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Molecular Mechanisms of Action and Cytotoxicity of Potential Anticancer Drugs
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Molecular Mechanisms of Action and Cytotoxicity of Potential Anticancer Drugs

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

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 10924

Special Issue Editor

Prof. Dr. Francisco Estevez

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Guest Editor
Department of Biochemistry and Molecular Biology, University Institute for Biomedical and Healthcare Research (IUIBS), University of Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
Interests: apoptosis; caspase; cell cycle; cell proliferation; cytotoxicity; in vitro antiproliferative activity; mitogen-activated protein kinases; reactive oxygen species; structure–activity relationship
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is the second leading cause of death worldwide. Chemotherapy is still an important treatment modality for these diseases. However, in many cases antineoplastic drugs are not only cytotoxic to tumor cells, but also affect normal cells, leading to serious adverse effects. In addition, resistance to chemotherapeutic drugs is another of the major limitations in the treatment. This has led to the development of new cytotoxic agents, and the understanding of key biological control mechanisms to identify drug targets may have important clinical implications. The development of new anticancer drugs and the understanding of key biological control mechanisms to identify drug targets may have important clinical implicationsMany of these promising compounds exhibit cancer-cell cytotoxicity through multiple signal transduction pathways. This Special Issue aims to cover advances on the interference in all phases of cancer progression by modulating key proteins involved in survival, proliferation, angiogenesis, apoptosis, metastasis and reverse multidrug resistance processes, as well as signal transduction pathways triggered by anticancer drug candidates.

Dr. Francisco Estevez
Guest Editor

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Keywords

  • apoptosis
  • cell viability
  • cell proliferation
  • cytotoxicity

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Published Papers (5 papers)

