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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 (31 December 2023) | Viewed by 24281

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Dr. Sergey Sedykh

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SB RAS Institute of Chemical Biology and Fundamental Medicine, Novosibirsk State University, Novosibirsk, Russia
Interests: exosomes; antibodies; catalytic antibodies; COVID-19; human milk; horse milk; milk exosomes; drug delivery; plant growth promoting bacteria; PGPB

Special Issue Information

Dear Colleagues,

The direction of anticancer therapy is highly relevant in the XXI century. Advances in the development of anticancer therapeutics have resulted in more than a hundred drugs on the market today directed to destroy, shrink, or slow the growth of cancer cells. Another critical area is tumor immunotherapy: advances in the development of bispecific antibodies and CAR-T therapy inspire many researchers worldwide. New therapeutic molecules continue to be studied in laboratories in vitro and in vivo, in animal models, and undergo preclinical and clinical trials.

This Special Issue brings together various manuscripts in anticancer therapy and anticancer drugs. In particular, the Special Issue is devoted to the new small molecules, inhibitors of repair enzymes, markers of therapy effectiveness, new combinations of drugs, new approaches in immunotherapy and gene therapy, and new drugs reducing cancer symptoms and directed against metastases. We invite the authors of reviews and research articles to join this Special Issue.

Dr. Sergey Sedykh
Guest Editor

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Keywords

cancer therapy
drug development
drug design
drug delivery
target therapy
cytostatic drugs
chemotherapy
immunotherapy
CAR-T
cell cycle
apoptosis
DNA repair

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Published Papers (9 papers)

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Research

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18 pages, 2430 KiB

Open AccessArticle

Potential of NRF2 Inhibitors—Retinoic Acid, K67, and ML-385—In Overcoming Doxorubicin Resistance in Promyelocytic Leukemia Cells

by Michał Juszczak, Paulina Tokarz and Katarzyna Woźniak

Int. J. Mol. Sci. 2024, 25(19), 10257; https://doi.org/10.3390/ijms251910257 - 24 Sep 2024

Viewed by 1419

Abstract

Drug resistance is one of the major obstacles to the clinical use of doxorubicin, an extensively used chemotherapeutic drug to treat various cancers, including leukemia. Inhibition of the nuclear factor erythroid 2-related factor 2 (NRF2) seems a promising strategy to reverse chemoresistance in cancer cells. NRF2 is a transcription factor that regulates both antioxidant defense and drug detoxification mechanisms. In this study, we investigated the potential of three inhibitors of NRF2—K67, retinoic acid and ML-385—to overcome doxorubicin resistance in promyelocytic leukemia HL-60 cells. For this purpose, low-dose doxorubicin was used to establish doxorubicin-resistant HL-60/DR cells. The expression of NRF2 and its main repressor, Kelch-like ECH-associated protein 1 (KEAP1), at mRNA and protein levels was examined. HL-60/DR cells overexpressed NRF2 at mRNA and protein levels and down-regulated KEAP1 protein compared to drug-sensitive HL-60 cells. The effects of NRF2 inhibitors on doxorubicin-resistant HL-60/DR cell viability, apoptosis, and intracellular reactive oxygen species (ROS) levels were analyzed. We observed that NRF2 inhibitors significantly sensitized doxorubicin-resistant HL-60/DR cells to doxorubicin, which was associated with increased intracellular ROS levels and the expression of CAS-9, suggesting the participation of the mitochondrial-dependent apoptosis pathway. Furthermore, ML-385 inhibitor was used to study the expression of NRF2–KEAP1 pathway genes. NRF2 gene and protein expression remained unchanged; however, we noted the down-regulation of KEAP1 protein upon ML-385 treatment. Additionally, the expression of NRF2-regulated antioxidant and detoxification genes including SOD2, HMOX2, and GSS was maintained upon ML-385 treatment. In conclusion, our results demonstrated that all the studied inhibitors, namely K67, retinoic acid, and ML-385, increased the efficacy of doxorubicin in doxorubicin-resistant HL-60/DR cells, and suggested a potential strategy of combination therapy using NRF2 inhibitors and doxorubicin in overcoming doxorubicin resistance in leukemia. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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14 pages, 16613 KiB

