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Novel Therapeutic Strategies for Cancer

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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 January 2023) | Viewed by 27634

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Dr. Junji Uchino

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Guest Editor

1. Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
2. Bannan Central Hospital, Hamamatsu, Shizuoka 438-0814, Japan
Interests: lung cancer; chemotherapy; clinical trial
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recently, cancer treatment has undergone remarkable developments, and the results of basic research are actually utilized in the clinical treatment.

Advances in molecular targeted therapies targeting driver mutations have transformed from cancer therapies that have relied on previous rules of thumb to therapies that can reasonably expect to be effective.

In recent years, technological innovations in different fields, such as informatics, AI, and next-generation sequencing, as well as the development of research infrastructure, such as cohorts, have led to the dramatic promotion of cancer research and the dramatic transformation of cancer medicine, making individual-appropriate prevention and medical treatment a reality.

Additional expectations are gathered for bridging research that will connect basic research with clinical practice and aim to establish new diagnoses and treatments.

On the other hand, with the advent of novel therapies and the aging of society, cancers that are also resistant to molecular targeted therapies and immunotherapies, cancers that arise in combination with multiple diseases such as diabetes and chronic inflammation, and cancers that should coexist until congenital life, the number of cancers that could not have existed before is increasing.

This Special Issue is calling for both original articles and reviews which provide a comprehensive elucidation about novel therapeutic strategies for cancer for developing novel research approaches as well as therapeutic strategies.

Dr. Junji Uchino
Guest Editor

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Keywords

malignant tumor
chemotherapy
targeted therapy
immunotherapy
biomarkers
cancer biology
drug resistance
combination therapy
radiation therapy

Published Papers (11 papers)

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Research

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13 pages, 2211 KiB

Open AccessArticle

Collagen-Specific Molecular Magnetic Resonance Imaging of Prostate Cancer

by Avan Kader, Jan O. Kaufmann, Dilyana B. Mangarova, Jana Moeckel, Lisa C. Adams, Julia Brangsch, Jennifer L. Heyl, Jing Zhao, Christine Verlemann, Uwe Karst, Federico Collettini, Timo A. Auer, Bernd Hamm and Marcus R. Makowski

Int. J. Mol. Sci. 2023, 24(1), 711; https://doi.org/10.3390/ijms24010711 - 31 Dec 2022

Cited by 3 | Viewed by 1993

Abstract

Constant interactions between tumor cells and the extracellular matrix (ECM) influence the progression of prostate cancer (PCa). One of the key components of the ECM are collagen fibers, since they are responsible for the tissue stiffness, growth, adhesion, proliferation, migration, invasion/metastasis, cell signaling, and immune recruitment of tumor cells. To explore this molecular marker in the content of PCa, we investigated two different tumor volumes (500 mm³ and 1000 mm³) of a xenograft mouse model of PCa with molecular magnetic resonance imaging (MRI) using a collagen-specific probe. For in vivo MRI evaluation, T1-weighted sequences before and after probe administration were analyzed. No significant signal difference between the two tumor volumes could be found. However, we detected a significant difference between the signal intensity of the peripheral tumor area and the central area of the tumor, at both 500 mm³ (p < 0.01, n = 16) and at 1000 mm³ (p < 0.01, n = 16). The results of our histologic analyses confirmed the in vivo studies: There was no significant difference in the amount of collagen between the two tumor volumes (p > 0.05), but within the tumor, higher collagen expression was observed in the peripheral area compared with the central area of the tumor. Laser ablation with inductively coupled plasma mass spectrometry further confirmed these results. The 1000 mm³ tumors contained 2.8 ± 1.0% collagen and the 500 mm³ tumors contained 3.2 ± 1.2% (n = 16). There was a strong correlation between the in vivo MRI data and the ex vivo histological data (y = −0.068x + 1.1; R² = 0.74) (n = 16). The results of elemental analysis by inductively coupled plasma mass spectrometry supported the MRI data (y = 3.82x + 0.56; R² = 0.79; n = 7). MRI with the collagen-specific probe in PCa enables differentiation between different tumor areas. This may help to differentiate tumor from healthy tissue, potentially identifying tumor areas with a specific tumor biology. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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18 pages, 9430 KiB

