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Current Research on Cancer Biology and Therapeutics: 2nd Edition

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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 (30 September 2024) | Viewed by 13918

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Special Issue Editor

Prof. Dr. Rafael Coveñas Rodríguez

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Guest Editor

Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neuroscience of Castilla and León (INCYL), University of Salamanca, c/Pintor Fernando Gallego 1, 37007 Salamanca, Spain
Interests: cancer and anticancer peptides; substance P/neurokinin-1 receptor system; neurokinin-1 receptor antagonists
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Special Issue Information

Dear Colleagues,

Cancer caused 10 million deaths in 2020 and remains a major health problem worldwide. Surgery, chemotherapy, and radiotherapy are the current cancer treatments, but unfortunately, the results are in many cases unsatisfactory. The development of promising cancer research fields (new cytostatics, stem cells, human genome) has not been translated into better perspectives for many cancer patients. To improve the diagnosis and treatment of tumors, novel specific anticancer strategies showing enhanced antitumor effects and decreased toxicity must be explored.

Cancer cells evade the immune system and show resistance to anticancer therapies, leading to cancer cell proliferation, survival, invasion, and metastasis. These mechanisms, as well as angiogenesis, are regulated by different ligands, receptors, and intracellular cascades that regulate the genetic/protein machinery of cancer cells; thus, anticancer drugs must specifically block these cellular events. This has opened up new research lines to explore new therapeutic strategies focused on targetable molecules. Accordingly, the main aim of this Special Issue is to increase knowledge about potential targetable molecules involved in previous mechanisms such as peptides, signal transduction molecules, transcription factors, kinases, DNA damage repair enzymes, and epigenetic regulatory proteins. Thus, new antiproliferative, antimetastatic, and antiangiogenic strategies are welcome, as well as apoptotic inducers, signal transduction inhibitors, cytotoxic peptide-conjugate-based cancer therapy, gene expression modulators, hormone therapies, and peptide-receptor radionuclide therapy. Studies focused on the function–structure relationships between ligands and receptors for the design and synthesis of new and more effective anticancer compounds are also welcome.

I hope that this Special Issue opens the door to developing promising molecular targets, to blocking tumor development, and to developing new compounds capable of specifically destroying tumor cells. New anticancer strategies targeting tumor-specific molecular derangements must serve to improve the diagnosis and treatment of tumors and increase the cure rate and quality of life of cancer patients.

Prof. Dr. Rafael Coveñas Rodríguez
Guest Editor

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Keywords

antiangiogenic
anticancer therapy
antimetastatic
apoptosis
antiproliferative
cancer
peptides
signaling molecules
transcription factors
tumor

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 179 KiB

Open AccessEditorial

Editorial for the Special Issue “Current Research on Cancer Biology and Therapeutics: 2nd Edition”

by Rafael Coveñas

Int. J. Mol. Sci. 2024, 25(21), 11777; https://doi.org/10.3390/ijms252111777 - 2 Nov 2024

Viewed by 755

Abstract

In the second edition of this Special Issue, several promising antitumor strategies have been presented in addition to those reported in the first edition, in which several compounds (acetylcorynoline, BaP1, sarco/endoplasmic reticulum calcium ATPase inhibitors, neuropeptide Y, neuropeptide Y antagonists, neurokinin-1 receptor antagonists) exerting antitumor effects against colorectal cancer, papillary thyroid carcinoma, cholangiocarcinoma, Ewing sarcoma, liver cancer, and breast cancer were reported [...] Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

Research

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19 pages, 2515 KiB

Open AccessArticle

Descriptive Analysis of Common Fusion Mutations in Papillary Thyroid Carcinoma in Hungary

by Richard Armos, Bence Bojtor, Janos Podani, Ildiko Illyes, Bernadett Balla, Zsuzsanna Putz, Andras Kiss, Andrea Kohanka, Erika Toth, Istvan Takacs, Janos P. Kosa and Peter Lakatos

Int. J. Mol. Sci. 2024, 25(19), 10787; https://doi.org/10.3390/ijms251910787 - 8 Oct 2024

