Molecules

Research

Jump to: Review

20 pages, 7938 KiB

Open AccessArticle

Assessment of Chemopreventive Potential of the Plant Extracts against Liver Cancer Using HepG2 Cell Line

by Deepthi Venkatachalapathy, Chandan Shivamallu, Shashanka K. Prasad, Gopenath Thangaraj Saradha, Parthiban Rudrapathy, Raghavendra G. Amachawadi, Sharanagouda S. Patil, Asad Syed, Abdallah M. Elgorban, Ali H. Bahkali, Shiva Prasad Kollur and Kanthesh M. Basalingappa

Molecules 2021, 26(15), 4593; https://doi.org/10.3390/molecules26154593 - 29 Jul 2021

Cited by 16 | Viewed by 3819

Abstract

The edible parts of the plants Camellia sinensis, Vitis vinifera and Withania somnifera were extensively used in ancient practices such as Ayurveda, owing to their potent biomedical significance. They are very rich in secondary metabolites such as polyphenols, which are very good [...] Read more.

The edible parts of the plants Camellia sinensis, Vitis vinifera and Withania somnifera were extensively used in ancient practices such as Ayurveda, owing to their potent biomedical significance. They are very rich in secondary metabolites such as polyphenols, which are very good antioxidants and exhibit anti-carcinogenic properties. This study aims to evaluate the anti-cancerous properties of these plant crude extracts on human liver cancer HepG2 cells. The leaves of Camellia sinensis, Withania somnifera and the seeds of Vitis vinifera were collected and methanolic extracts were prepared. Then, these extracts were subjected to DPPH, α- amylase assays to determine the antioxidant properties. A MTT assay was performed to investigate the viability of the extracts of HepG2 cells, and the mode of cell death was detected by Ao/EtBr staining and flow cytometry with PI Annexin- V FITC dual staining. Then, the protein expression of BAX and BCl2 was studied using fluorescent dye to determine the regulation of the BAX and BCl2 genes. We observed that all the three extracts showed the presence of bioactive compounds such as polyphenols or phytochemicals. The W. somnifera bioactive compounds were found to have the highest anti-proliferative activity on human liver cancer cells. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

18 pages, 8587 KiB

Open AccessArticle

Synthesis, Characterization, DNA/HSA Interactions, and Anticancer Activity of Two Novel Copper(II) Complexes with 4-Chloro-3-Nitrobenzoic Acid Ligand

by Zhen-Fang Zeng, Qiu-Ping Huang, Jie-Hui Cai, Guang-Jin Zheng, Qiu-Chan Huang, Zi-Lu Liu, Zi-Lu Chen and You-Huan Wei

Molecules 2021, 26(13), 4028; https://doi.org/10.3390/molecules26134028 - 1 Jul 2021

Cited by 21 | Viewed by 3341

Abstract

The purpose of this study was to identify new metal-based anticancer drugs; to this end, we synthesized two new copper(II) complexes, namely [Cu(ncba)₄(phen)] (1) and [Cu(ncba)₄(bpy)] (2), comprised 4-chloro-3-nitrobenzoic acid as the main ligand. The [...] Read more.

The purpose of this study was to identify new metal-based anticancer drugs; to this end, we synthesized two new copper(II) complexes, namely [Cu(ncba)₄(phen)] (1) and [Cu(ncba)₄(bpy)] (2), comprised 4-chloro-3-nitrobenzoic acid as the main ligand. The single-crystal XRD approach was employed to determine the copper(II) complex structures. Binding between these complexes and calf thymus DNA (CT-DNA) and human serum albumin (HSA) was explored by electronic absorption, fluorescence spectroscopy, and viscometry. Both complexes intercalatively bound CT-DNA and statically and spontaneously quenched DNA/HSA fluorescence. A CCK-8 assay revealed that complex 1 and complex 2 had substantial antiproliferative influences against human cancer cell lines. Moreover, complex 1 had greater antitumor efficacy than the positive control cisplatin. Flow cytometry assessment of the cell cycle demonstrated that these complexes arrested the HepG2 cell cycle and caused the accumulation of G0/G1-phase cells. The mechanism of cell death was elucidated by flow cytometry-based apoptosis assays. Western blotting revealed that both copper(II) complexes induced apoptosis by regulating the expression of the Bcl-2(Bcl-2, B cell lymphoma 2) protein family. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

32 pages, 7614 KiB

Open AccessArticle

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

by Faisal A. Almalki, Ashraf N. Abdalla, Ahmed M. Shawky, Mahmoud A. El Hassab and Ahmed M. Gouda

Molecules 2021, 26(13), 4002; https://doi.org/10.3390/molecules26134002 - 30 Jun 2021

Cited by 8 | Viewed by 3097

Abstract

In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed [...] Read more.

In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a–h were discussed. The antiproliferative activity of 16a–h was evaluated against three cancer (MCF7, A2780 and HT29, IC₅₀ = 0.01–40.50 μM) and one normal MRC5 (IC₅₀ = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC₅₀ = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G₂/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

12 pages, 7854 KiB

Open AccessArticle

A Novel N-Tert-Butyl Derivatives of Pseudothiohydantoin as Potential Target in Anti-Cancer Therapy

by Daria Kupczyk, Renata Studzińska, Szymon Baumgart, Rafał Bilski, Tomasz Kosmalski, Renata Kołodziejska and Alina Woźniak

Molecules 2021, 26(9), 2612; https://doi.org/10.3390/molecules26092612 - 29 Apr 2021

Cited by 6 | Viewed by 2184

Abstract

Tumors are currently more and more common all over the world; hence, attempts are being made to explain the biochemical processes underlying their development. The search for new therapeutic pathways, with particular emphasis on enzymatic activity and its modulation regulating the level of [...] Read more.

