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Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 23850

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Prof. Dr. Silvio Naviglio

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Department of Precision Medicine, School of Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy
Interests: cell signaling and signal transduction; cell cycle and growth; cancer therapy; naturally occurring molecules
Special Issues, Collections and Topics in MDPI journals

Dr. Luigi Sapio

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Guest Editor

Department of Precision Medicine, School of Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy
Interests: molecular mechanisms in cancer systems; target therapy; anticancer compounds; cell death and autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue "Innovation through Tradition: The Current Challenges in Cancer Treatment ". Enthused by the reception of our previous SI, we agreed to continue this Special Issue with a volume II this year.

Neoplastic diseases currently represent the second-leading cause of death worldwide. Despite the huge effort to improve both progression-free and overall survival, this tendency is expected to worsen significantly, rendering cancer a major future economic and health concern.

Assuming malignancy eradication as “a utopian dream”, our intent remains to make cancer a chronic condition, which could be achieved more easily by presenting new therapeutic approaches.

In view of the abovementioned goal, this Special Issue was conceived to provide more options in cancer treatment and expectation. Specifically, we aim to gather the latest research papers and up-to-date review articles focusing on unique tumour-related structural weaknesses, including genetic, metabolic, and pharmacological vulnerabilities.

Innovative technological and methodological strategies certainly constitute our topic of interest, but we are also interested in canonical approaches that have a direct impact on the course and outcome of the illness. Identifying new formulations of existing antineoplastic compounds capable of increasing the effectiveness and reducing the toxicity as well as recognizing new therapeutic partners, natural or synthetic molecules useful for improving performances, represent some “traditional” aspects that we intend to embrace.

Among the already published original articles, for instance, Salzillo et al. proposed Chlorogenic Acid (CGA) as a promising chemosensitizer and cardioprotective agent in Osteosarcoma therapy, recognizing p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxorubicin susceptibility. Latypova and colleagues, instead, designed a series of heterocyclic compounds having cytotoxic effects against different cancer cell lines. Additionally, Schmitz and co-workers recognized murine cell line L929 as an in vitro system for the rapid analysis of Methionine restriction (MetR). Using liquid chromatography/mass spectrometry analysis, they defined a metabolic fingerprint and identified specific metabolites representing normal or MetR conditions, providing a rapid and efficient model for testing potential cancer metabolic targets.

In accordance with the aims and scope of IJMS, we kindly encourage the submission of molecular studies in the biology, chemistry, and medicine fields. Moreover, review articles on fascinating topics in cancer therapy will be considered meticulously.

Prof. Dr. Silvio Naviglio
Dr. Luigi Sapio
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cancer biology
tumor-related vulnerabilities
novel therapeutic approaches
molecular biology and molecular medicine
omics analysis

Published Papers (9 papers)

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Research

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25 pages, 9408 KiB

Open AccessArticle

Disarib, a Specific BCL2 Inhibitor, Induces Apoptosis in Triple-Negative Breast Cancer Cells and Impedes Tumour Progression in Xenografts by Altering Mitochondria-Associated Processes

by Meghana Manjunath, Febina Ravindran, Shivangi Sharma, Humaira Siddiqua, Sathees C. Raghavan and Bibha Choudhary

Int. J. Mol. Sci. 2024, 25(12), 6485; https://doi.org/10.3390/ijms25126485 - 12 Jun 2024