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Research

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18 pages, 12312 KiB  
Article
RNAseq Analysis of Novel 1,3,4-Oxadiazole Chalcogen Analogues Reveals Anti-Tubulin Properties on Cancer Cell Lines
by Stefano Zoroddu, Luca Sanna, Valentina Bordoni, Weidong Lyu, Gabriele Murineddu, Gerard A. Pinna, Sonia Vanina Forcales, Arturo Sala, David J. Kelvin and Luigi Bagella
Int. J. Mol. Sci. 2023, 24(14), 11263; https://doi.org/10.3390/ijms241411263 - 9 Jul 2023
Cited by 3 | Viewed by 1850
Abstract
1,3,4-Oxadiazole derivatives are among the most studied anticancer drugs. Previous studies have analyzed the action of different 1,3,4-oxadiazole derivatives and their effects on cancer cells. This study investigated the characterization of two new compounds named 6 and 14 on HeLa and PC-3 cancer [...] Read more.
1,3,4-Oxadiazole derivatives are among the most studied anticancer drugs. Previous studies have analyzed the action of different 1,3,4-oxadiazole derivatives and their effects on cancer cells. This study investigated the characterization of two new compounds named 6 and 14 on HeLa and PC-3 cancer cell lines. Based on the previously obtained IC50, cell cycle effects were monitored by flow cytometry. RNA sequencing (RNAseq) was performed to identify differentially expressed genes, followed by functional annotation using gene ontology (GO), KEGG signaling pathway enrichment, and protein–protein interaction (PPI) network analyses. The tubulin polymerization assay was used to analyze the interaction of both compounds with tubulin. The results showed that 6 and 14 strongly inhibited the proliferation of cancer cells by arresting them in the G2/M phase of the cell cycle. Transcriptome analysis showed that exposure of HeLa and PC-3 cells to the compounds caused a marked reprograming of gene expression. Functional enrichment analysis indicated that differentially expressed genes were significantly enriched throughout the cell cycle and cancer-related biological processes. Furthermore, PPI network, hub gene, and CMap analyses revealed that compounds 14 and 6 shared target genes with established microtubule inhibitors, indicating points of similarity between the two molecules and microtubule inhibitors in terms of the mechanism of action. They were also able to influence the polymerization process of tubulin, suggesting the potential of these new compounds to be used as efficient chemotherapeutic agents. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Action and Cytotoxicity of Potential Anticancer Drugs)
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18 pages, 4103 KiB  
Article
In Silico Screening and Anticancer-Apoptotic Evaluation of Newly Synthesized Thienopyrimidine/Sulfonamide Hybrids
by Elshaymaa I. Elmongy, Faizah A. Binjubair, Ohoud Y. Alshehri, Kholoud A. Baeshen, Zaha A. Almukhalfi and Hanan A. Henidi
Int. J. Mol. Sci. 2023, 24(13), 10827; https://doi.org/10.3390/ijms241310827 - 29 Jun 2023
Cited by 5 | Viewed by 1591
Abstract
This work describes the design and synthesis of new hybrids of thienopyrimidine and sulfonamides. The binding affinity of the prepared compounds to FGFR-1 enzyme and caspase-3 was investigated via molecular docking. The cytotoxic effect was estimated for the synthesized compounds against human breast [...] Read more.
This work describes the design and synthesis of new hybrids of thienopyrimidine and sulfonamides. The binding affinity of the prepared compounds to FGFR-1 enzyme and caspase-3 was investigated via molecular docking. The cytotoxic effect was estimated for the synthesized compounds against human breast cancer cell lines (MCF-7 and MDA-MB231) using Doxorubicin as a reference. All the tested compounds exhibited moderate to excellent anticancer efficacy against both tested cell lines, among which 3b and 4bi were the best. All the synthesized compounds exhibited distinguishing selectivity index values greater than Doxorubicin. The influence of the new hybrids under inquiry was further examined on both FGFR-1 and Caspase-3. The results revealed that compound 3b showed observed concordance between anti-proliferative activity and Caspase-3 activity. In respect to the compounds’ effect on the apoptosis, compound 3b significantly increased the population of late apoptotic cells and necrotic cells. In silico pharmacokinetic investigation revealed that compound 3b showed the best intestinal absorption, BBB permeability, and, along with 4bi and 4bii, the best CNS penetrability. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Action and Cytotoxicity of Potential Anticancer Drugs)
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22 pages, 5786 KiB  
Article
Thiosemicarbazide Derivatives Targeting Human TopoIIα and IDO-1 as Small-Molecule Drug Candidates for Breast Cancer Treatment
by Barbara Kaproń, Robert Czarnomysy, Dominika Radomska, Krzysztof Bielawski and Tomasz Plech
Int. J. Mol. Sci. 2023, 24(6), 5812; https://doi.org/10.3390/ijms24065812 - 18 Mar 2023
Cited by 6 | Viewed by 1718
Abstract
In 2020, breast cancer became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases diagnosed. However, with early diagnosis and proper treatment, breast cancer has a good prognosis. Here, we investigated the effect of thiosemicarbazide derivatives, previously identified as [...] Read more.
In 2020, breast cancer became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases diagnosed. However, with early diagnosis and proper treatment, breast cancer has a good prognosis. Here, we investigated the effect of thiosemicarbazide derivatives, previously identified as dual inhibitors targeting topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1), on two distinct types of breast cancer cells (MCF-7 and MDA-MB-231). The investigated compounds (1–3) selectively suppressed the growth of breast cancer cells and promoted apoptosis via caspase-8- and caspase-9-related pathways. Moreover, these compounds caused S-phase cell cycle arrest and dose-dependently inhibited the activity of ATP-binding cassette transporters (MDR1, MRP1/2 and BCRP) in MCF-7 and MDA-MB-231 cells. Additionally, following incubation with compound 1, an increased number of autophagic cells within both types of the investigated breast cancer cells was observed. During preliminary testing of ADME-Tox properties, the possible hemolytic activities of compounds 1–3 and their effects on specific cytochrome P450 enzymes were evaluated. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Action and Cytotoxicity of Potential Anticancer Drugs)
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24 pages, 5673 KiB  
Article
New Pyrrole Derivatives as Promising Biological Agents: Design, Synthesis, Characterization, In Silico, and Cytotoxicity Evaluation
by Beatrice-Cristina Ivan, Stefania-Felicia Barbuceanu, Camelia Mia Hotnog, Adriana Iuliana Anghel, Robert Viorel Ancuceanu, Mirela Antonela Mihaila, Lorelei Irina Brasoveanu, Sergiu Shova, Constantin Draghici, Octavian Tudorel Olaru, George Mihai Nitulescu, Mihaela Dinu and Florea Dumitrascu
Int. J. Mol. Sci. 2022, 23(16), 8854; https://doi.org/10.3390/ijms23168854 - 9 Aug 2022
Cited by 22 | Viewed by 2817
Abstract
The current study describes the synthesis, physicochemical characterization and cytotoxicity evaluation of a new series of pyrrole derivatives in order to identify new bioactive molecules. The new pyrroles were obtained by reaction of benzimidazolium bromide derivatives with asymmetrical acetylenes in 1,2-epoxybutane under reflux [...] Read more.
The current study describes the synthesis, physicochemical characterization and cytotoxicity evaluation of a new series of pyrrole derivatives in order to identify new bioactive molecules. The new pyrroles were obtained by reaction of benzimidazolium bromide derivatives with asymmetrical acetylenes in 1,2-epoxybutane under reflux through the Huisgen [3 + 2] cycloaddition of several ylide intermediates to the corresponding dipolarophiles. The intermediates salts were obtained from corresponding benzimidazole with bromoacetonitrile. The structures of the newly synthesized compounds were confirmed by elemental analysis, spectral techniques (i.e., IR, 1H-NMR and 13C-NMR) and single-crystal X-ray analysis. The cytotoxicity of the synthesized compounds was evaluated on plant cells (i.e., Triticum aestivum L.) and animal cells using aquatic crustaceans (i.e., Artemia franciscana Kellogg and Daphnia magna Straus). The potential antitumor activity of several of the pyrrole derivatives was studied by performing in vitro cytotoxicity assays on human adenocarcinoma-derived cell lines (i.e., LoVo (colon), MCF-7 (breast), and SK-OV-3 (ovary)) and normal human umbilical vein endothelial cells (HUVECs). The obtained results of the cytotoxicity assessment indicated that the tested compounds had nontoxic activity on Triticum aestivum L., while on Artemia franciscana Kellogg nauplii, only compounds 2c and 4c had moderate toxicity. On Daphnia magna, 4b and 4c showed high toxicity; 2a, 2b, and 2c moderate to high toxicity; only 4a and 4d were nontoxic. The compound-mediated cytotoxicity assays showed that several pyrrole compounds demonstrated dose- and time-dependent cytotoxic activity against all tested tumor cell lines, the highest antitumor properties being achieved by 4a and its homologue 4d, especially against LoVo colon cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Action and Cytotoxicity of Potential Anticancer Drugs)
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Review

