathways which include upregulation of oncogenes and pro-angiogenic growth factors. Furthermore, oridonin also inhibits cell migration, invasion and metastasis via suppressing epithelial-to-mesenchymal transition and blocking downstream signaling targets in the cancer metastasis process. This review summarizes the recent applications of oridonin as an anti-angiogenic and anti-metastatic drug both in vitro and in vivo, and its potential mechanisms of action. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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30 pages, 1944 KiB

Open AccessReview

Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis

by Daniel E. Hagaman, Jossana A. Damasco, Joy Vanessa D. Perez, Raniv D. Rojo and Marites P. Melancon

Molecules 2021, 26(2), 384; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020384 - 13 Jan 2021

Cited by 8 | Viewed by 3775

Abstract

Patients with advanced prostate cancer can develop painful and debilitating bone metastases. Currently available interventions for prostate cancer bone metastases, including chemotherapy, bisphosphonates, and radiopharmaceuticals, are only palliative. They can relieve pain, reduce complications (e.g., bone fractures), and improve quality of life, but [...] Read more.

Patients with advanced prostate cancer can develop painful and debilitating bone metastases. Currently available interventions for prostate cancer bone metastases, including chemotherapy, bisphosphonates, and radiopharmaceuticals, are only palliative. They can relieve pain, reduce complications (e.g., bone fractures), and improve quality of life, but they do not significantly improve survival times. Therefore, additional strategies to enhance the diagnosis and treatment of prostate cancer bone metastases are needed. Nanotechnology is a versatile platform that has been used to increase the specificity and therapeutic efficacy of various treatments for prostate cancer bone metastases. In this review, we summarize preclinical research that utilizes nanotechnology to develop novel diagnostic imaging tools, translational models, and therapies to combat prostate cancer bone metastases. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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19 pages, 3689 KiB

Open AccessReview

Bile Acid Conjugates with Anticancer Activity: Most Recent Research

by Maria Luisa Navacchia, Elena Marchesi and Daniela Perrone

Molecules 2021, 26(1), 25; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26010025 - 23 Dec 2020

Cited by 17 | Viewed by 3870

Abstract

The advantages of a treatment modality that combines two or more therapeutic agents in cancer therapy encourages the study of hybrid functional compounds for pharmacological applications. In light of this, we reviewed recent works on hybrid molecules based on bile acids. Due to [...] Read more.

The advantages of a treatment modality that combines two or more therapeutic agents in cancer therapy encourages the study of hybrid functional compounds for pharmacological applications. In light of this, we reviewed recent works on hybrid molecules based on bile acids. Due to their biological properties, as well as their different chemical/biochemical reactive moieties, bile acids can be considered very interesting starting molecules for conjugation with natural or synthetic bioactive molecules. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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20 pages, 615 KiB

Open AccessFeature PaperReview

Regulation of Selenium/Sulfur Interactions to Enhance Chemopreventive Effects: Lessons to Learn from Brassicaceae

by Muna Ali Abdalla, Saad Sulieman and Karl H. Mühling

Molecules 2020, 25(24), 5846; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25245846 - 10 Dec 2020

Cited by 21 | Viewed by 2702

Abstract

Selenium (Se) is an essential trace element, which represents an integral part of glutathione peroxidase and other selenoproteins involved in the protection of cells against oxidative damage. Selenomethionine (SeMet), selenocysteine (SeCys), and methylselenocysteine (MeSeCys) are the forms of Se that occur in living [...] Read more.

Selenium (Se) is an essential trace element, which represents an integral part of glutathione peroxidase and other selenoproteins involved in the protection of cells against oxidative damage. Selenomethionine (SeMet), selenocysteine (SeCys), and methylselenocysteine (MeSeCys) are the forms of Se that occur in living systems. Se-containing compounds have been found to reduce carcinogenesis of animal models, and dietary supplemental Se might decrease cancer risk. Se is mainly taken up by plant roots in the form of selenate via high-affinity sulfate transporters. Consequently, owing to the chemical similarity between Se and sulfur (S), the availability of S plays a key role in Se accumulation owing to competition effects in absorption, translocation, and assimilation. Moreover, naturally occurring S-containing compounds have proven to exhibit anticancer potential, in addition to other bioactivities. Therefore, it is important to understand the interaction between Se and S, which depends on Se/S ratio in the plant or/and in the growth medium. Brassicaceae (also known as cabbage or mustard family) is an important family of flowering plants that are grown worldwide and have a vital role in agriculture and populations’ health. In this review we discuss the distribution and further interactions between S and Se in Brassicaceae and provide several examples of Se or Se/S biofortifications’ experiments in brassica vegetables that induced the chemopreventive effects of these crops by enhancing the production of Se- or/and S-containing natural compounds. Extensive further research is required to understand Se/S uptake, translocation, and assimilation and to investigate their potential role in producing anticancer drugs. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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15 pages, 1070 KiB

