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Molecular Therapy Targeting Cancer Specific Signal Pathways

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

Deadline for manuscript submissions: closed (30 December 2021) | Viewed by 14953

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Special Issue Editors

Dr. Kyung Keun Kim

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Guest Editor

Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
Interests: cancer metastasis; tumor progression; developing anti-cancer agents; molecular therapy; tumor microenvironment; receptor tyrosine kinase; chemoresistance

Dr. Hyungho Ha

E-Mail Website
Guest Editor

Laboratory of Medicinal chemistry, College of Pharmacy, Sunchon National University, 255 Jungangro, Sunchon, Junnam 57922, Korea
Interests: immune checkpoint inhibitor; immuno-oncology; small molecule inhibitors; medicinal chemistry

Prof. Dr. Hangun Kim

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Guest Editor

Laboratory of Pathophysiology, College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
Interests: molecular pathophysiology; disease model; novel bioactive compound
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This special issue covers all areas of molecular cancer therapeutics developing with pharmacological purpose against cancer development, growth, progression, metastasis, and therapy resistance but specializes in several areas: therapeutics in the form of small molecule, gene, peptide, protein, and so on, which target cancer specific signal pathways. This issue is focused on the selection of research papers and reviews that expand knowledge on recently discovered molecular therapeutics targeting cancer specific signaling pathways in tumor or TME, and on emerging concepts in cancer therapeutic fields. As targeting pathways, the conventional/unconventional/novel signal pathways in certain types of cancer cell or in the components of tumor microenvironment (TME) including blood vessels, immune cells, fibroblasts, signaling molecules and extracellular matrix are among good considerations. Also, identification of enhanced efficacy with combinational treatment, associated biology related to tumor microenvironment modulation, medicinal chemistry with altered bioactivity via modification or derivatizaion, therapeutic repositioning, molecular imaging of therapeutic effects are also to be covered. In addition, we sincerely welcome studies on the elucidation of advanced mechanisms of action for existing molecular thearapy, or establishment of new methodology for evaluation of above fields, or promoting the translation of preclinical research to a clinical application.

Dr. Kyung Keun Kim
Dr. Hangun Kim
Dr. Hyungho Ha
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

Molecular therapy
Small molecule
Gene
Peptide
Protein
Cancer
Tumor
Tumor microenvironment (TME)
Signal pathway
Mechanism of action
Bioactivity
Efficacy

Published Papers (5 papers)

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Research

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14 pages, 7059 KiB

Open AccessArticle

TAMpepK Suppresses Metastasis through the Elimination of M2-Like Tumor-Associated Macrophages in Triple-Negative Breast Cancer

by Chanju Lee, Soyoung Kim, Chanmi Jeong, Inhee Cho, Juyeon Jo, Ik-Hwan Han and Hyunsu Bae

Int. J. Mol. Sci. 2022, 23(4), 2157; https://doi.org/10.3390/ijms23042157 - 15 Feb 2022

Cited by 5 | Viewed by 2887

Abstract

Triple-negative breast cancer (TNBC) accounts for approximately 10–15% of all breast cancer cases and is characterized by high invasiveness, high metastatic potential, relapse proneness, and poor prognosis. M2-like tumor-associated macrophages (TAMs) contribute to tumorigenesis and are promising targets for inhibiting breast cancer metastasis. Therefore, we investigated whether melittin-conjugated pro-apoptotic peptide (TAMpepK) exerts therapeutic effects on breast cancer metastasis by targeting M2-like TAMs. TAMpepK is composed of M2-like TAM binding peptide (TAMpep) and pro-apoptotic peptide d(KLAKLAK)₂ (dKLA). A metastatic mouse model was constructed by injecting 4T1-luc2 cells either orthotopically or via tail vein injection, and tumor burden was quantified using a bioluminescence in vivo imaging system. We found that TAMpepK suppressed lung and lymph node metastases of breast cancer by eliminating M2-like TAMs without affecting the viability of M1-like macrophages and resident macrophages in the orthotopic model. Furthermore, TAMpepK reduced pulmonary seeding and the colonization of tumor cells in the tail vein injection model. The number of CD8⁺ T cells in contact with TAMs was significantly decreased in tumor nodules treated with TAMpepK, resulting in the functional activation of cytotoxic CD8⁺ T cells. Taken together, our findings suggest that TAMpepK could be a novel therapeutic agent for the inhibition of breast cancer metastasis by targeting M2-like TAMs. Full article