Viewed by 677

Abstract

Targeted cancer therapy aims to disrupt the functions of proteins that regulate cancer progression, mainly by using small molecule inhibitors (SMIs). SMIs exert their effect by modulating signalling pathways, organelle integrity, chromatin components, and several biosynthetic processes essential for cell division and survival. Antiapoptotic protein BCL2 is highly upregulated in many cancers compared with normal cells, making it an ideal target for cancer therapy. Around 75% of primary breast cancers overexpress BCL2, providing an opportunity to explore BCL2 inhibitors as a therapeutic option. Disarib is an SMI that has been developed as a selective BCL2 inhibitor. Disarib works by disrupting BCL2-BAK interaction and activating intrinsic apoptotic pathways in leukemic cells while sparing normal cells. We investigated the effects of Disarib, a BCL2 specific inhibitor, on breast cancer cells and xenografts. Cytotoxicity and fluorometric assays revealed that Disarib induced cell death by increasing reactive oxygen species and activating intrinsic apoptotic pathways in Triple-Negative Breast Cancer cells (MDA-MB-231 and MDA-MB-468). Disarib also affected the colony-forming properties of these cells. MDA-MB-231- and MDA-MB-468-derived xenografts showed a significant reduction in tumours upon Disarib treatment. Through the transcriptomics approach, we also explored the influence of BCL2 inhibitors on energy metabolism, mitochondrial dynamics, and epithelial-to-mesenchymal transition (EMT). Mitochondrial dynamics and glucose metabolism mainly regulate energy metabolism. The change in energetics regulates tumour growth through epithelial–mesenchymal transition, and angiogenesis. RNA sequencing (RNAseq) analysis revealed that BCL2 inhibitors ABT-199 and Disarib maintain Oxphos levels in MDA-MB-231. However, key glycolytic genes were significantly downregulated. Mitochondrial fission genes were seen to be downregulated both in RNAseq data and semi quantitative real time polymerase chain reaction (qRTPCR) in Disarib-treated TNBC cells and xenografts. Lastly, Disarib inhibited wound healing and epithelial-to-mesenchymal transition. This study showed that Disarib disrupts mitochondrial function, activates the intrinsic apoptotic pathway in breast cancer, and inhibits epithelial-to-mesenchymal transition both in vitro and in vivo. These findings highlight Disarib’s potential as a multifaceted therapeutic strategy for patients with Triple-Negative Breast Cancer. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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15 pages, 5948 KiB

Open AccessArticle

Bioinformatics Identification of Regulatory Genes and Mechanism Related to Hypoxia-Induced PD-L1 Inhibitor Resistance in Hepatocellular Carcinoma

by Mohan Huang, Sijun Yang, William Chi Shing Tai, Lingfeng Zhang, Yinuo Zhou, William Chi Shing Cho, Lawrence Wing Chi Chan and Sze Chuen Cesar Wong

Int. J. Mol. Sci. 2023, 24(10), 8720; https://doi.org/10.3390/ijms24108720 - 13 May 2023

Cited by 4 | Viewed by 2387

Abstract

The combination of a PD-L1 inhibitor and an anti-angiogenic agent has become the new reference standard in the first-line treatment of non-excisable hepatocellular carcinoma (HCC) due to the survival advantage, but its objective response rate remains low at 36%. Evidence shows that PD-L1 inhibitor resistance is attributed to hypoxic tumor microenvironment. In this study, we performed bioinformatics analysis to identify genes and the underlying mechanisms that improve the efficacy of PD-L1 inhibition. Two public datasets of gene expression profiles, (1) HCC tumor versus adjacent normal tissue (N = 214) and (2) normoxia versus anoxia of HepG2 cells (N = 6), were collected from Gene Expression Omnibus (GEO) database. We identified HCC-signature and hypoxia-related genes, using differential expression analysis, and their 52 overlapping genes. Of these 52 genes, 14 PD-L1 regulator genes were further identified through the multiple regression analysis of TCGA-LIHC dataset (N = 371), and 10 hub genes were indicated in the protein–protein interaction (PPI) network. It was found that POLE2, GABARAPL1, PIK3R1, NDC80, and TPX2 play critical roles in the response and overall survival in cancer patients under PD-L1 inhibitor treatment. Our study provides new insights and potential biomarkers to enhance the immunotherapeutic role of PD-L1 inhibitors in HCC, which can help in exploring new therapeutic strategies. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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24 pages, 18629 KiB

Open AccessArticle

Multi-Targeting Anticancer Activity of a New 4-Thiazolidinone Derivative with Anti-HER2 Antibodies in Human AGS Gastric Cancer Cells

by Agnieszka Gornowicz, Roman Lesyk, Robert Czarnomysy, Serhii Holota, Yulia Shepeta, Bożena Popławska, Magdalena Podolak, Wojciech Szymanowski, Krzysztof Bielawski and Anna Bielawska

Int. J. Mol. Sci. 2023, 24(7), 6791; https://doi.org/10.3390/ijms24076791 - 5 Apr 2023