Open AccessReview

Role of Bcl-2 Family Proteins in Photodynamic Therapy Mediated Cell Survival and Regulation

by Eric Chekwube Aniogo, Blassan Plackal Adimuriyil George and Heidi Abrahamse

Molecules 2020, 25(22), 5308; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25225308 - 13 Nov 2020

Cited by 23 | Viewed by 2878

Abstract

Photodynamic therapy (PDT) is a treatment modality that involves three components: combination of a photosensitizer, light and molecular oxygen that leads to localized formation of reactive oxygen species (ROS). The ROS generated from this promising therapeutic modality can be lethal to the cell [...] Read more.

Photodynamic therapy (PDT) is a treatment modality that involves three components: combination of a photosensitizer, light and molecular oxygen that leads to localized formation of reactive oxygen species (ROS). The ROS generated from this promising therapeutic modality can be lethal to the cell and leads to consequential destruction of tumor cells. However, sometimes the ROS trigger a stress response survival mechanism that helps the cells to cope with PDT-induced damage, resulting in resistance to the treatment. One preferred mechanism of cell death induced by PDT is apoptosis, and B-cell lymphoma 2 (Bcl-2) family proteins have been described as a major determinant of life or death decision of the death pathways. Apoptosis is a cellular self-destruction mechanism to remove old cells through the biological event of tissue homeostasis. The Bcl-2 family proteins act as a critical mediator of a life–death decision of cells in maintaining tissue homeostasis. There are several reports that show cancer cells developing resistance due to the increased interaction of the pro-survival Bcl-2 family proteins. However, the key mechanisms leading to apoptosis evasion and drug resistance have not been adequately understood. Therefore, it is critical to understand the mechanisms of PDT resistance, as well as the Bcl-2 family proteins, to give more insight into the treatment outcomes. In this review, we describe the role of Bcl-2 gene family proteins’ interaction in response to disease progression and PDT-induced resistance mechanisms. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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41 pages, 10627 KiB

Open AccessFeature PaperReview

Mitotic Poisons in Research and Medicine

by Jan Škubník, Michal Jurášek, Tomáš Ruml and Silvie Rimpelová

Molecules 2020, 25(20), 4632; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25204632 - 12 Oct 2020

Cited by 25 | Viewed by 6897

Abstract

Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one of the most common causes of human death in the world, mainly in low and [...] Read more.

Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one of the most common causes of human death in the world, mainly in low and middle-income countries. According to the World Health Organization (WHO), cancer treatment services are not available in more then 70% of low-income countries (90% of high-income countries have them available), and also approximately 70% of cancer deaths are reported in low-income countries. Various approaches on how to combat cancer diseases have since been described, targeting cell division being among them. The so-called mitotic poisons are one of the cornerstones in cancer therapies. The idea that cancer cells usually divide almost uncontrolled and far more rapidly than normal cells have led us to think about such compounds that would take advantage of this difference and target the division of such cells. Many groups of such compounds with different modes of action have been reported so far. In this review article, the main approaches on how to target cancer cell mitosis are described, involving microtubule inhibition, targeting aurora and polo-like kinases and kinesins inhibition. The main representatives of all groups of compounds are discussed and attention has also been paid to the presence and future of the clinical use of these compounds as well as their novel derivatives, reviewing the finished and ongoing clinical trials. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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20 pages, 7022 KiB

Open AccessReview

Review of the Synthesis and Anticancer Properties of Pyrazolo[4,3-e][1,2,4]triazine Derivatives

by Zofia Bernat, Anna Szymanowska, Mateusz Kciuk, Katarzyna Kotwica-Mojzych and Mariusz Mojzych