Tumors are currently more and more common all over the world; hence, attempts are being made to explain the biochemical processes underlying their development. The search for new therapeutic pathways, with particular emphasis on enzymatic activity and its modulation regulating the level of glucocorticosteroids, may contribute to the development and implementation of new therapeutic options in the treatment process. Our research focuses on understanding the role of 11β-HSD1 and 11β-HSD2 as factors involved in the differentiation and proliferation of neoplastic cells. In this work, we obtained the 9 novel N-tert-butyl substituted 2-aminothiazol-4(5H)-one (pseudothiohydantoin) derivatives, differing in the substituents at C-5 of the thiazole ring. The inhibitory activity and selectivity of the obtained derivatives in relation to two isoforms of 11β-HSD were evaluated. The highest inhibitory activity for 11β-HSD1 showed compound 3h, containing the cyclohexane substituent at the 5-position of the thiazole ring in the spiro system (82.5% at a conc. 10 µM). On the other hand, the derivative 3f with the phenyl substituent at C-5 showed the highest inhibition of 11β-HSD2 (53.57% at a conc. of 10 µM). A low selectivity in the inhibition of 11β-HSD2 was observed but, unlike 18β-glycyrrhetinic acid, these compounds were found to inhibit the activity of 11β-HSD2 to a greater extent than 11β-HSD1, which makes them attractive for further research on their anti-cancer activity. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

14 pages, 1328 KiB

Open AccessArticle

Preparation, Spectroscopic Characterization, Theoretical Investigations, and In Vitro Anticancer Activity of Cd(II), Ni(II), Zn(II), and Cu(II) Complexes of 4(3H)-Quinazolinone-Derived Schiff Base

by Ubale Panchsheela Ashok, Shiva Prasad Kollur, Nishad Anil, Bansode Prakash Arun, Sanjay Namdev Jadhav, Sanjay Sarsamkar, Vasant Baburao Helavi, Asha Srinivasan, Sandeep Kaulage, Ravindra Veerapur, Sarah Al-Rashed, Asad Syed, Joaquín Ortega-Castro, Juan Frau, Norma Flores-Holguín and Daniel Glossman-Mitnik

Molecules 2020, 25(24), 5973; https://doi.org/10.3390/molecules25245973 - 16 Dec 2020

Cited by 17 | Viewed by 3135

Abstract

Herein, we report the synthesis and characterization of a new Schiff base ligand 3-[[(E)-(3-hydroxyphenyl)-methylidene]amino]-2-methyl-quinazolin-4(3H)-one (HAMQ) and its Cd(II), Ni(II), Zn(II), and Cu(II) complexes (C₁–C₄ [...] Read more.

Herein, we report the synthesis and characterization of a new Schiff base ligand 3-[[(E)-(3-hydroxyphenyl)-methylidene]amino]-2-methyl-quinazolin-4(3H)-one (HAMQ) and its Cd(II), Ni(II), Zn(II), and Cu(II) complexes (C₁–C₄). The ligand HAMQ was synthesized by reacting 3-hydroxybenzaldehyde and 3-amino-2-methyl-4(3H)-quinazolinone in a 1:1 molar ratio. The structure of the ligand and its complexes (C₁–C₄) were evaluated using ultraviolet (UV)–visible (Vis) light spectroscopy, ¹H-NMR, Fourier-transform infrared (FT-IR) spectroscopy, MS, elemental analysis, conductance data, and thermogravimetric analysis (TGA). The characterization results suggested that the bidentate ligand, HAMQ, coordinated to the metal center through the lactum oxygen and the azomethine nitrogen. Moreover, all the metal complexes were analyzed using powder X-ray diffraction studies, which revealed that all of them belong to a triclinic crystal system. The research was supplemented by density functional theory (DFT) studies on the IR and UV–Vis spectra, as well as the chemical reactivity of the HAMQ and its four metallic derivatives making use of conceptual density functional theory (CDFT) by means of KID (Koopmans in DFT) methodology. The synthesized complexes displayed significant in vitro anticancer activity against human cancer cell lines (HeLa and HCT-115). Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

22 pages, 4195 KiB

Open AccessArticle

Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

by Ashraf N. Abdalla, Amal Qattan, Waleed H. Malki, Imran Shahid, Mohammad Akbar Hossain and Muhammad Ahmed

Molecules 2020, 25(20), 4606; https://doi.org/10.3390/molecules25204606 - 10 Oct 2020

Cited by 24 | Viewed by 3417

Abstract

The hormonal luminal-A is the most pre-dominant sub type of breast cancer (BC), and it is associated with a high level of cyclin D1 in Saudi patients. Tamoxifen is the golden therapy for hormonal BC, but resistance of cancer cells to tamoxifen contributes [...] Read more.

The hormonal luminal-A is the most pre-dominant sub type of breast cancer (BC), and it is associated with a high level of cyclin D1 in Saudi patients. Tamoxifen is the golden therapy for hormonal BC, but resistance of cancer cells to tamoxifen contributes to the recurrence of BC due to many reasons, including high levels of AIB1 and cyclin D1. Overcoming drug resistance could be achieved by exploring alternative targetable therapeutic pathways and new drugs or combinations. The objective of this study was to determine the differentially enriched pathways in 12 samples of Saudi women diagnosed with luminal-A using the PamChip peptide microarray-based kinase activity profiling, and to compare the activity of HAA₂₀₂₀ and dinaciclib with tamoxifen in singles and combinations in the MCF7 luminal-A cell line. Our results of network and pathway analysis of the 12 samples highlighted the importance of VEGFR and CDKs in promoting luminal-A breast cancer. The activation of VEGF signaling via VEGFR-2 leads to activation of PI3K/AKT kinases and an increase of cell survival, and leads to activation of Hsp90, which induces the phosphorylation of FAK1, resulting in cytoskeleton remodeling. PLC-gamma 1 is also activated, leading to FAK-2 and PKC activation. Notably, the G₁/S cell cycle phases and phosphorylation processes contribute to the top seven tumorigenesis processes in the 12 samples. Further, the MTT combination of HAA₂₀₂₀ and dinaciclib showed the best combination index (CI), was more clonogenic against MCF7 cells compared to the other combinations, and it also showed the best selectivity index (SI) in normal MRC5 cells. Interestingly, HAA₂₀₂₀ and dinaciclib showed a synergistic apoptotic and G₁ cell cycle effect in MCF7 cells, which was supported by their synergistic CDK2, cyclin D1, and PCNA inhibition activities. Additionally, the combination showed VEGFR-2 and Hsp90 inhibition activities in MCF7 cells. The results show the significance of targeting VEGFR-2 and cyclin D1 in Saudi luminal-A breast cancer patients, and the effect of combining HAA₂₀₂₀ and dinaciclib on those targets in the MCF7 model. It also warrants further preclinical and in vivo investigations for the combination of HAA₂₀₂₀ and dinaciclib as a possible future second-line treatment for luminal-A breast cancers. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

12 pages, 880 KiB

Open AccessArticle

Synthesis of Novel 2-(Isopropylamino)thiazol-4(5H)-one Derivatives and Their Inhibitory Activity of 11β-HSD1 and 11β-HSD2 in Aspect of Carcinogenesis Prevention

by Daria Kupczyk, Renata Studzińska, Rafał Bilski, Szymon Baumgart, Renata Kołodziejska and Alina Woźniak

Molecules 2020, 25(18), 4233; https://doi.org/10.3390/molecules25184233 - 15 Sep 2020

Cited by 7 | Viewed by 2521

Abstract

Glucocorticoid metabolism at the tissue level is regulated by two isoenzymes 11β-hydroxysteroid dehydrogenase (11β-HSD), which mutually convert biologically active cortisol and inactive cortisone. Recent research is focused on the role of 11β-HSD1 and 11β-HSD2 as autocrine factors of tumor cell proliferation and differentiation. [...] Read more.