Cited by 3 | Viewed by 1947

Abstract

Combining chemotherapy with immunotherapy still remains a regimen in anticancer therapy. Novel 4-thiazolidinone-bearing hybrid molecules possess well-documented anticancer activity, and together with anti-HER2 antibodies, may represent a promising strategy in treating patients with gastric cancer with confirmed human epidermal growth factor receptor 2 (HER2) expression. The aim of the study was to synthesize a new 4-thiazolidinone derivative (Les-4367) and investigate its molecular mechanism of action in combination with trastuzumab or pertuzumab in human AGS gastric cancer cells. AGS cell viability and antiproliferative potential were examined. The effect of the tested combinations as well as monotherapy on apoptosis and autophagy was also determined. Metalloproteinase-2 (MMP-2), intercellular adhesion molecule 1 (ICAM-1), pro-inflammatory and anti-inflammatory cytokine concentrations were also demonstrated by the ELISA technique. We proved that pertuzumab and trastuzumab were very effective in increasing the sensitivity of AGS gastric cancer cells to novel Les-4367. The molecular mechanism of action of the tested combination is connected with the induction of apoptosis. Additionally, the anticancer activity is not associated with the autophagy process. Decreased concentrations of pro-inflammatory cytokines, MMP-2 and ICAM-1—were observed. The novel combination of drugs based on anti-HER2 antibodies with Les-4367 is a promising strategy against AGS gastric cancer cells. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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17 pages, 8751 KiB

Open AccessArticle

A Proteomic Approach Reveals That miR-423-5p Modulates Glucidic and Amino Acid Metabolism in Prostate Cancer Cells

by Amalia Luce, Angela Lombardi, Carmela Ferri, Silvia Zappavigna, Madhura S. Tathode, Amanda K. Miles, David J. Boocock, Jayakumar Vadakekolathu, Marco Bocchetti, Roberto Alfano, Rossella Sperlongano, Angela Ragone, Luigi Sapio, Vincenzo Desiderio, Silvio Naviglio, Tarik Regad and Michele Caraglia

Int. J. Mol. Sci. 2023, 24(1), 617; https://doi.org/10.3390/ijms24010617 - 29 Dec 2022

Cited by 7 | Viewed by 1830

Abstract

Recently, we have demonstrated that miR-423-5p modulates the growth and metastases of prostate cancer (PCa) cells both in vitro and in vivo. Here, we have studied the effects of miR-423-5p on the proteomic profile in order to identify its intracellular targets and the affected pathways. Applying a quantitative proteomic approach, we analyzed the effects on the protein expression profile of miR-423-5p-transduced PCa cells. Moreover, a computational analysis of predicted targets of miR-423-5p was carried out by using several target prediction tools. Proteomic analysis showed that 63 proteins were differentially expressed in miR-423-5-p-transfected LNCaP cells if compared to controls. Pathway enrichment analysis revealed that stable overexpression of miR-423-5p in LNCaP PCa cells induced inhibition of glycolysis and the metabolism of several amino acids and a parallel downregulation of proteins involved in transcription and hypoxia, the immune response through Th17-derived cytokines, inflammation via amphorin signaling, and ion transport. Moreover, upregulated proteins were related to the S phase of cell cycle, chromatin modifications, apoptosis, blood coagulation, and calcium transport. We identified seven proteins commonly represented in miR-423-5p targets and differentially expressed proteins (DEPs) and analyzed their expression and influence on the survival of PCa patients from publicly accessible datasets. Overall, our findings suggest that miR-423-5p induces alterations in glucose and amino acid metabolism in PCa cells paralleled by modulation of several tumor-associated processes. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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14 pages, 3375 KiB

Open AccessArticle

Antagonistic Pharmacological Interaction between Sirtuin Inhibitor Cambinol and Paclitaxel in Triple-Negative Breast Cancer Cell Lines: An Isobolographic Analysis

by Anna Wawruszak, Jarogniew Luszczki, Estera Okon, Arkadiusz Czerwonka and Andrzej Stepulak

Int. J. Mol. Sci. 2022, 23(12), 6458; https://doi.org/10.3390/ijms23126458 - 9 Jun 2022