(This article belongs to the Special Issue Molecular Therapy Targeting Cancer Specific Signal Pathways)

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15 pages, 2075 KiB

Open AccessArticle

δ-Catenin Participates in EGF/AKT/p21^Waf Signaling and Induces Prostate Cancer Cell Proliferation and Invasion

by Yingjie Shen, Hyoung Jae Lee, Rui Zhou, Hangun Kim, Gen Chen, Young-Chang Cho and Kwonseop Kim

Int. J. Mol. Sci. 2021, 22(10), 5306; https://doi.org/10.3390/ijms22105306 - 18 May 2021

Cited by 8 | Viewed by 2188

Abstract

Prostate cancer (PCa) is the second most leading cause of death in males. Our previous studies have demonstrated that δ-catenin plays an important role in prostate cancer progression. However, the molecular mechanism underlying the regulation of δ-catenin has not been fully explored yet. In the present study, we found that δ-catenin could induce phosphorylation of p21^Waf and stabilize p21 in the cytoplasm, thus blocking its nuclear accumulation for the first time. We also found that δ-catenin could regulate the interaction between AKT and p21, leading to phosphorylation of p21 at Thr-145 residue. Finally, EGF was found to be a key factor upstream of AKT/δ-catenin/p21 for promoting proliferation and metastasis in prostate cancer. Our findings provide new insights into molecular controls of EGF and the development of potential therapeutics targeting δ-catenin to control prostate cancer progression. Full article

(This article belongs to the Special Issue Molecular Therapy Targeting Cancer Specific Signal Pathways)

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14 pages, 1885 KiB

Open AccessArticle

Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3

by Il Je Cho, Jae Kwang Kim, Eun Ok Kim, Sang Mi Park, Sang Chan Kim, Sung Hwan Ki and Sae Kwang Ku

Int. J. Mol. Sci. 2021, 22(9), 4743; https://doi.org/10.3390/ijms22094743 - 29 Apr 2021

Cited by 6 | Viewed by 2021

Abstract

Hemistepta lyrata (Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from H. lyrata has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of H. lyrata on hepatocellular carcinoma (HCC) cells and investigated the associated bioactive compounds and their relevant mechanisms. From the viability results of HCC cells treated with various H. lyrata extracts, HsA was identified as the major compound contributing to the H. lyrata-mediated cytotoxicity. HsA increased expression of cleaved PARP and cells with Sub-G1 phase, Annexin V binding, and TUNEL staining, which imply HsA induces apoptosis. In addition, HsA provoked oxidative stress by decreasing the reduced glutathione/oxidized glutathione ratio and accumulating reactive oxygen species and glutathione-protein adducts. Moreover, HsA inhibited the transactivation of signal transducer and activator of transcription 3 (STAT3) by its dephosphorylation at Y705 and glutathione conjugation. Stable expression of a constitutive active mutant of STAT3 prevented the reduction of cell viability by HsA. Finally, HsA enhanced the sensitivity of sorafenib-mediated cytotoxicity by exaggerating oxidative stress and Y705 dephosphorylation of STAT3. Therefore, HsA will be a promising candidate to induce apoptosis of HCC cells via downregulating STAT3 and sensitizing conventional chemotherapeutic agents. Full article

(This article belongs to the Special Issue Molecular Therapy Targeting Cancer Specific Signal Pathways)