Cited by 1 | Viewed by 996

Abstract

Thyroid cancer is the most common type of endocrine malignancy. Papillary thyroid carcinoma (PTC) is its predominant subtype, which is responsible for the vast majority of cases. It is true that PTC is a malignant tumor with a very good prognosis due to effective primary therapeutic approaches such as thyroidectomy and radioiodine (RAI) therapy. However, we are often required to indicate second-line treatments to eradicate the tumor properly. In these scenarios, molecular therapies are promising alternatives, especially if specifically targetable mutations are present. Many of these targetable gene alterations originate from gene fusions, which can be found using molecular diagnostics like next-generation sequencing (NGS). Nonetheless, molecular profiling is far from being a routine procedure in the initial phase of PTC diagnostics. As a result, the mutation status, except for BRAF V600E mutation, is not included in risk classification algorithms either. This study aims to provide a comprehensive analysis of fusion mutations in PTC and their associations with clinicopathological variables in order to underscore certain clinical settings when molecular diagnostics should be considered earlier, and to demonstrate yet unknown molecular–clinicopathological connections. We conducted a retrospective fusion mutation screening in formalin-fixed paraffin-embedded (FFPE) PTC tissue samples of 100 patients. After quality evaluation by an expert pathologist, RNA isolation was performed, and then NGS was applied to detect 23 relevant gene fusions in the tumor samples. Clinicopathological data were collected from medical and histological records. To obtain the most associations from the multivariate dataset, we used the d-correlation method for our principal component analysis (PCA). Further statistical analyses, including Chi-square tests and logistic regressions, were performed to identify additional significant correlations within certain subsets of the data. Fusion mutations were identified in 27% of the PTC samples, involving nine distinct genes: RET, NTRK3, CCDC6, ETV6, MET, ALK, NCOA4, EML4, and SQSTM1. RET and CCDC6 fusions were associated with type of thyroidectomy, RAI therapy, smaller tumor size, and history of Hashimoto’s disease. NCOA4 fusion correlated with sex, multifocality, microcarcinoma character, history of goiter, and obstructive pulmonary disease. EML4 fusion was also linked with surgical procedure type and smaller tumor size, as well as the history of hypothyroidism. SQSTM1 fusion was associated with multifocality and a medical history of thyroid/parathyroid adenoma. NTRK3 and ETV6 fusions showed significant associations with Hashimoto’s disease, and ETV6, also with endometriosis. Moreover, fusion mutations were linked to younger age at the time of diagnosis, particularly the fusion of ETV6. The frequent occurrence of fusion mutations and their associations with certain clinicopathological metrics highlight the importance of integrating molecular profiling into routine PTC management. Early detection of fusion mutations can inform surgical decisions and therapeutic strategies, potentially improving clinical outcomes. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

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32 pages, 11746 KiB

Open AccessArticle

Targeting Colorectal Cancer: Unravelling the Transcriptomic Impact of Cisplatin and High-THC Cannabis Extract

by Viktoriia Cherkasova, Yaroslav Ilnytskyy, Olga Kovalchuk and Igor Kovalchuk

Int. J. Mol. Sci. 2024, 25(8), 4439; https://doi.org/10.3390/ijms25084439 - 18 Apr 2024

Cited by 3 | Viewed by 2043

Abstract

Cisplatin and other platinum-derived chemotherapy drugs have been used for the treatment of cancer for a long time and are often combined with other medications. Unfortunately, tumours often develop resistance to cisplatin, forcing scientists to look for alternatives or synergistic combinations with other drugs. In this work, we attempted to find a potential synergistic effect between cisplatin and cannabinoid delta-9-THC, as well as the high-THC Cannabis sativa extract, for the treatment of HT-29, HCT-116, and LS-174T colorectal cancer cell lines. However, we found that combinations of the high-THC cannabis extract with cisplatin worked antagonistically on the tested colorectal cancer cell lines. To elucidate the mechanisms of drug interactions and the distinct impacts of individual treatments, we conducted a comprehensive transcriptomic analysis of affected pathways within the colorectal cancer cell line HT-29. Our primary objective was to gain a deeper understanding of the underlying molecular mechanisms associated with each treatment modality and their potential interactions. Our findings revealed an antagonistic interaction between cisplatin and high-THC cannabis extract, which could be linked to alterations in gene transcription associated with cell death (BCL2, BAD, caspase 10), DNA repair pathways (Rad52), and cancer pathways related to drug resistance. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

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23 pages, 3022 KiB

Open AccessArticle

The Effect of 4-(Dimethylamino)phenyl-5-oxopyrrolidines on Breast and Pancreatic Cancer Cell Colony Formation, Migration, and Growth of Tumor Spheroids

by Karolina Kairytė, Rita Vaickelionienė, Birutė Grybaitė, Kazimieras Anusevičius, Vytautas Mickevičius and Vilma Petrikaitė