Open AccessArticle

Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells

by María Ovejero-Sánchez, Gloria Asensio-Juárez, Myriam González, Pilar Puebla, Miguel Vicente-Manzanares, Rafael Pélaez, Rogelio González-Sarmiento and Ana Belén Herrero

Int. J. Mol. Sci. 2022, 23(21), 13019; https://doi.org/10.3390/ijms232113019 - 27 Oct 2022

Cited by 2 | Viewed by 1567

Abstract

Ovarian cancer (OC) is one of the most common gynecologic neoplasia and has the highest mortality rate, which is mainly due to late-stage diagnosis and chemotherapy resistance. There is an urgent need to explore new and better therapeutic strategies. We have previously described a family of Microtubule Destabilizing Sulfonamides (MDS) that does not trigger multidrug-mediated resistance in OC cell lines. MDS bind to the colchicine site of tubulin, disrupting the microtubule network and causing antiproliferative and cytotoxic effects. In this work, a novel microtubule-destabilizing agent (PILA9) was synthetized and characterized. This compound also inhibited OC cell proliferation and induced G2/M cell cycle arrest and apoptosis. Interestingly, PILA9 was significantly more cytotoxic than MDS. Here, we also analyzed the effect of these microtubule-destabilizing agents (MDA) in combination with Panobinostat, a pan-histone deacetylase inhibitor. We found that Panobinostat synergistically enhanced MDA-cytotoxicity. Mechanistically, we observed that Panobinostat and MDA induced α-tubulin acetylation and that the combination of both agents enhanced this effect, which could be related to the observed synergy. Altogether, our results suggest that MDA/Panobinostat combinations could represent new therapeutic strategies against OC. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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14 pages, 2589 KiB

Open AccessArticle

Modification of Regulatory T Cell Epitopes Promotes Effector T Cell Responses to Aspartyl/Asparaginyl β-Hydroxylase

by Sebastian Wirsching, Michael Fichter, Maximiliano L. Cacicedo, Katharina Landfester and Stephan Gehring

Int. J. Mol. Sci. 2022, 23(20), 12444; https://doi.org/10.3390/ijms232012444 - 18 Oct 2022

Cited by 1 | Viewed by 1495

Abstract

Cancer is a leading cause of death worldwide. The search for innovative therapeutic approaches is a principal focus of medical research. Vaccine strategies targeting a number of tumor-associated antigens are currently being evaluated. To date, none have garnered significant success. Purportedly, an immunosuppressive tumor microenvironment and the accumulation of regulatory T cells contribute to a lack of tumor vaccine efficacy. Aspartyl/asparaginyl β-hydroxylase (ASPH), a promising therapeutic target, is overexpressed in a variety of malignant tumors but is expressed negligibly in normal tissues. Computer analysis predicted that ASPH expresses four peptide sequences (epitopes) capable of stimulating regulatory T cell activity. The abolition of these putative regulatory T cell epitopes increased the CD4⁺ and CD8⁺ effector T cell responses to monocyte-derived dendritic cells pulsed with a modified, epitope-depleted version of ASPH in an ex vivo human lymphoid tissue-equivalent coculture system while simultaneously decreasing the overall number of FoxP3⁺ regulatory T cells. These findings suggest that the efficacy of all new vaccine candidates would profit from screening and eliminating potential tolerogenic regulatory T cell epitopes. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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18 pages, 6114 KiB

Open AccessArticle

Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase

by Ming-Hui Yang, Wei-You Li, Ching-Fen Wu, Yi-Ching Lee, Allan Yi-Nan Chen, Yu-Chang Tyan and Yi-Ming Arthur Chen

Int. J. Mol. Sci. 2022, 23(17), 10072; https://doi.org/10.3390/ijms231710072 - 3 Sep 2022

Cited by 1 | Viewed by 2913

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. Combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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23 pages, 6350 KiB