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16 pages, 2680 KiB

Open AccessArticle

Costunolide, a Sesquiterpene Lactone, Suppresses Skin Cancer via Induction of Apoptosis and Blockage of Cell Proliferation

by Sung Ho Lee, Young-Chang Cho and Jae Sung Lim

Int. J. Mol. Sci. 2021, 22(4), 2075; https://doi.org/10.3390/ijms22042075 - 19 Feb 2021

Cited by 14 | Viewed by 2680

Abstract

Costunolide is a naturally occurring sesquiterpene lactone that demonstrates various therapeutic actions such as anti-oxidative, anti-inflammatory, and anti-cancer properties. Costunolide has recently emerged as a potential anti-cancer agent in various types of cancer, including colon, lung, and breast cancer. However, its mode of action in skin cancer remains unclear. To determine the anti-cancer potential of costunolide in skin cancer, human epidermoid carcinoma cell line A431 was treated with costunolide. A lactate dehydrogenase assay showed that costunolide diminished the viability of A431 cells. Apoptotic cells were detected by annexin V/propidium iodide double staining and Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay assay, and costunolide induced cell apoptosis via activation of caspase-3 as well as induction of poly-ADP ribose polymerase cleavage in A431 cells. In addition, costunolide elevated the level of the pro-apoptotic protein Bax while lowering the levels of anti-apoptotic proteins, including Bcl-2 and Bcl-xL. To address the inhibitory effect of costunolide on cell proliferation and survival, various signaling pathways, including mitogen-activated protein kinases, signal transducer and activator of transcription 3 (STAT3), nuclear factor κB (NF-κB), and Akt, were investigated. Costunolide activated the p38 and c-Jun N-terminal kinase pathways while suppressing the extracellular signal-regulated kinase (ERK), STAT3, NF-κB, and Akt pathways in A431 cells. Consequently, it was inferred that costunolide suppresses cell proliferation and survival via these signaling pathways. Taken together, our data clearly indicated that costunolide exerts anti-cancer activity in A431 cells by suppressing cell growth via inhibition of proliferation and promotion of apoptosis. Therefore, it may be employed as a potentially tumor-specific candidate in skin cancer treatment. Full article

(This article belongs to the Special Issue Molecular Therapy Targeting Cancer Specific Signal Pathways)

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Review

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25 pages, 821 KiB

Open AccessReview

The Comprehensive “Omics” Approach from Metabolomics to Advanced Omics for Development of Immune Checkpoint Inhibitors: Potential Strategies for Next Generation of Cancer Immunotherapy

by Sang Jun Yoon, Chae Bin Lee, Soon Uk Chae, Seong Jun Jo and Soo Kyung Bae

Int. J. Mol. Sci. 2021, 22(13), 6932; https://doi.org/10.3390/ijms22136932 - 28 Jun 2021

Cited by 9 | Viewed by 4378

Abstract

In the past decade, immunotherapies have been emerging as an effective way to treat cancer. Among several categories of immunotherapies, immune checkpoint inhibitors (ICIs) are the most well-known and widely used options for cancer treatment. Although several studies continue, this treatment option has yet to be developed into a precise application in the clinical setting. Recently, omics as a high-throughput technique for understanding the genome, transcriptome, proteome, and metabolome has revolutionized medical research and led to integrative interpretation to advance our understanding of biological systems. Advanced omics techniques, such as multi-omics, single-cell omics, and typical omics approaches, have been adopted to investigate various cancer immunotherapies. In this review, we highlight metabolomic studies regarding the development of ICIs involved in the discovery of targets or mechanisms of action and assessment of clinical outcomes, including drug response and resistance and propose biomarkers. Furthermore, we also discuss the genomics, proteomics, and advanced omics studies providing insights and comprehensive or novel approaches for ICI development. The overview of ICI studies suggests potential strategies for the development of other cancer immunotherapies using omics techniques in future studies. Full article

(This article belongs to the Special Issue Molecular Therapy Targeting Cancer Specific Signal Pathways)

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