Open AccessArticle

Expression Pattern of Sonic Hedgehog, Patched and Smoothened in Clear Cell Renal Carcinoma

by Ana Dunatov Huljev, Nela Kelam, Benjamin Benzon, Violeta Šoljić, Natalija Filipović, Valdi Pešutić Pisac, Merica Glavina Durdov and Katarina Vukojević

Int. J. Mol. Sci. 2023, 24(10), 8935; https://doi.org/10.3390/ijms24108935 - 18 May 2023

Cited by 2 | Viewed by 1877

Abstract

Clear cell renal cell carcinoma (ccRCC) is the deadliest neoplasm of the urinary tract, and we are still far from completely understanding ccRCC development and treatment. The renal tissue paraffin blocks (20) of patients with ccRCC were collected at the University Hospital in Split from 2019 to 2020, and tissue sections were stained with patched (PTCH), anti-smoothened (SMO) and anti-Sonic Hedgehog (SHH) antibodies. SHH was highly expressed (31.9%) in grade 1 tumour, it being higher than all other grades and the control (p < 0.001–p < 0.0001). The trend of a linear decrease in the expression of SHH was observed with the progression of the tumour grade (p < 0.0001). PTCH expression was significantly lower in grades 1 and 2 in comparison to the control (p < 0.01) and grade 4 (p < 0.0001). A significant increase in the expression of SMO was found in grade 4 compared to all other grades (p < 0.0001) and the control (p < 0.001). The strong expression of SHH was observed in carcinoma cells of the G1 stage with a diffuse staining pattern (>50% of neoplastic cells). Stroma and/or inflammatory infiltrate display no staining and no expression of SHH in G1 and G2, while mild focal staining (10–50% of neoplastic cells) was observed in G3 and G4. Patients with high PTCH and low SMO expression had significant time survival differences (p = 0.0005 and p = 0.029, respectively). Therefore, high levels of PTCH and low levels of SMO expression are important markers of better survival rates in ccRCC patients. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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15 pages, 3810 KiB

Open AccessArticle

RAD51 Inhibition Shows Antitumor Activity in Hepatocellular Carcinoma

by Mingang Pan, Yu Sha, Jianguo Qiu, Yunmeng Chen, Lele Liu, Muyu Luo, Ailong Huang and Jie Xia

Int. J. Mol. Sci. 2023, 24(9), 7905; https://doi.org/10.3390/ijms24097905 - 26 Apr 2023

Cited by 3 | Viewed by 2621

Abstract

Hepatocellular carcinoma (HCC), the major type of liver cancer, causes a high annual mortality worldwide. RAD51 is the critical recombinase responsible for homologous recombination (HR) repair in DNA damage. In this study, we identified that RAD51 was upregulated in HCC and that RAD51 silencing or inhibition reduced the proliferation, migration, and invasion of HCC cells and enhanced cell apoptosis and DNA damage. HCC cells with the combinatorial treatments of RAD51 siRNA or inhibitor and sorafenib demonstrated a synergistic effect in inhibiting HCC cell proliferation, migration, and invasion, as well as inducing cell apoptosis and DNA damage. Single RAD51 silencing or sorafenib reduced RAD51 protein expression and weakened HR efficiency, and their combination almost eliminated RAD51 protein expression and inhibited HR efficiency further. An in vivo tumor model confirmed the RAD51 inhibitor’s antitumor activity and synergistic antitumor activity with sorafenib in HCC. RNA-Seq and gene set enrichment analysis (GSEA) in RAD51-inactivated Huh7 cells indicated that RAD51 knockdown upregulated cell apoptosis and G1/S DNA damage checkpoint pathways while downregulating mitotic spindle and homologous recombination pathways. Our findings suggest that RAD51 inhibition exhibits antitumor activities in HCC and synergizes with sorafenib. Targeting RAD51 may provide a novel therapeutic approach in HCC. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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12 pages, 5744 KiB