Molecules 2020, 25(17), 3948; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25173948 - 29 Aug 2020

Cited by 22 | Viewed by 3370

Abstract

This review focuses on the cytotoxic effect of new synthetic pyrazolo[4,3-e][1,2,4]triazine derivatives against different tumor cell lines. Some annulated pyrazolotriazines i.e., pyrazolo[4,3-e][1,2,4]triazolo[4,3-b][1,2,4]triazines and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine demonstrated significant broad cytotoxic activity in micromolar range concentration, [...] Read more.

This review focuses on the cytotoxic effect of new synthetic pyrazolo[4,3-e][1,2,4]triazine derivatives against different tumor cell lines. Some annulated pyrazolotriazines i.e., pyrazolo[4,3-e][1,2,4]triazolo[4,3-b][1,2,4]triazines and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine demonstrated significant broad cytotoxic activity in micromolar range concentration, which could have excellent potential to be new candidate therapeutic agents in cancer chemotherapy. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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15 pages, 1106 KiB

Open AccessReview

Annexin A1: A Bane or a Boon in Cancer? A Systematic Review

by Thanusha Ganesan, Ajantha Sinniah, Zaridatul Aini Ibrahim, Zamri Chik and Mohammed Abdullah Alshawsh

Molecules 2020, 25(16), 3700; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25163700 - 14 Aug 2020

Cited by 13 | Viewed by 2599

Abstract

Annexin A1 has been extensively investigated as an anti-inflammatory protein, but its role in different types of cancer has not been consolidated in a single systematic review to date. Thus, the aim of this paper is to systematically review and critically analyse 18 [...] Read more.

Annexin A1 has been extensively investigated as an anti-inflammatory protein, but its role in different types of cancer has not been consolidated in a single systematic review to date. Thus, the aim of this paper is to systematically review and critically analyse 18 studies (in-vivo and in-vitro) to consolidate, in a concerted manner, all the information on differential expression of Annexin A1 in different types of cancer and the role this protein plays in tumorigenesis. Pubmed, Scopus, Web of Science, and ScienceDirect were used for the literature search and the keywords used are “annexin A1,” “lipocortin 1,” “cancer,” “malignancy,” “neoplasm,” “neoplasia,” and “tumor.” A total of 1128 articles were retrieved by implementing a standard search strategy subjected to meticulous screening processes and 442 articles were selected for full article screening. A total of 18 articles that adhered to the inclusion criteria were included in the systematic review and these articles possessed low to moderate bias. These studies showed a strong correlation between Annexin A1 expression and cancer progression via modulation of various cancer-associated pathways. Differential expression of Annexin A1 is shown to play a role in cellular proliferation, metastasis, lymphatic invasion, and development of resistance to anti-cancer treatment. Meta-analysis in the future may provide a statistically driven association between Annexin A1 expression and malignancy progression. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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31 pages, 1191 KiB

Open AccessReview

Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications

by Ahmed El-Sharkawy and Ahmed Malki

Molecules 2020, 25(14), 3219; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25143219 - 15 Jul 2020

Cited by 74 | Viewed by 9162

Abstract

Vitamin D and its active metabolites are important nutrients for human skeletal health. UV irradiation of skin converts 7-dehydrocholesterol into vitamin D3, which metabolized in the liver and kidneys into its active form, 1α,25-dihydroxyvitamin D3. Apart from its classical role in calcium and [...] Read more.