Int. J. Mol. Sci. 2024, 25(3), 1834; https://doi.org/10.3390/ijms25031834 - 2 Feb 2024

Cited by 2 | Viewed by 1242

Abstract

A series of hydrazones, azoles, and azines bearing a 4-dimethylaminophenyl-5-oxopyrrolidine scaffold was synthesized. Their cytotoxic effect against human pancreatic carcinoma Panc-1 and triple-negative breast cancer MDA-MB-231 cell lines was established by MTT assay. Pyrrolidinone derivatives 3c and 3d, with incorporated 5-chloro and 5-methylbenzimidazole fragments; hydrazone 5k bearing a 5-nitrothien-2-yl substitution; and hydrazone 5l with a naphth-1-yl fragment in the structure significantly decreased the viability of both cancer cell lines. Compounds 3c and 5k showed the highest selectivity, especially against the MDA-MB-231 cancer cell line. The EC₅₀ values of the most active compound 5k against the MDA-MB231 cell line was 7.3 ± 0.4 μM, which were slightly higher against the Panc-1 cell line (10.2 ± 2.6 μM). Four selected pyrrolidone derivatives showed relatively high activity in a clonogenic assay. Compound 5k was the most active in both cell cultures, and it completely disturbed MDA-MB-231 cell colony growth at 1 and 2 μM and showed a strong effect on Panc-1 cell colony formation, especially at 2 μM. The compounds did not show an inhibitory effect on cell line migration by the ‘wound-healing’ assay. Compound 3d most efficiently inhibited the growth of Panc-1 spheroids and reduced cell viability in MDA-MB-231 spheroids. Considering these different activities in biological assays, the selected pyrrolidinone derivatives could be further tested to better understand the structure–activity relationship and their mechanism of action. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

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19 pages, 5084 KiB

Open AccessArticle

Anti-Algics in the Therapeutic Response of Breast and Urological Cancers

by Ana Catarina Matos, João Lorigo, Inês Alexandra Marques, Ana Margarida Abrantes, Matilde Jóia-Gomes, Pedro Sa-Couto, Ana Cristina Gonçalves, Ana Valentim, Edgar Tavares-Silva, Arnaldo Figueiredo, Ana Salomé Pires and Maria Filomena Botelho

Int. J. Mol. Sci. 2024, 25(1), 468; https://doi.org/10.3390/ijms25010468 - 29 Dec 2023

Cited by 1 | Viewed by 1566

Abstract

The effect of anti-algics on tumor progression and the overall survival of patients is controversial and remains unclear. Herein, we disclose the in vitro effects of the local anesthetics lidocaine, ropivacaine, and levobupivacaine on breast (MCF7), prostate (PC3, LNCaP), and bladder (TCCSUP, HT1376) cancer cell lines, both as monotherapy and in combination with standard-of-care therapeutics. Assays for cell proliferation, viability, death profile, and migration were performed. Additionally, we explored the clinical outcomes of opioid use through a cross-sectional study involving 200 metastatic prostate cancer patients. The main clinical data collected included the type of opioid therapy administered, dosage, treatment duration, disease progression, and overall survival. Results obtained demonstrate that treatment with local anesthetics has a promising selective anti-tumor effect on these types of cancer, with higher effects when associated with docetaxel. This points out the use of local anesthetics as an added value in the treatment of prostate carcinoma patients. Alternatively, chronic opioid use was correlated with reduced overall survival (p < 0.05) and progression-free survival (p < 0.05) at each treatment line in the observational study. While these results provide valuable insights, larger prospective studies are imperative to comprehensively evaluate the clinical impact of opioid analgesics in prostate cancer patients. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

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Review

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26 pages, 2404 KiB

Open AccessReview

Glioma and Peptidergic Systems: Oncogenic and Anticancer Peptides

by Manuel Lisardo Sánchez, Arturo Mangas and Rafael Coveñas

Int. J. Mol. Sci. 2024, 25(14), 7990; https://doi.org/10.3390/ijms25147990 - 22 Jul 2024

Cited by 2 | Viewed by 1019

Abstract

Glioma cells overexpress different peptide receptors that are useful for research, diagnosis, management, and treatment of the disease. Oncogenic peptides favor the proliferation, migration, and invasion of glioma cells, as well as angiogenesis, whereas anticancer peptides exert antiproliferative, antimigration, and anti-angiogenic effects against gliomas. Other peptides exert a dual effect on gliomas, that is, both proliferative and antiproliferative actions. Peptidergic systems are therapeutic targets, as peptide receptor antagonists/peptides or peptide receptor agonists can be administered to treat gliomas. Other anticancer strategies exerting beneficial effects against gliomas are discussed herein, and future research lines to be developed for gliomas are also suggested. Despite the large amount of data supporting the involvement of peptides in glioma progression, no anticancer drugs targeting peptidergic systems are currently available in clinical practice to treat gliomas. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