Open AccessArticle

CT and MRI Imaging of Theranostic Bimodal Fe₃O₄@Au NanoParticles in Tumor Bearing Mice

by Alexey A. Lipengolts, Yulia A. Finogenova, Vsevolod A. Skribitsky, Kristina E. Shpakova, Adi Anaki, Menachem Motiei, Alevtina S. Semkina, Maxim A. Abakumov, Anna V. Smirnova, Elena Y. Grigorieva and Rachela Popovtzer

Int. J. Mol. Sci. 2023, 24(1), 70; https://doi.org/10.3390/ijms24010070 - 21 Dec 2022

Cited by 12 | Viewed by 3366

Abstract

Gold-containing nanoparticles are proven to be an effective radiosensitizer in the radiotherapy of tumors. Reliable imaging of nanoparticles in a tumor and surrounding normal tissues is crucial both for diagnostics and for nanoparticle application as radiosensitizers. The Fe₃O₄ core was introduced into gold nanoparticles to form a core/shell structure suitable for MRI imaging. The aim of this study was to assess the in vivo bimodal CT and MRI enhancement ability of novel core/shell Fe₃O₄@Au theranostic nanoparticles. Core/shell Fe₃O₄@Au nanoparticles were synthesized and coated with PEG and glucose. C57Bl/6 mice bearing Ca755 mammary adenocarcinoma tumors received intravenous injections of the nanoparticles. CT and MRI were performed at several timepoints between 5 and 102 min, and on day 17 post-injection. Core/shell Fe₃O₄@Au nanoparticles provided significant enhancement of the tumor and tumor blood vessels. Nanoparticles also accumulated in the liver and spleen and were retained in these organs for 17 days. Mice did not show any signs of toxicity over the study duration. These results indicate that theranostic bimodal Fe₃O₄@Au nanoparticles are non-toxic and serve as effective contrast agents both for CT and MRI diagnostics. These nanoparticles have potential for future biomedical applications in cancer diagnostics and beyond. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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11 pages, 1461 KiB

Open AccessArticle

Urine Molecular Biomarkers for Detection and Follow-Up of Small Renal Masses

by Algirdas Žalimas, Raimonda Kubiliūtė, Kristina Žukauskaitė, Rasa Sabaliauskaitė, Mantas Trakymas, Simona Letautienė, Edita Mišeikytė Kaubrienė, Jurgita Ušinskienė, Albertas Ulys and Sonata Jarmalaitė

Int. J. Mol. Sci. 2022, 23(24), 16110; https://doi.org/10.3390/ijms232416110 - 17 Dec 2022

Cited by 2 | Viewed by 2016

Abstract

Active surveillance (AS) is the best strategy for small renal masses (SRMs) management; however, reliable methods for early detection and disease aggressiveness prediction are urgently needed. The aim of the present study was to validate DNA methylation biomarkers for non-invasive SRM detection and prognosis. The levels of methylated genes TFAP2B, TAC1, PCDH8, ZNF677, FLRT2, and FBN2 were evaluated in 165 serial urine samples prospectively collected from 39 patients diagnosed with SRM, specifically renal cell carcinoma (RCC), before and during the AS via quantitative methylation-specific polymerase chain reaction. Voided urine samples from 92 asymptomatic volunteers were used as the control. Significantly higher methylated TFAP2B, TAC1, PCDH8, ZNF677, and FLRT2 levels and/or frequencies were detected in SRM patients’ urine samples as compared to the control. The highest diagnostic power (AUC = 0.74) was observed for the four biomarkers panel with 92% sensitivity and 52% specificity. Methylated PCDH8 level positively correlated with SRM size at diagnosis, while TFAP2B had the opposite effect and was related to SRM progression. To sum up, SRMs contribute significantly to the amount of methylated DNA detectable in urine, which might be used for very early RCC detection. Moreover, PCDH8 and TFAP2B methylation have the potential to be prognostic biomarkers for SRMs. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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18 pages, 4789 KiB