Cited by 3 | Viewed by 2067

Abstract

Breast cancer (BC) is a heterogeneous disease with different intrinsic subtypes. The most aggressive subtype of BC–triple-negative breast cancer (TNBC) is characterized by high heterogeneity and metastasis rate, poor prognosis and lack of therapeutic targets due to the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Targeted therapies have been approved for many other cancers and even other subtypes of BC, but treatment options for TNBC are still mainly limited to chemotherapy. Therefore, new, more effective treatment regimens are needed. Combined chemotherapy with two or more active agents is considered a promising anti-neoplasm tool in order to achieve better therapeutic response and reduce therapy-related adverse effects. The study demonstrated an antagonistic effect commonly used in TNBC therapy cytostatic drug-paclitaxel (PAX) and sirtuin inhibitor: cambinol (CAM) in BT-549, MDA-MB-468 and HCC1937 TNBC cell lines. The type of pharmacological interaction was determined by a precise and rigorous pharmacodynamic method-isobolographic analysis. The cytotoxic and anti-proliferative effects of CAM used alone or combined with PAX were determined utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2′-deoxyuridine (BrdU) assays, respectively. Induction of apoptosis in TNBC cell lines after PAX and CAM treatment applied individually or in combination was determined by flow cytometry (FACS) as a number of cells with active caspase-3. It has been observed that both agents used separately inhibit cell proliferation and induce apoptosis; however, applying them in combination ameliorated antiproliferative and pro-apoptotic effects in all analyzed TNBC cell lines. Our results demonstrate that CAM and PAX used in combination act antagonistically, limiting anti-cancer efficacy and showing the importance of preclinical testing. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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14 pages, 3396 KiB

Open AccessArticle

BRCA1/2 Serves as a Biomarker for Poor Prognosis in Breast Carcinoma

by Tong Yi Jin, Kyoung Sik Park, Sang Eun Nam, Young Bum Yoo, Won Seo Park and Ik Jin Yun

Int. J. Mol. Sci. 2022, 23(7), 3754; https://doi.org/10.3390/ijms23073754 - 29 Mar 2022

Cited by 16 | Viewed by 4279

Abstract

BRCA1/2 are breast cancer susceptibility genes that are involved in DNA repair and transcriptional control. They are dysregulated in breast cancer, making them attractive therapeutic targets. Here, we performed a systematic multiomics analysis to expound BRCA1/2 functions as prognostic biomarkers in breast cancer. First, using different web-based bioinformatics platforms (Oncomine, TIMER 2.0, UALCAN, and cBioportal), the expression of BRCA1/2 was assessed. Then, the R package was used to analyze the diagnostic value of BRCA1/2 in patients. Next, we determined the relationship between BRCA1/2 mRNA expression and prognosis in patients (PrognoScan Database, R2: Kaplan Meier Scanner and Kaplan–Meier Plotter). Subsequently, the association of BRCA1/2 with mutation frequency alteration and copy number alterations in breast cancer was investigated using the cBioportal platform. After that, we identified known and predicted structural genes and proteins essential for BRCA1/2 functions using GeneMania and STRING db. Finally, GO and KEGG pathway enrichment analyses were performed to elucidate the potential biological functions of the co-expression genes of BRCA1/2. The BRCA1/2 mRNA level in breast cancer tissues was considerably higher than in normal tissues, with AUCs of 0.766 and 0.829, respectively. Overexpression of BRCA1/2 was significantly related to the worse overall survival (p < 0.001) and was correlated to clinicopathological characteristics including lymph nodes, estrogen receptors, and progesterone receptors (p < 0.01). The alteration frequencies of both the gens have been checked, and the results show that BRCA1 and BRCA2 show different alteration frequencies. Their mutation sites differ from each other. GO and KEGG showed that BRCA1/2 was mainly enriched in catalytic activity, acting on DNA, chromosomal region, organelle fission, cell cycle, etc. The 20 most frequently changed genes were closely related to BRCA1/2, including PALB2 and RAD51 relatively. Our study provides suggestive evidence of the prognostic role of BRCA1/2 in breast cancer and the therapeutic target for breast cancer. Furthermore, BRCA1/2 may influence BRCA prognosis through catalytic activity, acting on DNA, chromosomal regions, organelle fission, and the cell cycle. Nevertheless, further validation is warranted. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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Review

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22 pages, 1919 KiB

Open AccessReview

YAP at the Crossroads of Biomechanics and Drug Resistance in Human Cancer

by Miao Huang, Heyang Wang, Cole Mackey, Michael C. Chung, Juan Guan, Guangrong Zheng, Arkaprava Roy, Mingyi Xie, Christopher Vulpe and Xin Tang