Glucocorticoid metabolism at the tissue level is regulated by two isoenzymes 11β-hydroxysteroid dehydrogenase (11β-HSD), which mutually convert biologically active cortisol and inactive cortisone. Recent research is focused on the role of 11β-HSD1 and 11β-HSD2 as autocrine factors of tumor cell proliferation and differentiation. Herein, we report the synthesis of novel 2-(isopropylamino)thiazol-4(5H)-one derivatives and their inhibitory activity for 11β-HSD1 and 11β-HSD2. The derivative containing the spiro system of thiazole and cyclohexane rings shows the highest degree of 11β-HSD1 inhibition (54.53% at 10 µM) and is the most selective inhibitor of this enzyme among the tested compounds. In turn, derivatives containing ethyl and n-propyl group at C-5 of thiazole ring inhibit the activity of 11β-HSD2 to a high degree (47.08 and 54.59% at 10 µM respectively) and are completely selective. Inhibition of the activity of these enzymes may have a significant impact on the process of formation and course of tumors. Therefore, these compounds can be considered as potential pharmaceuticals supporting anti-cancer therapy. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

12 pages, 3152 KiB

Open AccessArticle

Identification of the Effects of Aspirin and Sulindac Sulfide on the Inhibition of HMGA2-Mediated Oncogenic Capacities in Colorectal Cancer

by Titus Ime Ekanem, Wei-Lun Tsai, Yi-Hsuan Lin, Wan-Qian Tan, Hsin-Yi Chang, Tsui-Chin Huang, Hsin-Yi Chen and Kuen-Haur Lee

Molecules 2020, 25(17), 3826; https://doi.org/10.3390/molecules25173826 - 22 Aug 2020

Cited by 8 | Viewed by 2937

Abstract

Distant metastatic colorectal cancer (CRC) is present in approximately 25% of patients at initial diagnosis, and eventually half of CRC patients will develop metastatic disease. The 5-year survival rate for patients with metastatic CRC is a mere 12.5%; thus, there is an urgent [...] Read more.

Distant metastatic colorectal cancer (CRC) is present in approximately 25% of patients at initial diagnosis, and eventually half of CRC patients will develop metastatic disease. The 5-year survival rate for patients with metastatic CRC is a mere 12.5%; thus, there is an urgent need to investigate the molecular mechanisms of cancer progression in CRC. High expression of human high-mobility group A2 (HMGA2) is related to tumor progression, a poor prognosis, and a poor response to therapy for CRC. Therefore, HMGA2 is an attractive target for cancer therapy. In this study, we identified aspirin and sulindac sulfide as novel potential inhibitors of HMGA2 using a genome-wide mRNA signature-based approach. In addition, aspirin and sulindac sulfide induced cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration. Moreover, a gene set enrichment analysis (GSEA) revealed that gene sets related to inflammation were positively correlated with HMGA2 and that the main molecular function of these genes was categorized as a G-protein-coupled receptor (GPCR) activity event. Collectively, this is the first study to report that aspirin and sulindac sulfide are novel potential inhibitors of HMGA2, which can induce cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration through influencing inflammatory-response genes, the majority of which are involved in GPCR signaling. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

23 pages, 2364 KiB

Open AccessArticle

The Curcumin Analogue, MS13 (1,5-Bis(4-hydroxy-3- methoxyphenyl)-1,4-pentadiene-3-one), Inhibits Cell Proliferation and Induces Apoptosis in Primary and Metastatic Human Colon Cancer Cells

by Nor Isnida Ismail, Iekhsan Othman, Faridah Abas, Nordin H. Lajis and Rakesh Naidu

Molecules 2020, 25(17), 3798; https://doi.org/10.3390/molecules25173798 - 20 Aug 2020

Cited by 20 | Viewed by 4362

Abstract

The cytotoxic and apoptotic effects of turmeric (Curcuma longa) on colon cancer have been well documented but specific structural modifications of curcumin have been shown to possess greater growth-suppressive potential on colon cancer than curcumin. Therefore, the aim of this study is to [...] Read more.

The cytotoxic and apoptotic effects of turmeric (Curcuma longa) on colon cancer have been well documented but specific structural modifications of curcumin have been shown to possess greater growth-suppressive potential on colon cancer than curcumin. Therefore, the aim of this study is to identify the anti-cancer properties of curcumin analogue-MS13, a diarylpentanoid on the cytotoxicity, anti-proliferative and apoptotic activity of primary (SW480) and metastatic (SW620) human colon cancer cells. A cell viability assay showed that MS13 has greater cytotoxicity effect on SW480 (EC₅₀: 7.5 ± 2.8 µM) and SW620 (EC₅₀: 5.7 ± 2.4 µM) compared to curcumin (SW480, EC₅₀: 30.6 ± 1.4 µM) and SW620, EC₅₀: 26.8 ± 2.1 µM). Treatment with MS13 at two different doses 1X EC₅₀ and 2X EC₅₀ suppressed the colon cancer cells growth with lower cytotoxicity against normal cells. A greater anti-proliferative effect was also observed in MS13 treated colon cancer cells compared to curcumin at 48 and 72 h. Subsequent analysis on the induction of apoptosis showed that MS13 treated cells exhibited morphological features associated with apoptosis. The findings are also consistent with cellular apoptotic activities shown by increased caspase-3 activity and decreased Bcl-2 protein level in both colon cancer cell lines. In conclusion, MS13 able to suppress colon cancer cell growth by inhibiting cell proliferation and induce apoptosis in primary and metastatic human colon cancer cells. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

16 pages, 6221 KiB

Open AccessArticle

New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking

by Julia Krzywik, Maral Aminpour, Ewa Maj, Witold Mozga, Joanna Wietrzyk, Jack A. Tuszyński and Adam Huczyński

Molecules 2020, 25(15), 3540; https://doi.org/10.3390/molecules25153540 - 2 Aug 2020

Cited by 13 | Viewed by 5116

Abstract

Colchicine is a well-known anticancer compound showing antimitotic effect on cells. Its high cytotoxic activity against different cancer cell lines has been demonstrated many times. In this paper we report the syntheses and spectroscopic analyses of novel colchicine derivatives obtained by structural modifications [...] Read more.