Open AccessArticle

Suppression of Tumor Growth and Cell Migration by Indole-Based Benzenesulfonamides and Their Synergistic Effects in Combination with Doxorubicin

by Phuong Linh Nguyen, Ahmed Elkamhawy, Young Hee Choi, Chang Hoon Lee, Kyeong Lee and Jungsook Cho

Int. J. Mol. Sci. 2022, 23(17), 9903; https://doi.org/10.3390/ijms23179903 - 31 Aug 2022

Cited by 9 | Viewed by 1741

Abstract

Pharmacological inhibition of the enzyme activity targeting carbonic anhydrases (CAs) demonstrated antiglaucoma and anticancer effects through pH control. Recently, we reported a series of indole-based benzenesulfonamides as potent CA inhibitors. The present study aimed to evaluate the antitumor effects of these compounds against various cancer cell lines, including breast cancer (MDA-MB-231, MCF-7, and SK-BR-3), lung cancer (A549), and pancreatic cancer (Panc1) cells. Overall, more potent cytotoxicity was observed on MCF-7 and SK-BR-3 cells than on lung or pancreatic cancer cells. Among the 15 compounds tested, A6 and A15 exhibited potent cytotoxic and antimigratory activities against MCF-7 and SK-BR-3 cells in the CoCl₂-induced hypoxic condition. While A6 and A15 markedly reduced the viability of control siRNA-treated cells, these compounds could not significantly reduce the viability of CA IX-knockdown cells, suggesting the role of CA IX in their anticancer activities. To assess whether these compounds exerted synergism with a conventional anticancer drug doxorubicin (DOX), the cytotoxic effects of A6 or A15 combined with DOX were analyzed using Chou−Talalay and Bliss independence methods. Our data revealed that both A6 and A15 significantly enhanced the anticancer activity of DOX. Among the tested pairs, the combination of DOX with A15 showed the strongest synergism on SK-BR-3 cells. Moreover, this combination further attenuated cell migration compared to the respective drug. Collectively, our results demonstrated that A6 and A15 suppressed tumor growth and cell migration of MCF-7 and SK-BR-3 cells through inhibition of CA IX, and the combination of these compounds with DOX exhibited synergistic cytotoxic effects on these breast cancer cells. Therefore, A6 and A15 may serve as potential anticancer agents alone or in combination with DOX against breast cancer. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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19 pages, 4475 KiB

Open AccessArticle

Thiosemicarbazones Can Act Synergistically with Anthracyclines to Downregulate CHEK1 Expression and Induce DNA Damage in Cell Lines Derived from Pediatric Solid Tumors

by Silvia Paukovcekova, Maria Krchniakova, Petr Chlapek, Jakub Neradil, Jan Skoda and Renata Veselska

Int. J. Mol. Sci. 2022, 23(15), 8549; https://doi.org/10.3390/ijms23158549 - 1 Aug 2022

Cited by 3 | Viewed by 1730

Abstract

Anticancer therapy by anthracyclines often leads to the development of multidrug resistance (MDR), with subsequent treatment failure. Thiosemicarbazones have been previously suggested as suitable anthracycline partners due to their ability to overcome drug resistance through dual Pgp-dependent cytotoxicity-inducing effects. Here, we focused on combining anthracyclines (doxorubicin, daunorubicin, and mitoxantrone) and two thiosemicarbazones (DpC and Dp44mT) for treating cell types derived from the most frequent pediatric solid tumors. Our results showed synergistic effects for all combinations of treatments in all tested cell types. Nevertheless, further experiments revealed that this synergism was independent of Pgp expression but rather resulted from impaired DNA repair control leading to cell death via mitotic catastrophe. The downregulation of checkpoint kinase 1 (CHEK1) expression by thiosemicarbazones and the ability of both types of agents to induce double-strand breaks in DNA may explain the Pgp-independent synergism between anthracyclines and thiosemicarbazones. Moreover, the concomitant application of these agents was found to be the most efficient approach, achieving the strongest synergistic effect with lower concentrations of these drugs. Overall, our study identified a new mechanism that offers an avenue for combining thiosemicarbazones with anthracyclines to treat tumors regardless the Pgp status. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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Review