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13 pages, 2355 KiB

Open AccessReview

Suppressing Anaphase-Promoting Complex/Cyclosome–Cell Division Cycle 20 Activity to Enhance the Effectiveness of Anti-Cancer Drugs That Induce Multipolar Mitotic Spindles

by Scott C. Schuyler, Hsin-Yu Chen and Kai-Ping Chang

Int. J. Mol. Sci. 2024, 25(12), 6329; https://doi.org/10.3390/ijms25126329 - 7 Jun 2024

Cited by 1 | Viewed by 1492

Abstract

Paclitaxel induces multipolar spindles at clinically relevant doses but does not substantially increase mitotic indices. Paclitaxel’s anti-cancer effects are hypothesized to occur by promoting chromosome mis-segregation on multipolar spindles leading to apoptosis, necrosis and cyclic-GMP-AMP Synthase–Stimulator of Interferon Genes (cGAS-STING) pathway activation in daughter cells, leading to secretion of type I interferon (IFN) and immunogenic cell death. Eribulin and vinorelbine have also been reported to cause increases in multipolar spindles in cancer cells. Recently, suppression of Anaphase-Promoting Complex/Cyclosome–Cell Division Cycle 20 (APC/C-CDC20) activity using CRISPR/Cas9 mutagenesis has been reported to increase sensitivity to Kinesin Family 18a (KIF18a) inhibition, which functions to suppress multipolar mitotic spindles in cancer cells. We propose that a way to enhance the effectiveness of anti-cancer agents that increase multipolar spindles is by suppressing the APC/C-CDC20 to delay, but not block, anaphase entry. Delaying anaphase entry in genomically unstable cells may enhance multipolar spindle-induced cell death. In genomically stable healthy human cells, delayed anaphase entry may suppress the level of multipolar spindles induced by anti-cancer drugs and lower mitotic cytotoxicity. We outline specific combinations of molecules to investigate that may achieve the goal of enhancing the effectiveness of anti-cancer agents. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

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14 pages, 1131 KiB

Open AccessReview

Biomarker Identification through Proteomics in Colorectal Cancer

by Desirée Martín-García, Marilina García-Aranda and Maximino Redondo

Int. J. Mol. Sci. 2024, 25(4), 2283; https://doi.org/10.3390/ijms25042283 - 14 Feb 2024

Cited by 3 | Viewed by 2926

Abstract

Colorectal cancer (CRC) is a devastating disease that ranks third in diagnosis and as the second leading cause of cancer-related deaths. The early detection of CRC has been shown to be the most effective strategy to improve treatment outcomes and patient survival. Therefore, current lines of research focus on the development of reliable diagnostic tools. Targeted therapies, in combination with standard chemotherapy and immune checkpoint inhibitors, have emerged as promising treatment protocols in CRC. However, their effectiveness is linked to the molecular characteristics of each patient. The importance of discovering biomarkers that help predict response to therapies and assess prognosis is evident as they allow for a fundamental step towards personalized care and successful treatments. Among the ongoing efforts to identify them, mass spectrometry-based translational proteomics presents itself as a unique opportunity as it enables the discovery and application of protein biomarkers that may revolutionize the early detection and treatment of CRC. Our objective is to show the most recent studies focused on the identification of CRC-related protein markers, as well as to provide an updated view of advances in the field of proteomics and cancer. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

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Other

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15 pages, 1767 KiB

Open AccessCase Report

PARP Inhibitors in Brain Metastases from Epithelial Ovarian Cancer through a Multimodal Patient Journey: Case Reports and Literature Review

by Simona Frezzini, Giulia Tasca, Lucia Borgato, Lucia Sartor, Annamaria Ferrero, Grazia Artioli, Alessandra Modena and Alessandra Baldoni

Int. J. Mol. Sci. 2024, 25(14), 7887; https://doi.org/10.3390/ijms25147887 - 18 Jul 2024

Cited by 1 | Viewed by 1127

Abstract

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. We identified, across different cancer centers, six cases of both BRCA wild-type and BRCA-mutated EOCs spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as per clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for the optimal disease control of this unfortunate patient subset. Albeit not being directly investigated in BM patients, PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: 2nd Edition)

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