Colchicine is a well-known anticancer compound showing antimitotic effect on cells. Its high cytotoxic activity against different cancer cell lines has been demonstrated many times. In this paper we report the syntheses and spectroscopic analyses of novel colchicine derivatives obtained by structural modifications at C7 (carbon-nitrogen single bond) and C10 (methylamino group) positions. All the obtained compounds have been tested in vitro to determine their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX, and BALB/3T3 cell lines. The majority of obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin and cisplatin against the tested cancerous cell lines. Additionally, most of the presented derivatives were able to overcome the resistance of LoVo/DX cells. Additionally, their mode of binding to β-tubulin was evaluated in silico. Molecular docking studies showed that apart from the initial amides 1 and 2, compound 14, which had the best antiproliferative activity (IC₅₀ = 0.1–1.6 nM), stood out also in terms of its predicted binding energy and probably binds best into the active site of βI-tubulin isotype. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

24 pages, 24575 KiB

Open AccessArticle

The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer

by Marta Hałas-Wiśniewska, Wioletta Zielińska, Magdalena Izdebska and Alina Grzanka

Molecules 2020, 25(13), 3045; https://doi.org/10.3390/molecules25133045 - 3 Jul 2020

Cited by 19 | Viewed by 3606

Abstract

Background: Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids—piperlongumine (PL), sanguinarine (SAN) and their combination—on the [...] Read more.

Background: Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids—piperlongumine (PL), sanguinarine (SAN) and their combination—on the basic life processes of the A549 cell line was considered reasonable. Methods: The aim was achieved by analyzing the cytotoxic effects of PL and SAN and their combination in the ratio of 4:1 on the induction of cell death, changes in the distribution of cell cycle phases, reorganization of cytoskeleton and metastatic potential of A549 cells. The versatility of the applied concentration ratio was evaluated in terms of other cancer cell lines: MCF-7, H1299 and HepG2. Results: The results obtained from the MTT assay indicated that the interaction between the alkaloids depends on the concentration and type of cells. Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells. The combined effects of PL and SAN increased apoptosis and favored metastasis inhibition. Conclusion: Selected alkaloids exhibit a cytotoxic effect on A549 cells. In turn, treatment with the combination of PL and SAN in a 4:1 ratio indicates a synergistic effect and is associated with an increase in the level of reactive oxygen species (ROS). Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

11 pages, 1324 KiB

Open AccessArticle

Sesquiterpene Lactones from Calea pinnatifida: Absolute Configuration and Structural Requirements for Antitumor Activity

by Lhaís Araújo Caldas, Mariana T. Rodrigues, Andrea N. L. Batista, João M. Batista, Jr., João H. G. Lago, Marcelo J. P. Ferreira, Ileana G. S. Rubio and Patricia Sartorelli

Molecules 2020, 25(13), 3005; https://doi.org/10.3390/molecules25133005 - 30 Jun 2020

Cited by 2 | Viewed by 2388

Abstract

This work describes the chromatographic fractionation of the aerial parts of Calea pinnatifida and the structural characterization and determination of the absolute configuration of the isolated compounds as well as their antitumor potential. The HPLC fractionation of the CH₂Cl₂ phase [...] Read more.

This work describes the chromatographic fractionation of the aerial parts of Calea pinnatifida and the structural characterization and determination of the absolute configuration of the isolated compounds as well as their antitumor potential. The HPLC fractionation of the CH₂Cl₂ phase of the MeOH extract from the leaves of C. pinnatifida led to the isolation of two related sesquiterpene lactones (STLs): calein C (1) and calealactone B (2). Additionally, during the purification process, a derivative of calein C (3) was formed as a product of the Michael addition of MeOH. The structures of Compounds 1–3 were established based on spectroscopic and spectrometric data, while the absolute stereochemistry was established by vibrational circular dichroism. In order to evaluate the effect of the conjugated double bonds on the cytotoxic activity of STLs, Compounds 1–3 were tested against anaplastic (KTC-2) and papillary (TPC-1) thyroid carcinoma cells. Calein C was the most active of the STLs, and displayed activity against both KTC-2 and TPC-1. On the other hand, the calein C derivative (3) was the least cytotoxic of all the compounds tested. These results are promising and suggest the importance of studying sesquiterpene lactones isolated from C. pinnatifida in terms of antitumor activity, especially considering the effects of α,β-unsaturated carbonyl systems. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

13 pages, 2458 KiB

Open AccessArticle

Tumoricidal Potential of Novel Amino-1,10-phenanthroline Derived Imine Ligands: Chemical Preparation, Structure, and Biological Investigations

by Kollur Shiva Prasad, Renjith Raveendran Pillai, Chandan Shivamallu, Shashanka K. Prasad, Anisha S. Jain, Sushma Pradeep, Stevan Armaković, Sanja J. Armaković, Chandrashekar Srinivasa, Sharadadevi Kallimani, Raghavendra G. Amachawadi, Veena Malligere Ankegowda, Najat Marraiki, Abdallah M. Elgorban and Asad Syed

Molecules 2020, 25(12), 2865; https://doi.org/10.3390/molecules25122865 - 22 Jun 2020

Cited by 11 | Viewed by 3427

Abstract

Herein we report the synthesis and structural elucidation of two novel imine-based ligands, 2-(1,10-phenanthrolin-5-yl)imino)methyl)-5-bromophenol (PIB) and N-(1,10-phenanthrolin-5-yl)-1-(thiophen-3-yl)methanimine (PTM) ligands. An in vitro cytotoxicity assay of the synthesized molecules was carried out against breast, cervical, colorectal, and prostate cancer cell lines as well [...] Read more.

Herein we report the synthesis and structural elucidation of two novel imine-based ligands, 2-(1,10-phenanthrolin-5-yl)imino)methyl)-5-bromophenol (PIB) and N-(1,10-phenanthrolin-5-yl)-1-(thiophen-3-yl)methanimine (PTM) ligands. An in vitro cytotoxicity assay of the synthesized molecules was carried out against breast, cervical, colorectal, and prostate cancer cell lines as well as immortalized human keratinocytes. The observations indicated that both the molecules possesses dose-dependent selective cytotoxicity of cancer cells with no detrimental effect on the normal cell lines. Furthermore, the detailed computational analysis of newly synthetized ligands (PIB and PTM) has been conducted in order to identify their most important parts from the perspective of local reactivity. The IC₅₀ values of PIB treatment on MCF-7, HeLa, HCT-116 and PC-3 were 15.10, 16.25, 17.88, 17.55 and 23.86 micromoles, respectively. Meanwhile, the IC₅₀ values of PTM on MCF-7, HeLa, HCT-116, PC-3 and HaCat were observed to be 14.82, 15.03, 17.88, 17.28 and 21.22 micromoles, respectively. For computational analysis, we have employed the combination of Density Functional Theory (DFT) calculations and MD simulations. DFT calculations provided us with information about structure and reactivity descriptors based on the electron distribution. Surfaces of molecular electrostatic potential (MEP) and averaged local ionization energy (ALIE) indicated the sites within studied molecules that are most reactive. These results indicated the importance of nitrogen atoms and OH group. Additionally, the values of bond dissociation for hydrogen abstraction showed that both molecules, especially the PTM, are stable toward the influence of autoxidation mechanism. On the other side, MD simulations gave us an insight how ligands interact with water molecules. Namely, the radial distribution functions (RDF) indicated that the hydrogen atom of the OH group in the case of the PIB has the most pronounced interactions with water. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