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23 pages, 384 KiB

Open AccessReview

Non-Small Cell Lung Cancer Treatment with Molecularly Targeted Therapy and Concurrent Radiotherapy—A Review

by Katarzyna Król, Anna Mazur, Paulina Stachyra-Strawa and Ludmiła Grzybowska-Szatkowska

Int. J. Mol. Sci. 2023, 24(6), 5858; https://doi.org/10.3390/ijms24065858 - 20 Mar 2023

Cited by 5 | Viewed by 2751

Abstract

Lung cancer is the leading cause of death worldwide for both men and women. Surgery can be offered as a radical treatment at stages I and II and selected cases of stage III (III A). Whereas at more advanced stages, combined modalities of treatment are applied: radiochemotherapy (IIIB) and molecularly targeted treatment (small molecule tyrosine kinase inhibitors, VEGF receptor inhibitors, monoclonal antibodies, and immunological treatment with monoclonal antibodies). Combination treatment, composed of radiotherapy and molecular therapy, is increasingly employed in locally advanced and metastatic lung cancer management. Recent studies have indicated a synergistic effect of such treatment and modification of immune response. The combination of immunotherapy and radiotherapy may result in the enhancement of the abscopal effect. Anti-angiogenic therapy, in combination with RT, is associated with high toxicity and should be not recommended. In this paper, the authors discuss the role of molecular treatment and the possibility of its concurrent use with radiotherapy in non-small cell lung cancer (NSCLC). Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

19 pages, 1407 KiB

Open AccessReview

Tumor Vasculature as an Emerging Pharmacological Target to Promote Anti-Tumor Immunity

by Hong-Tai Tzeng and Yu-Jie Huang

Int. J. Mol. Sci. 2023, 24(5), 4422; https://doi.org/10.3390/ijms24054422 - 23 Feb 2023

Cited by 6 | Viewed by 2273

Abstract

Tumor vasculature abnormality creates a microenvironment that is not suitable for anti-tumor immune response and thereby induces resistance to immunotherapy. Remodeling of dysfunctional tumor blood vessels by anti-angiogenic approaches, known as vascular normalization, reshapes the tumor microenvironment toward an immune-favorable one and improves the effectiveness of immunotherapy. The tumor vasculature serves as a potential pharmacological target with the capacity of promoting an anti-tumor immune response. In this review, the molecular mechanisms involved in tumor vascular microenvironment-modulated immune reactions are summarized. In addition, the evidence of pre-clinical and clinical studies for the combined targeting of pro-angiogenic signaling and immune checkpoint molecules with therapeutic potential are highlighted. The heterogeneity of endothelial cells in tumors that regulate tissue-specific immune responses is also discussed. The crosstalk between tumor endothelial cells and immune cells in individual tissues is postulated to have a unique molecular signature and may be considered as a potential target for the development of new immunotherapeutic approaches. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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36 pages, 3133 KiB

Open AccessReview

Combination Therapy Using Polyphenols: An Efficient Way to Improve Antitumoral Activity and Reduce Resistance

by Alina Florentina Vladu, Denisa Ficai, Alexandra Gabriela Ene and Anton Ficai

Int. J. Mol. Sci. 2022, 23(18), 10244; https://doi.org/10.3390/ijms231810244 - 6 Sep 2022