Vitamin D and its active metabolites are important nutrients for human skeletal health. UV irradiation of skin converts 7-dehydrocholesterol into vitamin D3, which metabolized in the liver and kidneys into its active form, 1α,25-dihydroxyvitamin D3. Apart from its classical role in calcium and phosphate regulation, scientists have shown that the vitamin D receptor is expressed in almost all tissues of the body, hence it has numerous biological effects. These includes fetal and adult homeostatic functions in development and differentiation of metabolic, epidermal, endocrine, neurological and immunological systems of the body. Moreover, the expression of vitamin D receptor in the majority of immune cells and the ability of these cells to actively metabolize 25(OH)D3 into its active form 1,25(OH)₂D3 reinforces the important role of vitamin D signaling in maintaining a healthy immune system. In addition, several studies have showed that vitamin D has important regulatory roles of mechanisms controlling proliferation, differentiation and growth. The administration of vitamin D analogues or the active metabolite of vitamin D activates apoptotic pathways, has antiproliferative effects and inhibits angiogenesis. This review aims to provide an up-to-date overview on the effects of vitamin D and its receptor (VDR) in regulating inflammation, different cell death modalities and cancer. It also aims to investigate the possible therapeutic benefits of vitamin D and its analogues as anticancer agents. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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31 pages, 4385 KiB

Open AccessReview

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

by Solomon Habtemariam

Molecules 2020, 25(6), 1426; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25061426 - 20 Mar 2020

Cited by 38 | Viewed by 5212

Abstract

Berberine is multifunctional natural product with potential to treat diverse pathological conditions. Its broad-spectrum anticancer effect through direct effect on cancer cell growth and metastasis have been established both in vitro and in vivo. The cellular targets that account to the anticancer effect [...] Read more.

Berberine is multifunctional natural product with potential to treat diverse pathological conditions. Its broad-spectrum anticancer effect through direct effect on cancer cell growth and metastasis have been established both in vitro and in vivo. The cellular targets that account to the anticancer effect of berberine are incredibly large and range from kinases (protein kinase B (Akt), mitogen activated protein kinases (MAPKs), cell cycle checkpoint kinases, etc.) and transcription factors to genes and protein regulators of cell survival, motility and death. The direct effect of berberine in cancer cells is however relatively weak and occur at moderate concentration range (10–100 µM) in most cancer cells. The poor pharmacokinetics profile resulting from poor absorption, efflux by permeability-glycoprotein (P-gc) and extensive metabolism in intestinal and hepatic cells are other dimensions of berberine’s limitation as anticancer agent. This communication addresses the research efforts during the last two decades that were devoted to enhancing the anticancer potential of berberine. Strategies highlighted include using berberine in combination with other chemotherapeutic agents either to reduce toxic side effects or enhance their anticancer effects; the various novel formulation approaches which by order of magnitude improved the pharmacokinetics of berberine; and semisynthetic approaches that enhanced potency by up to 100-fold. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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21 pages, 1522 KiB

Open AccessReview

An Overview of the Potential Antineoplastic Effects of Casticin

by Shanaya Ramchandani, Irum Naz, Jong Hyun Lee, Muhammad Rashid Khan and Kwang Seok Ahn

Molecules 2020, 25(6), 1287; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25061287 - 12 Mar 2020

Cited by 32 | Viewed by 5847

Abstract

Cancer persists as one of the leading causes of deaths worldwide, contributing to approximately 9.6 million deaths per annum in recent years. Despite the numerous advancements in cancer treatment, there is still abundant scope to mitigate recurrence, adverse side effects and toxicities caused [...] Read more.

Cancer persists as one of the leading causes of deaths worldwide, contributing to approximately 9.6 million deaths per annum in recent years. Despite the numerous advancements in cancer treatment, there is still abundant scope to mitigate recurrence, adverse side effects and toxicities caused by existing pharmaceutical drugs. To achieve this, many phytochemicals from plants and natural products have been tested against cancer cell lines in vivo and in vitro. Likewise, casticin, a flavonoid extracted from the Vitex species, has been isolated from the leaves and seeds of V. trifolia and V. agnus-castus. Casticin possesses a wide range of therapeutic properties, including analgesic, anti-inflammatory, antiangiogenic, antiasthmatic and antineoplastic activities. Several studies have been conducted on the anticancer effects of casticin against cancers, including breast, bladder, oral, lung, leukemia and hepatocellular carcinomas. The compound inhibits invasion, migration and proliferation and induces apoptosis (casticin-induced, ROS-mediated and mitochondrial-dependent) and cell cycle arrest (G0/G1, G2/M, etc.) through different signaling pathways, namely the PI3K/Akt, NF-κB, STAT3 and FOXO3a/FoxM1 pathways. This review summarizes the chemo-preventive ability of casticin as an antineoplastic agent against several malignancies. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs II)

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