12 pages, 1889 KiB

Open AccessArticle

Antitumor Activity of New Olivacine Derivatives

by Janusz Piasny, Benita Wiatrak, Agnieszka Dobosz, Beata Tylińska and Tomasz Gębarowski

Molecules 2020, 25(11), 2512; https://doi.org/10.3390/molecules25112512 - 28 May 2020

Cited by 7 | Viewed by 3231

Abstract

Olivacine is an alkaloid-containing pyridocarbazole structure. It is isolated from the bark of the evergreen timber tree, Aspidosperma olivaceum. Its well-documented anticancer activity led to the synthesis of new derivatives, which are semisynthetic and fully synthetic pyridocarbazoles. This study aimed to evaluate the [...] Read more.

Olivacine is an alkaloid-containing pyridocarbazole structure. It is isolated from the bark of the evergreen timber tree, Aspidosperma olivaceum. Its well-documented anticancer activity led to the synthesis of new derivatives, which are semisynthetic and fully synthetic pyridocarbazoles. This study aimed to evaluate the potential antineoplastic activity of four newly synthesized olivacine derivatives. Multidrug resistance is a common phenomenon causing failure in the chemotherapy of many tumors. It is mainly related to increased function of P-glycoprotein, an efflux pump removing cytostatic out of the cells. The cell lines used in the study were colorectal carcinoma cell lines: LoVo (doxorubicin-sensitive) and LoVo/DX (doxorubicin-resistant). The NHDF cell line was used to assess cell viability. First, the cells were incubated with olivacine derivatives. In the next step, the following assays were performed: DCF-DA assay, MTT assay, rhodamine 123 assay, detection of apoptosis, proliferation inhibition-mitotic index. The tested compounds showed higher antineoplastic potential and lower toxicity than the reference compound ellipticine. The results indicate that the new olivacine derivatives are good candidates for future anticancer drugs. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

19 pages, 3975 KiB

Open AccessArticle

Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors

by Ashraf N. Abdalla, Mohamed E. Abdallah, Akhmed Aslam, Ammar Bader, Antonio Vassallo, Nunziatina De Tommasi, Waleed H. Malki, Ahmed M. Gouda, Mohammed H. Mukhtar, Mahmoud Zaki El-Readi, Hamad M. Alkahtani, Alaa A.-M. Abdel-Aziz and Adel S. El-Azab

Molecules 2020, 25(9), 2220; https://doi.org/10.3390/molecules25092220 - 8 May 2020

Cited by 26 | Viewed by 4745

Abstract

Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in [...] Read more.

Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in AML, which has a central role in the regulation of apoptosis and cell proliferation through client proteins including the growth factor receptors and cyclin dependent kinases. The objective of the first part of this study is to investigate the putative Hsp90 inhibition activity of three novel previously synthesized quinazolines, which showed HL60 cytotoxicity and VEGFR2 and EGFR kinases inhibition activities. Using surface plasmon resonance, compound 1 (HAA₂₀₂₀) showed better Hsp90 inhibition compared to 17-AAG, and a docking study revealed that it fits nicely into the ATPase site. The objective of the second part is to maximize the anti-leukemic activity of HAA₂₀₂₀, which was combined with each of the eleven standard inhibitors. The best resulting synergistic effect in HL60 cells was with the pan cyclin-dependent kinases (CDK) inhibitor dinaciclib, using an MTT assay. Furthermore, the inhibiting effect of the Hsp90α gene by the combination of HAA₂₀₂₀ and dinaciclib was associated with increased caspase-7 and TNF-α, leading to apoptosis in HL60 cells. In addition, the combination upregulated p27 simultaneously with the inhibition of cyclinD3 and CDK2, leading to abolished HL60 proliferation and survival. The actions of HAA₂₀₂₀ propagated the apoptotic and cell cycle control properties of dinaciclib, showing the importance of co-targeting Hsp90 and CDK, which could lead to the better management of leukemia. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

15 pages, 4182 KiB

Open AccessArticle

A Tryptophan Metabolite, 8-Hydroxyquinaldic Acid, Exerts Antiproliferative and Anti-Migratory Effects on Colorectal Cancer Cells

by Katarzyna Walczak, Ewa Langner, Karolina Szalast, Anna Makuch-Kocka, Piotr Pożarowski and Tomasz Plech

Molecules 2020, 25(7), 1655; https://doi.org/10.3390/molecules25071655 - 3 Apr 2020

Cited by 24 | Viewed by 3348

Abstract

8-Hydroxyquinaldic acid, the end-metabolite of tryptophan, is well-known metal chelator; however, its role in humans, especially in cancer promotion and progression, has not been fully revealed. Importantly, 8-hydroxyquinaldic acid is the analog of kynurenic acid with evidenced antiproliferative activity towards various cancer cells. [...] Read more.

8-Hydroxyquinaldic acid, the end-metabolite of tryptophan, is well-known metal chelator; however, its role in humans, especially in cancer promotion and progression, has not been fully revealed. Importantly, 8-hydroxyquinaldic acid is the analog of kynurenic acid with evidenced antiproliferative activity towards various cancer cells. In this study, we revealed that 8-hydroxyquinaldic acid inhibited not only proliferation and mitochondrial activity in colon cancer HT-29 and LS-180 cells, but it also decreased DNA synthesis up to 90.9% for HT-29 cells and 76.1% for LS-180 cells. 8-Hydroxyquinaldic acid induced changes in protein expression of cell cycle regulators (CDK4, CDK6, cyclin D1, cyclin E) and CDKs inhibitors (p21 Waf1/Cip1, p27 Kip1), but the effect was dependent on the tested cell line. Moreover, 8-hydroxyquinaldic acid inhibited migration of colon cancer HT-29 and LS-180 cells and increased the expression of β-catenin and E-cadherin. Importantly, antiproliferative and anti-migratory concentrations of 8-hydroxyquinaldic acid were non-toxic in vitro and in vivo. We reported for the first time antiproliferative and anti-migratory activity of 8-hydroxyquinaldic acid against colon cancer HT-29 and LS-180 cells. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

13 pages, 2481 KiB

Open AccessArticle

Thermodynamic and Spectroscopic Studies of the Complexes Formed in Tartaric Acid and Lanthanide(III) Ions Binary Systems

by Michal Zabiszak, Martyna Nowak, Zbigniew Hnatejko, Jakub Grajewski, Kazuma Ogawa, Malgorzata T. Kaczmarek and Renata Jastrzab

Molecules 2020, 25(5), 1121; https://doi.org/10.3390/molecules25051121 - 3 Mar 2020

Cited by 16 | Viewed by 3727

Abstract

Binary complexes of tartaric acid with lanthanide(III) ions were investigated. The studies have been performed in aqueous solution using the potentiometric method with computer analysis of the data for detection of the complexes set, determination of the stability constants of these compounds. The [...] Read more.