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13 pages, 5393 KiB  
Review
Epigenetic Modulators as Therapeutic Agents in Cancer
by Eshaan Patnaik, Chikezie Madu and Yi Lu
Int. J. Mol. Sci. 2023, 24(19), 14964; https://doi.org/10.3390/ijms241914964 - 6 Oct 2023
Cited by 15 | Viewed by 2183
Abstract
Epigenetics play a crucial role in gene regulation and cellular processes. Most importantly, its dysregulation can contribute to the development of tumors. Epigenetic modifications, such as DNA methylation and histone acetylation, are reversible processes that can be utilized as targets for therapeutic intervention. [...] Read more.
Epigenetics play a crucial role in gene regulation and cellular processes. Most importantly, its dysregulation can contribute to the development of tumors. Epigenetic modifications, such as DNA methylation and histone acetylation, are reversible processes that can be utilized as targets for therapeutic intervention. DNA methylation inhibitors disrupt DNA methylation patterns by inhibiting DNA methyltransferases. Such inhibitors can restore normal gene expression patterns, and they can be effective against various forms of cancer. Histone deacetylase inhibitors increase histone acetylation levels, leading to altered gene expressions. Like DNA methylation inhibitors, histone methyltransferase inhibitors target molecules involved in histone methylation. Bromodomain and extra-terminal domain inhibitors target proteins involved in gene expression. They can be effective by inhibiting oncogene expression and inducing anti-proliferative effects seen in cancer. Understanding epigenetic modifications and utilizing epigenetic inhibitors will offer new possibilities for cancer research. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Action and Cytotoxicity of Potential Anticancer Drugs)
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