Int. J. Mol. Sci. 2023, 24(15), 12491; https://doi.org/10.3390/ijms241512491 - 6 Aug 2023

Cited by 1 | Viewed by 2606

Abstract

Biomechanical forces are of fundamental importance in biology, diseases, and medicine. Mechanobiology is an emerging interdisciplinary field that studies how biological mechanisms are regulated by biomechanical forces and how physical principles can be leveraged to innovate new therapeutic strategies. This article reviews state-of-the-art mechanobiology knowledge about the yes-associated protein (YAP), a key mechanosensitive protein, and its roles in the development of drug resistance in human cancer. Specifically, the article discusses three topics: how YAP is mechanically regulated in living cells; the molecular mechanobiology mechanisms by which YAP, along with other functional pathways, influences drug resistance of cancer cells (particularly lung cancer cells); and finally, how the mechanical regulation of YAP can influence drug resistance and vice versa. By integrating these topics, we present a unified framework that has the potential to bring theoretical insights into the design of novel mechanomedicines and advance next-generation cancer therapies to suppress tumor progression and metastasis. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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14 pages, 1907 KiB

Open AccessReview

Treatment of Advanced Non-Small Cell Lung Cancer with RET Fusions: Reality and Hopes

by Danilo Rocco, Luigi Sapio, Luigi Della Gravara, Silvio Naviglio and Cesare Gridelli

Int. J. Mol. Sci. 2023, 24(3), 2433; https://doi.org/10.3390/ijms24032433 - 26 Jan 2023

Cited by 8 | Viewed by 2917

Abstract

RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles. This class of medications currently represents the standard of care for both naïve and patients that have not received selective RET-TKIs in the first-line setting. However, we presently lack a satisfactory understanding of resistance mechanism developing after selective RET-TKIs usage, as well as a specific treatment for patients progressing on selpercatinib or pralsetinib. Chemotherapy ± immunotherapy is considered as a recommended subsequent second-line regimen in these patients. Therefore, it is of paramount importance to better define and understand the resistance mechanisms triggered by RET-TKIs. With this in mind, the present review article has been conceived to provide a comprehensive overview about RET+ advanced NSCLC, both from a therapeutic and molecular point of view. Besides comparing the clinical outcome achieved in RET+ advanced NSCLC patients after multikinase inhibitors (MKIs) and/or RET-selective TKIs’ administration, we focused on the molecular mechanisms accountable for their long-term resistance. Finally, a critical perspective on many of today’s most debated issues and concerns is provided, with the purpose of shaping the possible pharmacological approaches for tomorrow’s therapies. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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25 pages, 9377 KiB

Open AccessReview

Application of Ultrasound Combined with Microbubbles for Cancer Therapy

by Deepa Sharma, Kai Xuan Leong and Gregory J. Czarnota

Int. J. Mol. Sci. 2022, 23(8), 4393; https://doi.org/10.3390/ijms23084393 - 15 Apr 2022

Cited by 27 | Viewed by 4140

Abstract

At present, cancer is one of the leading causes of death worldwide. Treatment failure remains one of the prime hurdles in cancer treatment due to the metastatic nature of cancer. Techniques have been developed to hinder the growth of tumours or at least to stop the metastasis process. In recent years, ultrasound therapy combined with microbubbles has gained immense success in cancer treatment. Ultrasound-stimulated microbubbles (USMB) combined with other cancer treatments including radiation therapy, chemotherapy or immunotherapy has demonstrated potential improved outcomes in various in vitro and in vivo studies. Studies have shown that low dose radiation administered with USMB can have similar effects as high dose radiation therapy. In addition, the use of USMB in conjunction with radiotherapy or chemotherapy can minimize the toxicity of high dose radiation or chemotherapeutic drugs, respectively. In this review, we discuss the biophysical properties of USMB treatment and its applicability in cancer therapy. In particular, we highlight important preclinical and early clinical findings that demonstrate the antitumour effect combining USMB and other cancer treatment modalities (radiotherapy and chemotherapy). Our review mainly focuses on the tumour vascular effects mediated by USMB and these cancer therapies. We also discuss several current limitations, in addition to ongoing and future efforts for applying USMB in cancer treatment. Full article

(This article belongs to the Special Issue Innovation through Tradition: The Current Challenges in Cancer Treatment 2.0)

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