Binary complexes of tartaric acid with lanthanide(III) ions were investigated. The studies have been performed in aqueous solution using the potentiometric method with computer analysis of the data for detection of the complexes set, determination of the stability constants of these compounds. The mode of the coordination of complexes found was determined using spectroscopy, which shows: Infrared, circular dichroism, ultraviolet, visible as well as luminescence spectroscopy. The overall stability constants of the complexes as well as the equilibrium constants of the reaction were determined. Analysis of the equilibrium constants of the reactions and spectroscopic data allowed the effectiveness of the carboxyl groups in the process of complex formation. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

13 pages, 1961 KiB

Open AccessArticle

Conjugation of Aspergillus flavipes Taxol with Porphyrin Increases the Anticancer Activity of Taxol and Ameliorates Its Cytotoxic Effects

by Ashraf S. A. El-Sayed, Maher Fathalla, Marwa A. Yassin, Nabila Zein, Shaima Morsy, Mahmoud Sitohy and Basel Sitohy

Molecules 2020, 25(2), 263; https://doi.org/10.3390/molecules25020263 - 9 Jan 2020

Cited by 35 | Viewed by 3936

Abstract

Taxol is one of the potential anticancer drugs; however, the yield of Taxol and its cytotoxicity are common challenges. Thus, manipulating the Taxol biosynthetic pathway from endophytic fungi, in addition to chemical modification with biocompatible polymers, is the challenge. Four fungal isolates, namely, [...] Read more.

Taxol is one of the potential anticancer drugs; however, the yield of Taxol and its cytotoxicity are common challenges. Thus, manipulating the Taxol biosynthetic pathway from endophytic fungi, in addition to chemical modification with biocompatible polymers, is the challenge. Four fungal isolates, namely, Aspergillus flavipes, A. terreus, A. flavus, and A. parasiticus, were selected from our previous study as potential Taxol producers, and their potency for Taxol production was evaluated in response to fluconazole and silver nitrate. A higher Taxol yield was reported in the cultures of A. flavipes (185 µg/L) and A. terreus (66 µg/L). With addition of fluconazole, the yield of Taxol was increased 1.8 and 1.2-fold for A. flavipes and A. terreus, respectively, confirming the inhibition of sterol biosynthesis and redirecting the geranyl phosphate pool to terpenoids synthesis. A significant inhibition of ergosterol biosynthesis by A. flavipes with addition of fluconazole was observed, correlating with the increase on Taxol yield. To increase the Taxol solubility and to reduce its cytotoxicity, Taxol was modified via chemical conjugation with porphyrin, and the degree of conjugation was checked from the Thin layer chromatography and UV spectral analysis. The antiproliferative activity of native and modified Taxol conjugates was evaluated; upon porphyrin conjugation, the activity of Taxol towards HepG2 was increased 1.5-fold, while its cytotoxicity to VERO cells was reduced 3-fold. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

12 pages, 2836 KiB

Open AccessArticle

Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy

by Taj Mohammad, Sagar Batra, Rashmi Dahiya, Mohammad Hassan Baig, Irfan Ahmad Rather, Jae-June Dong and Imtaiyaz Hassan

Molecules 2019, 24(24), 4589; https://doi.org/10.3390/molecules24244589 - 15 Dec 2019

Cited by 40 | Viewed by 4554

Abstract

Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. [...] Read more.

Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2 in-complex with the selected compound. We found that binding of 6-N,6-N-dimethyl-9-(2-phenylethyl)purine-2,6-diamine stabilizes the structure of CDK2 and causes minimal conformational change. Finally, we suggest that the compound (PubChem ID 101874157) would be a promising scaffold to be further exploited as a potential inhibitor of CDK2 for therapeutic management of cancer after required validation. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

Review

Jump to: Research

56 pages, 25664 KiB

Open AccessReview

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

by Mohammed A. S. Abourehab, Alaa M. Alqahtani, Bahaa G. M. Youssif and Ahmed M. Gouda

Molecules 2021, 26(21), 6677; https://doi.org/10.3390/molecules26216677 - 4 Nov 2021

Cited by 99 | Viewed by 13069

Abstract

Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been [...] Read more.

Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

15 pages, 995 KiB

Open AccessReview

Cytotoxic and Proapoptotic Effects of Resveratrol in In Vitro Studies on Selected Types of Gastrointestinal Cancers

by Katarzyna Ratajczak and Sylwia Borska

Molecules 2021, 26(14), 4350; https://doi.org/10.3390/molecules26144350 - 18 Jul 2021

Cited by 7 | Viewed by 2550

Abstract

Cancer diseases are currently one of the greatest health challenges in clinical medicine worldwide. Classic methods of treatment often lead to numerous side effects, including the development of multidrug resistance. For this reason, increasing hope is being placed on compounds of natural origin, [...] Read more.

Cancer diseases are currently one of the greatest health challenges in clinical medicine worldwide. Classic methods of treatment often lead to numerous side effects, including the development of multidrug resistance. For this reason, increasing hope is being placed on compounds of natural origin, mainly due to their pleiotropic effect on different types of cells, protective effect on normal cells and toxic effect on cancerous ones. The most studied group are the polyphenolic compounds, which include resveratrol. The effectiveness of polyphenols in the treatment and prevention of many diseases, including cancer of various origins, has become the basis of many scientific studies. The anticancer effect of resveratrol has been demonstrated at all stages of the carcinogenesis process. Additionally, whether administered by itself or in combination with cytostatics, it may play a significant role in the process of reversing multidrug resistance. A review of the effects of resveratrol in in vitro conditions proves that it has a stronger or weaker antiproliferative and proapoptotic effect on the cells of certain neoplasms of the gastrointestinal tract. Despite the differences in the effect of this compound on different types of cancer, a similar tendency can be observed especially regarding the correlation between the concentration of the compound and the incubation time on the one hand and the antitumour effect on the other hand. The information included in this review may prove helpful in planning in vivo and clinical studies in the future. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

24 pages, 5634 KiB

Open AccessReview

What Can Electrochemical Methods Offer in Determining DNA–Drug Interactions?

by Sandra Ramotowska, Aleksandra Ciesielska and Mariusz Makowski

Molecules 2021, 26(11), 3478; https://doi.org/10.3390/molecules26113478 - 7 Jun 2021

Cited by 33 | Viewed by 5607

Abstract

The interactions of compounds with DNA have been studied since the recognition of the role of nucleic acid in organisms. The design of molecules which specifically interact with DNA sequences allows for the control of the gene expression. Determining the type and strength [...] Read more.

