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Special Issue "Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies"

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: 31 December 2021.

Special Issue Editor

Dr. Morito Kurata
E-Mail Website
Guest Editor
Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
Interests: cancer; oncogene; tumorigenesis; drug resistance; CRISPR screenings

Special Issue Information

Dear Colleagues,

Efforts to discover drugs that can cure cancers are continuing. Tyrosine kinase inhibitors, such as imatinib, represent a significant achievement for the treatment of chronic myelogenous leukemia with a BCR-ABL translocation. BCR-ABL has a strong oncogenic effect and represents a good target for inhibition; therefore, finding oncogenic molecules is a straightforward way to find molecular targets. However, inhibitors for strong oncogenes, such as MYC and RAS, are not used at the clinical phage. Improved chemical approaches or other regulators of these genes await discovery. By contrast, molecular targets can be found using a variety of strategies. Comprehensive screening is one promising approach for identifying new oncogenic targets of cancer cell survival. The recent development of CRISPR screening now provides a powerful tool for finding essential molecules relevant to cancers. A CRISPR library can identify essential cancer-specific molecules that could also be therapeutic targets. CRISPR screenings with novel modified methods have revealed synergistic and synthetic lethal combinations of drugs. In addition, a CRISPR library can induce drug resistance by random mutation, and this would be useful for overcoming the serious concerns of drug resistance. This Special Issue focuses on studies related to basic strategies and comprehensive screening for molecular targets for cancer cures. Up-to-date review articles and commentaries are also welcome.

Dr. Morito Kurata
Guest Editor

Manuscript Submission Information

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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
  • Molecular Targeted therapy
  • Oncogene
  • Drug resisntance
  • CRISPR screening
  • Synthetic lethal
  • Synergistic drug

Published Papers (4 papers)

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Research

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Article
Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways
Int. J. Mol. Sci. 2021, 22(17), 9621; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179621 - 06 Sep 2021
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Abstract
Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of [...] Read more.
Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways. Full article
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Article
NMNAT1 Is a Survival Factor in Actinomycin D-Induced Osteosarcoma Cell Death
Int. J. Mol. Sci. 2021, 22(16), 8869; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168869 - 18 Aug 2021
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Abstract
Osteosarcoma is a frequent and extremely aggressive type of pediatric cancer. New therapeutic approaches are needed to improve the overall survival of osteosarcoma patients. Our previous results suggest that NMNAT1, a key enzyme in nuclear NAD+ synthesis, facilitates the survival of cisplatin-treated [...] Read more.
Osteosarcoma is a frequent and extremely aggressive type of pediatric cancer. New therapeutic approaches are needed to improve the overall survival of osteosarcoma patients. Our previous results suggest that NMNAT1, a key enzyme in nuclear NAD+ synthesis, facilitates the survival of cisplatin-treated osteosarcoma cells. A high-throughput cytotoxicity screening was performed to identify novel pathways or compounds linked to the cancer-promoting role of NMNAT1. Nine compounds caused higher toxicity in the NMNAT1 KO U2OS cells compared to their wild type counterparts, and actinomycin D (ActD) was the most potent. ActD-treatment of NMNAT1 KO cells increased caspase activity and secondary necrosis. The reduced NAD+ content in NMNAT1 KO cells was further decreased by ActD, which partially inhibited NAD+-dependent enzymes, including the DNA nick sensor enzyme PARP1 and the NAD+-dependent deacetylase SIRT1. Impaired PARP1 activity increased DNA damage in ActD-treated NMNAT1 knockout cells, while SIRT1 impairment increased acetylation of the p53 protein, causing the upregulation of pro-apoptotic proteins (NOXA, BAX). Proliferation was decreased through both PARP- and SIRT-dependent pathways. On the one hand, PARP inhibitors sensitized wild type but not NMNAT1 KO cells to ActD-induced anti-clonogenic effects; on the other hand, over-acetylated p53 induced the expression of the anti-proliferative p21 protein leading to cell cycle arrest. Based on our results, NMNAT1 acts as a survival factor in ActD-treated osteosarcoma cells. By inhibiting both PARP1- and SIRT1-dependent cellular pathways, NMNAT1 inhibition can be a promising new tool in osteosarcoma chemotherapy. Full article
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Review

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Review
Nanobodies Enhancing Cancer Visualization, Diagnosis and Therapeutics
Int. J. Mol. Sci. 2021, 22(18), 9778; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189778 - 10 Sep 2021
Viewed by 380
Abstract
Worldwide, cancer is a serious health concern due to the increasing rates of incidence and mortality. Conventional cancer imaging, diagnosis and treatment practices continue to substantially contribute to the fight against cancer. However, these practices do have some risks, adverse effects and limitations, [...] Read more.
Worldwide, cancer is a serious health concern due to the increasing rates of incidence and mortality. Conventional cancer imaging, diagnosis and treatment practices continue to substantially contribute to the fight against cancer. However, these practices do have some risks, adverse effects and limitations, which can affect patient outcomes. Although antibodies have been developed, successfully used and proven beneficial in various oncology practices, the use of antibodies also comes with certain challenges and limitations (large in size, poor tumor penetration, high immunogenicity and a long half-life). Therefore, it is vital to develop new ways to visualize, diagnose and treat cancer. Nanobodies are novel antigen-binding fragments that possess many advantageous properties (small in size, low immunogenicity and a short half-life). Thus, the use of nanobodies in cancer practices may overcome the challenges experienced with using traditional antibodies. In this review, we discuss (1) the challenges with antibody usage and the superior qualities of nanobodies; (2) the use of antibodies and nanobodies in cancer imaging, diagnosis, drug delivery and therapy (surgery, radiotherapy, chemotherapy and immunotherapy); and (3) the potential improvements in oncology practices due to the use of nanobodies as compared to antibodies. Full article
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Review
Overview of Ferroptosis and Synthetic Lethality Strategies
Int. J. Mol. Sci. 2021, 22(17), 9271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179271 - 27 Aug 2021
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Abstract
Ferroptosis, a term first proposed in 2012, is iron-dependent, non-apoptotic regulatory cell death induced by erastin. Ferroptosis was originally discovered during synthetic lethal screening for drugs sensitive to RAS mutant cells, and is closely related to synthetic lethality. Ferroptosis sensitizes cancer stem cells [...] Read more.
Ferroptosis, a term first proposed in 2012, is iron-dependent, non-apoptotic regulatory cell death induced by erastin. Ferroptosis was originally discovered during synthetic lethal screening for drugs sensitive to RAS mutant cells, and is closely related to synthetic lethality. Ferroptosis sensitizes cancer stem cells and tumors that undergo epithelial−mesenchymal transition and are resistant to anticancer drugs or targeted therapy. Therefore, ferroptosis-inducing molecules are attractive new research targets. In contrast, synthetic lethal strategies approach mechanisms and genetic abnormalities that cannot be directly targeted by conventional therapeutic strategies, such as RAS mutations, hypoxia, and abnormalities in the metabolic environment. They also target the environment and conditions specific to malignant cells, have a low toxicity to normal cells, and can be used in combination with known drugs to produce new ones. However, the concept of synthetic lethality has not been widely adopted with ferroptosis. In this review, we surveyed the literature on ferroptosis-related factors and synthetic lethality to examine the potential therapeutic targets in ferroptosis-related molecules, focusing on factors related to synthetic lethality, discovery methods, clinical application stages, and issues in drug discovery. Full article
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