Open AccessArticle

Specific S100 Proteins Bind Tumor Necrosis Factor and Inhibit Its Activity

by Alexey S. Kazakov, Marina Y. Zemskova, Gleb K. Rystsov, Alisa A. Vologzhannikova, Evgenia I. Deryusheva, Victoria A. Rastrygina, Andrey S. Sokolov, Maria E. Permyakova, Ekaterina A. Litus, Vladimir N. Uversky, Eugene A. Permyakov and Sergei E. Permyakov

Int. J. Mol. Sci. 2022, 23(24), 15956; https://doi.org/10.3390/ijms232415956 - 15 Dec 2022

Cited by 5 | Viewed by 3040

Abstract

Tumor necrosis factor (TNF) inhibitors (anti-TNFs) represent a cornerstone of the treatment of various immune-mediated inflammatory diseases and are among the most commercially successful therapeutic agents. Knowledge of TNF binding partners is critical for identification of the factors able to affect clinical efficacy of the anti-TNFs. Here, we report that among eighteen representatives of the multifunctional S100 protein family, only S100A11, S100A12 and S100A13 interact with the soluble form of TNF (sTNF) in vitro. The lowest equilibrium dissociation constants (K_d) for the complexes with monomeric sTNF determined using surface plasmon resonance spectroscopy range from 2 nM to 28 nM. The apparent K_d values for the complexes of multimeric sTNF with S100A11/A12 estimated from fluorimetric titrations are 0.1–0.3 µM. S100A12/A13 suppress the cytotoxic activity of sTNF against Huh-7 cells, as evidenced by the MTT assay. Structural modeling indicates that the sTNF-S100 interactions may interfere with the sTNF recognition by the therapeutic anti-TNFs. Bioinformatics analysis reveals dysregulation of TNF and S100A11/A12/A13 in numerous disorders. Overall, we have shown a novel potential regulatory role of the extracellular forms of specific S100 proteins that may affect the efficacy of anti-TNF treatment in various diseases. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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12 pages, 1706 KiB

Open AccessArticle

FLIM of NAD(P)H in Lymphatic Nodes Resolves T-Cell Immune Response to the Tumor

by Anna V. Izosimova, Marina V. Shirmanova, Vladislav I. Shcheslavskiy, Daria A. Sachkova, Artem M. Mozherov, George V. Sharonov, Elena V. Zagaynova and Diana V. Yuzhakova

Int. J. Mol. Sci. 2022, 23(24), 15829; https://doi.org/10.3390/ijms232415829 - 13 Dec 2022

Cited by 9 | Viewed by 1896

Abstract

Assessment of T-cell response to the tumor is important for diagnosis of the disease and monitoring of therapeutic efficacy. For this, new non-destructive label-free methods are required. Fluorescence lifetime imaging (FLIM) of metabolic coenzymes is a promising innovative technology for the assessment of the functional status of cells. The purpose of this work was to test whether FLIM can resolve metabolic alterations that accompany T-cell reactivation to the tumors. The study was carried out on C57Bl/6 FoxP3-EGFP mice bearing B16F0 melanoma. Autofluorescence of the immune cells in fresh lymphatic nodes (LNs) was investigated. It was found that fluorescence lifetime parameters of nicotinamide adenine dinucleotide (phosphate) NAD(P)H are sensitive to tumor development. Effector T-cells in the LNs displayed higher contribution of free NADH, the form associated with glycolysis, in all tumors and the presence of protein-bound NADPH, associated with biosynthetic processes, in the tumors of large size. Flow cytometry showed that the changes in the NADH fraction of the effector T-cells correlated with their activation, while changes in NADPH correlated with cell proliferation. In conclusion, FLIM of NAD(P)H in fresh lymphoid tissue is a powerful tool for assessing the immune response to tumor development. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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24 pages, 4515 KiB

Open AccessReview

Milk Exosomes: Next-Generation Agents for Delivery of Anticancer Drugs and Therapeutic Nucleic Acids

by Anna M. Timofeeva, Anastasia P. Paramonik, Sergey S. Sedykh and Georgy A. Nevinsky

Int. J. Mol. Sci. 2023, 24(12), 10194; https://doi.org/10.3390/ijms241210194 - 15 Jun 2023

Cited by 30 | Viewed by 5080

Abstract

Exosomes are nanovesicles 40–120 nm in diameter secreted by almost all cell types and providing humoral intercellular interactions. Given the natural origin and high biocompatibility, the potential for loading various anticancer molecules and therapeutic nucleic acids inside, and the surface modification possibility for targeted delivery, exosomes are considered to be a promising means of delivery to cell cultures and experimental animal organisms. Milk is a unique natural source of exosomes available in semi-preparative and preparative quantities. Milk exosomes are highly resistant to the harsh conditions of the gastrointestinal tract. In vitro studies have demonstrated that milk exosomes have an affinity to epithelial cells, are digested by cells by endocytosis mechanism, and can be used for oral delivery. With milk exosome membranes containing hydrophilic and hydrophobic components, exosomes can be loaded with hydrophilic and lipophilic drugs. This review covers a number of scalable protocols for isolating and purifying exosomes from human, cow, and horse milk. Additionally, it considers passive and active methods for drug loading into exosomes, as well as methods for modifying and functionalizing the surface of milk exosomes with specific molecules for more efficient and specific delivery to target cells. In addition, the review considers various approaches to visualize exosomes and determine cellular localization and bio-distribution of loaded drug molecules in tissues. In conclusion, we outline new challenges for studying milk exosomes, a new generation of targeted delivery agents. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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16 pages, 2987 KiB

Open AccessBrief Report

The Tumorigenicity of Breast Cancer Cells Is Reduced upon Treatment with Small Extracellular Vesicles Isolated from Heparin Treated Cell Cultures

by Yunliang Chen and Michael Scully

Int. J. Mol. Sci. 2023, 24(21), 15736; https://doi.org/10.3390/ijms242115736 - 29 Oct 2023

Viewed by 1747

Abstract

As a member of the HPSG family, heparin is often used as a specific probe of their role in cell physiology; indeed, we have previously shown a reduction in the tumorigenicity of breast cancer cells when cultured in its presence. However, a partial reversal of the anti-tumorigenic effect occurred when the treated cells were cultured in fresh medium without heparin, which led us to consider whether a more persistent effect could be achieved by treatment of the cells with small extracellular vesicles (sEV) from heparin-treated cells. The tumorigenicity was analyzed using sEV isolated from the culture medium of heparin-treated MCF-7 and MDA-MB231 breast cancer cells (sEV-HT) or from conditioned medium following the termination of treatment (heparin discontinued, sEV-HD). Tumorigenicity was reduced in cells cultured in the presence of sEV-HT compared to that of cells cultured in the presence of sEV from untreated cells (sEV-Ctrl). sEV-HD were also observed to exert an anti-tumorigenic effect on the expression of pro-tumorigenic and cell cycle regulatory proteins, as well as signaling activities when added to fresh cultures of MCF-7 and MDA-MB231 cells. The anti-tumorigenic activity of the heparin-derived sEV may arise from observed changes in the miRNA content or from heparin, which was observed to be bound to the sEV. sEV may constitute a relatively stable reservoir of circulating heparin, allowing heparin activity to persist in the circulation even after therapy has been discontinued. These findings can be considered as a special additional pharmacological characteristic of heparin clinical therapy. Full article

(This article belongs to the Special Issue Anticancer Therapy)

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