The interactions of compounds with DNA have been studied since the recognition of the role of nucleic acid in organisms. The design of molecules which specifically interact with DNA sequences allows for the control of the gene expression. Determining the type and strength of such interaction is an indispensable element of pharmaceutical studies. Cognition of the therapeutic action mechanisms is particularly important for designing new drugs. Owing to their sensitivity, simplicity, and low costs, electrochemical methods are increasingly used for this type of research. Compared to other techniques, they require a small number of samples and are characterized by a high reliability. These methods can provide information about the type of interaction and the binding strength, as well as the damage caused by biologically active molecules targeting the cellular DNA. This review paper summarizes the various electrochemical approaches used for the study of the interactions between pharmaceuticals and DNA. The main focus is on the papers from the last decade, with particular attention on the voltammetric techniques. The most preferred experimental approaches, the electrode materials and the new methods of modification are presented. The data on the detection ranges, the binding modes and the binding constant values of pharmaceuticals are summarized. Both the importance of the presented research and the importance of future prospects are discussed. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

21 pages, 2560 KiB

Open AccessReview

Quo Vadis Advanced Prostate Cancer Therapy? Novel Treatment Perspectives and Possible Future Directions

by Jana Kvízová, Vladimíra Pavlíčková, Eva Kmoníčková, Tomáš Ruml and Silvie Rimpelová

Molecules 2021, 26(8), 2228; https://doi.org/10.3390/molecules26082228 - 12 Apr 2021

Cited by 5 | Viewed by 3756

Abstract

Prostate cancer is a very common disease, which is, unfortunately, often the cause of many male deaths. This is underlined by the fact that the early stages of prostate cancer are often asymptomatic. Therefore, the disease is usually detected and diagnosed at late [...] Read more.

Prostate cancer is a very common disease, which is, unfortunately, often the cause of many male deaths. This is underlined by the fact that the early stages of prostate cancer are often asymptomatic. Therefore, the disease is usually detected and diagnosed at late advanced or even metastasized stages, which are already difficult to treat. Hence, it is important to pursue research and development not only in terms of novel diagnostic methods but also of therapeutic ones, as well as to increase the effectiveness of the treatment by combinational medicinal approach. Therefore, in this review article, we focus on recent approaches and novel potential tools for the treatment of advanced prostate cancer; these include not only androgen deprivation therapy, antiandrogen therapy, photodynamic therapy, photothermal therapy, immunotherapy, multimodal therapy, but also poly(ADP-ribose) polymerase, Akt and cyclin-dependent kinase inhibitors. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

39 pages, 9124 KiB

Open AccessReview

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

by Shalini Sundramurthi Chelliah, Ervin Ashley Lourdes Paul, Muhamad Noor Alfarizal Kamarudin and Ishwar Parhar

Molecules 2021, 26(4), 1169; https://doi.org/10.3390/molecules26041169 - 22 Feb 2021

Cited by 15 | Viewed by 5718

Abstract

Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are [...] Read more.

Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are not well suited for standard therapy and instead, subjected to a palliative approach. HGG tumors are highly infiltrative and the complex tumor microenvironment as well as high tumor heterogeneity often poses the main challenges towards the standard treatment. Therefore, a one-fit-approach may not be suitable for HGG management. Thus, a multimodal approach of standard therapy with immunotherapy, nanomedicine, repurposing of older drugs, use of phytochemicals, and precision medicine may be more advantageous than a single treatment model. This multimodal approach considers the environmental and genetic factors which could affect the patient’s response to therapy, thus improving their outcome. This review discusses the current views and advances in potential HGG therapeutic approaches and, aims to bridge the existing knowledge gap that will assist in overcoming challenges in HGG. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

31 pages, 2318 KiB

Open AccessReview

Anti-neoplastic Potential of Flavonoids and Polysaccharide Phytochemicals in Glioblastoma

by Ayesha Atiq and Ishwar Parhar

Molecules 2020, 25(21), 4895; https://doi.org/10.3390/molecules25214895 - 23 Oct 2020

Cited by 24 | Viewed by 4414

Abstract

Clinically, gliomas are classified into four grades, with grade IV glioblastoma multiforme being the most malignant and deadly, which accounts for 50% of all gliomas. Characteristically, glioblastoma involves the aggressive proliferation of cells and invasion of normal brain tissue, outcomes as poor patient [...] Read more.

Clinically, gliomas are classified into four grades, with grade IV glioblastoma multiforme being the most malignant and deadly, which accounts for 50% of all gliomas. Characteristically, glioblastoma involves the aggressive proliferation of cells and invasion of normal brain tissue, outcomes as poor patient prognosis. With the current standard therapy of glioblastoma; surgical resection and radiotherapy followed by adjuvant chemotherapy with temozolomide, it remains fatal, because of the development of drug resistance, tumor recurrence, and metastasis. Therefore, the need for the effective therapeutic option for glioblastoma remains elusive. Previous studies have demonstrated the chemopreventive role of naturally occurring pharmacological agents through preventing or reversing the initiation phase of carcinogenesis or arresting the cancer progression phase. In this review, we discuss the role of natural phytochemicals in the amelioration of glioblastoma, with the aim to improve therapeutic outcomes, and minimize the adverse side effects to improve patient’s prognosis and enhancing their quality of life. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

34 pages, 2827 KiB

Open AccessReview

Structural and Functional Aspects of Targeting the Secreted Human Group IIA Phospholipase A₂

by Ryung Rae Kim, Zheng Chen, Timothy J. Mann, Karine Bastard, Kieran F. Scott and W. Bret Church

Molecules 2020, 25(19), 4459; https://doi.org/10.3390/molecules25194459 - 28 Sep 2020

Cited by 30 | Viewed by 4810

Abstract

Human group IIA secretory phospholipase A₂ (hGIIA) promotes the proliferation of cancer cells, making it a compelling therapeutic target, but it is also significant in other inflammatory conditions. Consequently, suitable inhibitors of hGIIA have always been sought. The activation of phospholipases A [...] Read more.