Cited by 28 | Viewed by 3415

Abstract

Polyphenols represent a structural class of mainly natural organic chemicals that contain multiple phenol structural units. The beneficial properties of polyphenols have been extensively studied for their antitumor, anti-inflammatory, and antibacterial effects, but nowadays, their medical applications are starting to be extended to many other applications due to their prebiotic role and their impact on the microbiota. This review focused on the use of polyphenols in cancer treatment. Their antineoplastic effects have been demonstrated in various studies when they were tested on numerous cancer lines and some in in vivo models. A431 and SCC13 human skin cancer cell lines treated with EGCG presented a reduced cell viability and enhanced cell death due to the inactivation of β-catenin signaling. Additionally, resveratrol showed a great potential against breast cancer mainly due to its ability to exert both anti-estrogenic and estrogenic effects (based on the concentration) and because it has a high affinity for estrogen receptors ERα and Erβ. Polyphenols can be combined with different classical cytostatic agents to enhance their therapeutic effects on cancer cells and to also protect healthy cells from the aggressiveness of antitumor drugs due to their anti-inflammatory properties. For instance, curcumin has been reported to reduce the gastrointestinal toxicity associated with chemotherapy. In the case of 5-FU-induced, it reduced the gastrointestinal toxicity by increasing the intestinal permeability and inhibiting mucosal damage. Co-administration of EGCG and doxorubicin induced the death of liver cancer cells. EGCG has the ability to inhibit autophagic activity and stop hepatoma Hep3B cell proliferation This symbiotic approach is well-known in medical practice including in multiple chemotherapy. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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25 pages, 2841 KiB

Open AccessReview

DNA and RNA Binding Proteins: From Motifs to Roles in Cancer

by Ondrej Bonczek, Lixiao Wang, Sivakumar Vadivel Gnanasundram, Sa Chen, Lucia Haronikova, Filip Zavadil-Kokas and Borivoj Vojtesek

Int. J. Mol. Sci. 2022, 23(16), 9329; https://doi.org/10.3390/ijms23169329 - 18 Aug 2022

Cited by 1 | Viewed by 3659

Abstract

DNA and RNA binding proteins (DRBPs) are a broad class of molecules that regulate numerous cellular processes across all living organisms, creating intricate dynamic multilevel networks to control nucleotide metabolism and gene expression. These interactions are highly regulated, and dysregulation contributes to the development of a variety of diseases, including cancer. An increasing number of proteins with DNA and/or RNA binding activities have been identified in recent years, and it is important to understand how their activities are related to the molecular mechanisms of cancer. In addition, many of these proteins have overlapping functions, and it is therefore essential to analyze not only the loss of function of individual factors, but also to group abnormalities into specific types of activities in regard to particular cancer types. In this review, we summarize the classes of DNA-binding, RNA-binding, and DRBPs, drawing particular attention to the similarities and differences between these protein classes. We also perform a cross-search analysis of relevant protein databases, together with our own pipeline, to identify DRBPs involved in cancer. We discuss the most common DRBPs and how they are related to specific cancers, reviewing their biochemical, molecular biological, and cellular properties to highlight their functions and potential as targets for treatment. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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20 pages, 1796 KiB

Open AccessReview

The Advances in Epigenetics for Cancer Radiotherapy

by Yuexuan Wang, Yu Han, Yuzhen Jin, Qiang He and Zhicheng Wang

Int. J. Mol. Sci. 2022, 23(10), 5654; https://doi.org/10.3390/ijms23105654 - 18 May 2022

Cited by 9 | Viewed by 2914

Abstract

Cancer is an important factor threatening human life and health; in recent years, its morbidity and mortality remain high and demosntrate an upward trend. It is of great significance to study its pathogenesis and targeted therapy. As the complex mechanisms of epigenetic modification has been increasingly discovered, they are more closely related to the occurrence and development of cancer. As a reversible response, epigenetic modification is of great significance for the improvement of classical therapeutic measures and the discovery of new therapeutic targets. It has become a research focusto explore the multi-level mechanisms of RNA, DNA, chromatin and proteins. As an important means of cancer treatment, radiotherapy has made great progress in technology, methods, means and targeted sensitization after years of rapid development, and even research on radiotherapy based on epigenetic modification is rampant. A series of epigenetic effects of radiation on DNA methylation, histone modification, chromosome remodeling, RNA modification and non-coding RNA during radiotherapy affects the therapeutic effects and prognosis. Starting from the epigenetic mechanism of tumorigenesis, this paper reviews the latest progress in the mechanism of interaction between epigenetic modification and cancer radiotherapy and briefly introduces the main types, mechanisms and applications of epigenetic modifiers used for radiotherapy sensitization in order to explore a more individual and dynamic approach of cancer treatment based on epigenetic mechanism. This study strives to make a modest contribution to the progress of human disease research. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Cancer)

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