Human group IIA secretory phospholipase A₂ (hGIIA) promotes the proliferation of cancer cells, making it a compelling therapeutic target, but it is also significant in other inflammatory conditions. Consequently, suitable inhibitors of hGIIA have always been sought. The activation of phospholipases A₂ and the catalysis of glycerophospholipid substrates generally leads to the release of fatty acids such as arachidonic acid (AA) and lysophospholipid, which are then converted to mediator compounds, including prostaglandins, leukotrienes, and the platelet-activating factor. However, this ability of hGIIA to provide AA is not a complete explanation of its biological role in inflammation, as it has now been shown that it also exerts proinflammatory effects by a catalysis-independent mechanism. This mechanism is likely to be highly dependent on key specific molecular interactions, and the full mechanistic descriptions of this remain elusive. The current candidates for the protein partners that may mediate this catalysis-independent mechanism are also introduced in this review. A key discovery has been that selective inhibition of the catalysis-independent activity of hGIIA is achieved with cyclised derivatives of a pentapeptide, FLSYK, derived from the primary sequence of hGIIA. The effects of hGIIA on cell function appear to vary depending on the pathology studied, and so its mechanism of action is complex and context-dependent. This review is comprehensive and covers the most recent developments in the understanding of the many facets of hGIIA function and inhibition and the insight they provide into their clinical application for disease treatment. A cyclic analogue of FLSYK, c2, the most potent analogue known, has now been taken into clinical trials targeting advanced prostate cancer. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

26 pages, 4672 KiB

Open AccessReview

Current Perspectives of the Applications of Polyphenols and Flavonoids in Cancer Therapy

by Xavier Montané, Oliwia Kowalczyk, Belen Reig-Vano, Anna Bajek, Krzysztof Roszkowski, Remigiusz Tomczyk, Wojciech Pawliszak, Marta Giamberini, Agnieszka Mocek-Płóciniak and Bartosz Tylkowski

Molecules 2020, 25(15), 3342; https://doi.org/10.3390/molecules25153342 - 23 Jul 2020

Cited by 92 | Viewed by 7046

Abstract

The development of anticancer therapies that involve natural drugs has undergone exponential growth in recent years. Among the natural compounds that produce beneficial effects on human health, polyphenols have shown potential therapeutic applications in cancer due to their protective functions in plants, their [...] Read more.

The development of anticancer therapies that involve natural drugs has undergone exponential growth in recent years. Among the natural compounds that produce beneficial effects on human health, polyphenols have shown potential therapeutic applications in cancer due to their protective functions in plants, their use as food additives, and their excellent antioxidant properties. The possibility of combining conventional drugs—which are usually more aggressive than natural compounds—with polyphenols offers very valuable advantages such as the building of more efficient anticancer therapies with less side effects on human health. This review shows a wide range of trials in which polyphenolic compounds play a crucial role as anticancer medicines alone or in combination with other drugs at different stages of cancer: cancer initiation, promotion, and growth or progression. Moreover, the future directions in applications of various polyphenols in cancer therapy are emphasized. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

21 pages, 676 KiB

Open AccessReview

Use of Fluorescence In Situ Hybridization (FISH) in Diagnosis and Tailored Therapies in Solid Tumors

by Natalia Magdalena Chrzanowska, Janusz Kowalewski and Marzena Anna Lewandowska

Molecules 2020, 25(8), 1864; https://doi.org/10.3390/molecules25081864 - 17 Apr 2020

Cited by 65 | Viewed by 16254

Abstract

Fluorescence in situ hybridization (FISH) is a standard technique used in routine diagnostics of genetic aberrations. Thanks to simple FISH procedure is possible to recognize tumor-specific abnormality. Its applications are limited to designed probe type. Gene rearrangements e.g., ALK, ROS1 reflecting numerous [...] Read more.

Fluorescence in situ hybridization (FISH) is a standard technique used in routine diagnostics of genetic aberrations. Thanks to simple FISH procedure is possible to recognize tumor-specific abnormality. Its applications are limited to designed probe type. Gene rearrangements e.g., ALK, ROS1 reflecting numerous translocational partners, deletions of critical regions e.g., 1p and 19q, gene fusions e.g., COL1A1-PDGFB, genomic imbalances e.g., 6p, 6q, 11q and amplifications e.g., HER2 are targets in personalized oncology. Confirmation of genetic marker is frequently a direct indication to start specific, targeted treatment. In other cases, detected aberration helps pathologists to better distinguish soft tissue sarcomas, or to state a final diagnosis. Our main goal is to show that applying FISH to formalin-fixed paraffin-embedded tissue sample (FFPE) enables assessing genomic status in the population of cells deriving from a primary tumor or metastasis. Although many more sophisticated techniques are available, like Real-Time PCR or new generation sequencing, FISH remains a commonly used method in many genetic laboratories. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Figure 1

25 pages, 7572 KiB

Open AccessReview

Encapsulation for Cancer Therapy

by Xavier Montané, Anna Bajek, Krzysztof Roszkowski, Josep M. Montornés, Marta Giamberini, Szymon Roszkowski, Oliwia Kowalczyk, Ricard Garcia-Valls and Bartosz Tylkowski

Molecules 2020, 25(7), 1605; https://doi.org/10.3390/molecules25071605 - 31 Mar 2020

Cited by 65 | Viewed by 7120

Abstract

The current rapid advancement of numerous nanotechnology tools is being employed in treatment of many terminal diseases such as cancer. Nanocapsules (NCs) containing an anti-cancer drug offer a very promising alternative to conventional treatments, mostly due to their targeted delivery and precise action, [...] Read more.

The current rapid advancement of numerous nanotechnology tools is being employed in treatment of many terminal diseases such as cancer. Nanocapsules (NCs) containing an anti-cancer drug offer a very promising alternative to conventional treatments, mostly due to their targeted delivery and precise action, and thereby they can be used in distinct applications: as biosensors or in medical imaging, allowing for cancer detection as well as agents/carriers in targeted drug delivery. The possibility of using different systems—inorganic nanoparticles, dendrimers, proteins, polymeric micelles, liposomes, carbon nanotubes (CNTs), quantum dots (QDs), biopolymeric nanoparticles and their combinations—offers multiple benefits to early cancer detection as well as controlled drug delivery to specific locations. This review focused on the key and recent progress in the encapsulation of anticancer drugs that include methods of preparation, drug loading and drug release mechanism on the presented nanosystems. Furthermore, the future directions in applications of various nanoparticles are highlighted. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery and Development)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Anticancer Drug Discovery and Development

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (29 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI