Drug Resistance and Novel Targets for Cancer Therapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 53187

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Instituto de Saúde de Nova Friburgo, Universidade Federal Fluminense, Nova Friburgo, Brazil
Interests: natural product; organic synthesis; cancer drugs; chemotherapeutic molecular targets
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
Interests: organic synthesis; medicinal chemistry; naphthoquinones; triazoles
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-599, Brazil
Interests: my research interests are focused on the better understanding of cellular and molecular mechanisms of cancer drug resistance; by providing the molecular basis of chemoresistance mechanisms; we might help identify potential molecular targets and therapeutic strategies to surpass drug resistance and potentiate the cytotoxic effects of chemotherapeutic agents in cancer

Special Issue Information

Dear Colleagues,

Drug resistance is a complex phenomenon resulting from one or more mechanisms which render cells resistant to anticancer drugs. Molecular hallmarks of cancer and therapeutics against drug resistance mechanisms are the leading targets for cancer treatment. Molecular targeted therapy is gaining interest due to its specificity to cancer while sparing normal cells. Despite this, drug resistance still represents a major obstacle that limits sustained clinical benefits not only for targeted cancer therapies, but also conventional chemotherapy. Notably, while some cancer patients do not respond to anticancer drugs due to primary resistance, even responders might eventually relapse following acquired resistance.

In this context, we are proposing a new Special Issue encompassing these two major molecular pathways involved in cancer treatment, such as the determinations of new cancer-related molecular targets, the development of drugs that block them, and drugs that aim to avoid resistance to treatment. We invite the submission of innovative research papers and review articles discussing new molecular targets or anticancer drugs. We encourage articles related, but not restricted, to apoptosis induction, proliferative signaling, migration, angiogenesis, metastasis, immune checkpoint, tumor-vaccine-related targets, chimeric antigen receptor T-cells, or their possible drug-resistance mechanisms. Therefore, this Special Issue aims to approach novel molecular targets, their bullets, and possible resistance mechanisms that might be targeted to potentiate more durable and effective responses for cancer therapy.

Dr. Bruno Kaufmann Robbs
Prof. Dr. Fernando de Carvalho da Silva
Dr. Gabriela Nestal De Moraes
Guest Editors

Manuscript Submission Information

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Keywords

  • cancer
  • drug resistance
  • targeted therapy
  • conventional chemotherapy
  • natural products
  • molecular targets
  • cancer hallmarks
  • therapeutic agents

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Published Papers (26 papers)

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Editorial

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7 pages, 208 KiB  
Editorial
Drug Resistance and Novel Targets for Cancer Therapy: An Overview of Recent Findings
by Gabriel Ouverney, Déborah Hottz and Bruno Kaufmann Robbs
Biomedicines 2024, 12(4), 816; https://doi.org/10.3390/biomedicines12040816 - 8 Apr 2024
Viewed by 610
Abstract
The complex nature of cancer cells poses a challenge to the scientific community [...] Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)

Research

Jump to: Editorial, Review, Other

15 pages, 3997 KiB  
Article
Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer
by Siddhant Bhoir, Oluwatobi Ogundepo, Xiuping Yu, Runhua Shi and Arrigo De Benedetti
Biomedicines 2023, 11(11), 2987; https://doi.org/10.3390/biomedicines11112987 - 7 Nov 2023
Cited by 1 | Viewed by 1598
Abstract
Cellular organisms possess intricate DNA damage repair and tolerance pathways to manage various DNA lesions arising from endogenous or exogenous sources. The dysregulation of these pathways is associated with cancer development and progression. Synthetic lethality (SL), a promising cancer therapy concept, involves exploiting [...] Read more.
Cellular organisms possess intricate DNA damage repair and tolerance pathways to manage various DNA lesions arising from endogenous or exogenous sources. The dysregulation of these pathways is associated with cancer development and progression. Synthetic lethality (SL), a promising cancer therapy concept, involves exploiting the simultaneous functional loss of two genes for selective cell death. PARP inhibitors (PARPis) have demonstrated success in BRCA-deficient tumors. Cisplatin (CPT), a widely used chemotherapy agent, forms DNA adducts and crosslinks, rendering it effective against various cancers, but less so for prostate cancer (PCa) due to resistance and toxicity. Here, we explore the therapeutic potential of TLK1, a kinase upregulated in androgen-insensitive PCa cells, as a target for enhancing CPT-based therapy. TLK1 phosphorylates key homologous recombination repair (HRR) proteins, RAD54L and RAD54B, which are critical for HRR alongside RAD51. The combination of CPT with TLK1 inhibitor J54 exhibits SL in androgen-insensitive PCa cells. The formation of double-strand break intermediates during inter-strand crosslink processing necessitates HRR for effective repair. Therefore, targeting TLK1 with J54 enhances the SL of CPT by impeding HRR, leading to increased sensitivity in PCa cells. These findings suggest a promising approach for improving CPT-based therapies in PCa, particularly in androgen-insensitive cases. By elucidating the role of TLK1 in CPT resistance, this study provides valuable insights into potential therapeutic targets to overcome PCa resistance to CPT chemotherapy. Further investigations into TLK1 inhibition in combination with other DNA-damaging agents may pave the way for more effective and targeted treatments for PCa and other cancers that exhibit resistance to traditional chemotherapy agents. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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24 pages, 4936 KiB  
Article
Involvement of the AKT Pathway in Resistance to Erlotinib and Cabozantinib in Triple-Negative Breast Cancer Cell Lines
by Cory Lefebvre, Sierra Pellizzari, Vasudeva Bhat, Kristina Jurcic, David W. Litchfield and Alison L. Allan
Biomedicines 2023, 11(9), 2406; https://doi.org/10.3390/biomedicines11092406 - 28 Aug 2023
Viewed by 1162
Abstract
Resistance to protein tyrosine kinase inhibitors (TKIs) presents a significant challenge in therapeutic target development for cancers such as triple-negative breast cancer (TNBC), where conventional therapies are ineffective at combatting systemic disease. Due to increased expression, the receptor tyrosine kinases EGFR (epidermal growth [...] Read more.
Resistance to protein tyrosine kinase inhibitors (TKIs) presents a significant challenge in therapeutic target development for cancers such as triple-negative breast cancer (TNBC), where conventional therapies are ineffective at combatting systemic disease. Due to increased expression, the receptor tyrosine kinases EGFR (epidermal growth factor receptor) and c-Met are potential targets for treatment. However, targeted anti-EGFR and anti-c-Met therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that adaptive responses in regulatory kinase networks within the EGFR and c-Met signaling axes contribute to the development of acquired erlotinib and cabozantinib resistance. To test this, we developed two separate models for cabozantinib and erlotinib resistance using the MDA-MB-231 and MDA-MB-468 cell lines, respectively. We observed that erlotinib- or cabozantinib-resistant cell lines demonstrate enhanced cell proliferation, migration, invasion, and activation of EGFR or c-Met downstream signaling (respectively). Using a SILAC (Stable Isotope Labeling of Amino acids in Cell Culture)-labeled quantitative mass spectrometry proteomics approach, we assessed the effects of erlotinib or cabozantinib resistance on the phosphoproteome, proteome, and kinome. Using this integrated proteomics approach, we identified several potential kinase mediators of cabozantinib resistance and confirmed the contribution of AKT1 to erlotinib resistance in TNBC-resistant cell lines. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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17 pages, 3567 KiB  
Article
In Vitro Study of the Multimodal Effect of Na+/K+ ATPase Blocker Ouabain on the Tumor Microenvironment and Malignant Cells
by Octavia-Oana Harich, Oana-Isabella Gavriliuc, Valentin-Laurentiu Ordodi, Alexandru Tirziu, Virgil Paunescu, Carmen Panaitescu and Maria-Florina Bojin
Biomedicines 2023, 11(8), 2205; https://doi.org/10.3390/biomedicines11082205 - 5 Aug 2023
Viewed by 1370
Abstract
Na+/K+ ATPase is a protein involved in the active transport of ions across the cellular membrane. Ouabain is a cardiotonic glycoside that, by inhibiting the Na+/K+ pump, interferes with cell processes mediated directly by the pump, but [...] Read more.
Na+/K+ ATPase is a protein involved in the active transport of ions across the cellular membrane. Ouabain is a cardiotonic glycoside that, by inhibiting the Na+/K+ pump, interferes with cell processes mediated directly by the pump, but also indirectly influences other cellular processes such as cell cycle and proliferation, growth, cell differentiation, angiogenesis, migration, adhesion, and invasion. We used the SK-BR-3 breast cancer cell line, mesenchymal stem cells (MSCs), and tumor-associated fibroblasts (TAFs) in vitro to determine the effects of ouabain exposure on these cellular types. The results showed a multi-level effect of ouabain mainly on tumor cells, in a dose-dependent manner, while the TAFs and their normal counterparts were not significantly influenced. Following exposure to ouabain, the SK-BR-3 cells changed their morphologic appearance, decreased the expression of immunophenotypic markers (CD29, Her2, VEGF), the proliferation rate was significantly decreased (Ki67 index), the cells were blocked in the G0 phase of the cell cycle and suffered necrosis. These data were correlated with the variable expression of α and β Na+/K+ pump subunits in tumor cells, resulting in decreased ability to adhere to the VCAM-1 substrate in functional flow chamber studies. Being indicative of the pro-apoptotic and inhibitory effect of ouabain on tumor invasion and metastasis, the results support the addition of ouabain to the oncological therapeutic arsenal, trailing the “repurposing drugs” approach. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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12 pages, 3899 KiB  
Article
Combination Therapy with Trastuzumab and Niraparib: Quantifying Early Proliferative Alterations in HER2+ Breast Cancer Models
by Ameer Mansur, Patrick N. Song, Yun Lu, Andrew C. Burns, Luke Sligh, Eddy S. Yang and Anna G. Sorace
Biomedicines 2023, 11(8), 2090; https://doi.org/10.3390/biomedicines11082090 - 25 Jul 2023
Viewed by 1235
Abstract
HER2–targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2–targeted therapies, have demonstrated sensitivity to poly–(ADP–ribose) polymerase (PARP) inhibition, independent of DNA repair [...] Read more.
HER2–targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2–targeted therapies, have demonstrated sensitivity to poly–(ADP–ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition. Treatment response was evaluated in HER2+ and HER2– breast cancer cells. Further, we evaluated the utility of 3′–Deoxy–3′–[18F]–fluorothymidine positron emission tomography ([18F]FLT–PET) imaging for early response assessment in a HER2+ patient derived xenograft (PDX) model of breast cancer. In vitro, we observed decreased cell viability. In vivo, we observed decreased inhibition in tumor growth in combination therapies, compared to vehicle and monotherapy–treated cohorts. Early assessment of cellular proliferation corresponds to endpoint cell viability. Standard summary statistics of [18F]FLT uptake from PET were insensitive to early proliferative changes. Meanwhile, histogram analysis of [18F]FLT uptake indicated the potential translatability of imaging proliferation biomarkers. This study highlights the potential of combined trastuzumab and PARP inhibition in HER2+ breast cancer, while demonstrating a need for optimization of [18F]FLT–PET quantification in heterogeneous models of HER2+ breast cancer. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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13 pages, 2311 KiB  
Article
Novel Iron Chelator SK4 Drives Cytotoxicity through Inhibiting Mitochondrial Metabolism in Ovarian and Triple Negative Breast Cancer Cell Lines
by Gina Abdelaal, Andrew Carter, William Cheung, Mihalis Panayiotidis, Seth Racey, David Tétard and Stephany Veuger
Biomedicines 2023, 11(7), 2073; https://doi.org/10.3390/biomedicines11072073 - 24 Jul 2023
Viewed by 1525
Abstract
Anti-cancer therapy by iron chelation has been shown to inhibit many cellular processes including DNA replication, mitochondrial metabolism and oncogenic signalling pathways (e.g., EGFR). Iron chelator SK4 represents a double pronged approach towards treating cancer. SK4 enters through LAT1, a commonly overexpressed amino [...] Read more.
Anti-cancer therapy by iron chelation has been shown to inhibit many cellular processes including DNA replication, mitochondrial metabolism and oncogenic signalling pathways (e.g., EGFR). Iron chelator SK4 represents a double pronged approach towards treating cancer. SK4 enters through LAT1, a commonly overexpressed amino acid transporter in tumours, thus targeting iron addiction and LAT1 overexpression. The aim of this study was to characterise the mode of action of SK4 through proteomics, metabolomics, lipidomics and seahorse real-time analysis in ovarian cell line SKOV3 and triple negative breast cancer cell line MDA MB 231. Pathway enrichment of proteomics data showed an overrepresentation of metabolism related pathways. Metabolic change after SK4 exposure have been confirmed in investigations of changes in basal and maximal mitochondrial respiration using seahorse real-time analysis of mitochondrial metabolism. Metabolomics also showed an increase in AMP and glucose-1-phosphate. Interestingly, our lipidomics data show a decrease in phospholipid synthesis in the SKOV3 cells which is in contrast with previous data which showed an upregulation of ceramide driven apoptosis. In summary, our data highlight impairment of energy metabolism as a mechanism of action underlying SK4 apoptosis, but also suggest a potential role of ceramide induction in the phenotypic outcome of the cell model. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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18 pages, 5351 KiB  
Article
Integrative CRISPR Activation and Small Molecule Inhibitor Screening for lncRNA Mediating BRAF Inhibitor Resistance in Melanoma
by Sama Shamloo, Andreas Kloetgen, Stavroula Petroulia, Kathryn Hockemeyer, Sonja Sievers, Aristotelis Tsirigos, Ioannis Aifantis and Jochen Imig
Biomedicines 2023, 11(7), 2054; https://doi.org/10.3390/biomedicines11072054 - 21 Jul 2023
Cited by 1 | Viewed by 1367
Abstract
The incidence of melanoma, being one of the most commonly occurring cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. The conventional targeted therapy is well [...] Read more.
The incidence of melanoma, being one of the most commonly occurring cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. The conventional targeted therapy is well defined and effective for advanced-stage melanomas for patients not responding to the standard-of-care immunotherapy. However, targeted therapies do not prove to be as effective as patients inevitably develop V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-inhibitor resistance to the respective drugs. Factors which are driving melanoma drug resistance mainly involve mutations in the mitogen-activated protein kinase (MAPK) pathway, e.g., BRAF splice variants, neuroblastoma RAS viral oncogene homolog (NRAS) amplification or parallel survival pathways. However, those mechanisms do not explain all cases of occurring resistances. Therefore, other factors accounting for BRAFi resistance must be better understood. Among them there are long non-coding RNAs (lncRNAs), but these remain functionally poorly understood. Here, we conduct a comprehensive, unbiased, and integrative study of lncRNA expression, coupled with a Clustered Regularly Interspaced Short Palindromic Repeats/Cas9-mediated activation (CRISPRa) and small molecule inhibitor screening for BRAF inhibitor resistance to expand the knowledge of potentially druggable lncRNAs, their function, and pave the way for eventual combinatorial treatment approaches targeting diverse pathways in melanoma. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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16 pages, 4027 KiB  
Article
A2AR Expression and Immunosuppressive Environment Independent of KRAS and GNAS Mutations in Pseudomyxoma Peritonei
by Shigeki Kusamura, Adele Busico, Elena Conca, Iolanda Capone, Luca Agnelli, Daniele Lorenzini, Silvia Brich, Marta Angelini, Chiara Costanza Volpi, Desirè Viola Trupia, Vincenzo Lagano, Tommaso Torelli, Annunziata Gloghini, Dario Baratti, Marcello Guaglio, Massimo Milione, Marcello Deraco and Federica Perrone
Biomedicines 2023, 11(7), 2049; https://doi.org/10.3390/biomedicines11072049 - 20 Jul 2023
Cited by 1 | Viewed by 1446
Abstract
In pseudomyxoma peritonei (PMP), KRAS and GNAS mutations are frequent. We hypothesized that these mutations may contribute to the suppression of antitumor immunity: KRAS may induce GMCSF expression, while GNAS may enhance the expression of cyclic adenosine monophosphate and A2AR signaling. This study [...] Read more.
In pseudomyxoma peritonei (PMP), KRAS and GNAS mutations are frequent. We hypothesized that these mutations may contribute to the suppression of antitumor immunity: KRAS may induce GMCSF expression, while GNAS may enhance the expression of cyclic adenosine monophosphate and A2AR signaling. This study aimed to explore possible mechanisms facilitated by KRAS and GNAS mutations for escaping immune surveillance. Additionally, we looked for new potential therapeutic and prognostic targets in this rare disease which is poorly characterized at the molecular level. GM-CSF, A2AR, CD73, CD39, and PD-L1 expression was investigated by immunohistochemistry in 40 PMPs characterized for GNAS and KRAS mutational status. Immune cell populations were studied by immunohistochemistry and nanostring nCounter®. Following the criteria of a prognostic nomogram reported for PMP, we stratified the patients into two different risk groups, with 28 “low-risk” and 12 “high-risk” patients. We observed the expression of GM-CSF (74%); CD39 (37%); CD73 (53%); A2AR (74%); and PD-L1 (16%) which was unrelated to GNAS or KRAS status. The tumor microenvironment showed the presence of CD4+ T cells (86%); CD8+ T cells (27%); CD20+ B (67%); CD15+ cells (86%); and CD163+ M2 macrophages (67%), while CD56+ NK cells were absent. CD163 expression (27%) in PMP tumor cells was associated with poor prognosis. GNAS mutation and A2AR expression were not associated with a specific immune transcriptional signature. However, the expression assay revealed 21 genes associated with prognosis. The “high-risk” patients exhibited worse progression-free survival (HR = 2.3, CI 95%: 1.1–5.1, p = 0.034) and significant downregulation of MET, IL8, PPARG, DTX4, HMGA1, ZIC2, WNT5B, and CCRL2. In conclusion, we documented the presence of immunosuppressive factors such as GM-CSF, A2AR, and PD-L1 in PMP. These factors were not associated with GNAS and KRAS status and could be explored as therapeutic molecular targets. Additionally, a set of potential prognostic biomarkers, including CD163 expression in tumor cells, deserve further investigation. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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24 pages, 5198 KiB  
Article
Anticancer Activity and Molecular Targets of Piper cernuum Substances in Oral Squamous Cell Carcinoma Models
by Thaíssa Queiróz Machado, Maria Emanuelle Damazio Lima, Rafael Carriello da Silva, Arthur Ladeira Macedo, Lucas Nicolau de Queiroz, Bianca Roberta Peres Angrisani, Anna Carolina Carvalho da Fonseca, Priscilla Rodrigues Câmara, Vitor Von-Held Rabelo, Carlos Alexandre Carollo, Davyson de Lima Moreira, Elan Cardozo Paes de Almeida, Thatyana Rocha Alves Vasconcelos, Paula Alvarez Abreu, Alessandra Leda Valverde and Bruno Kaufmann Robbs
Biomedicines 2023, 11(7), 1914; https://doi.org/10.3390/biomedicines11071914 - 6 Jul 2023
Cited by 1 | Viewed by 1526
Abstract
Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, with high morbidity and mortality rates. The development of new drugs to treat OSCC is paramount. Piper plant species have shown many biological activities. In the present study, we show that dichloromethane [...] Read more.
Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, with high morbidity and mortality rates. The development of new drugs to treat OSCC is paramount. Piper plant species have shown many biological activities. In the present study, we show that dichloromethane partition of Piper cernuum (PCLd) is nontoxic in chronic treatment in mice, reduces the amount of atypia in tongues of chemically induced OSCC, and significantly increases animal survival. To identify the main active compounds, chromatographic purification of PCLd was performed, where fractions 09.07 and 14.05 were the most active and selective. These fractions promoted cell death by apoptosis characterized by phosphatidyl serine exposition, DNA fragmentation, and activation of effector caspase-3/7 and were nonhemolytic. LC–DAD–MS/MS analysis did not propose matching spectra for the 09.07 fraction, suggesting compounds not yet known. However, aporphine alkaloids were annotated in fraction 14.05, which are being described for the first time in P. cernuum and corroborate the observed cytotoxic activity. Putative molecular targets were determined for these alkaloids, in silico, where the androgen receptor (AR), CHK1, CK2, DYRK1A, EHMT2, LXRβ, and VEGFR2 were the most relevant. The results obtained from P. cernuum fractions point to promising compounds as new preclinical anticancer candidates. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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20 pages, 12927 KiB  
Article
Multiple Omics Analysis of the Role of RBM10 Gene Instability in Immune Regulation and Drug Sensitivity in Patients with Lung Adenocarcinoma (LUAD)
by Liusheng Wu, Qi Liu, Xin Ruan, Xinyu Luan, Yanfeng Zhong, Jixian Liu, Jun Yan and Xiaoqiang Li
Biomedicines 2023, 11(7), 1861; https://doi.org/10.3390/biomedicines11071861 - 29 Jun 2023
Cited by 3 | Viewed by 1470
Abstract
Objective: The RNA-binding protein RBM10 can regulate apoptosis during the proliferation and migration of pancreatic cancer, endometrial cancer, and osteosarcoma cells; however, the molecular mechanism underlying lung adenocarcinoma is rarely reported. Recent studies have detected multiple truncated and missense mutations in RBM10 in [...] Read more.
Objective: The RNA-binding protein RBM10 can regulate apoptosis during the proliferation and migration of pancreatic cancer, endometrial cancer, and osteosarcoma cells; however, the molecular mechanism underlying lung adenocarcinoma is rarely reported. Recent studies have detected multiple truncated and missense mutations in RBM10 in lung adenocarcinoma, but the role of RBM10 in lung adenocarcinoma is unclear. This study mainly explored the immune regulation mechanism of RBM10 in the development of lung adenocarcinoma and its influence on sensitivity to targeted therapy drugs. Methods: The transcriptome data of CGAP were used to analyze the RNA-seq data of lung adenocarcinoma patients from different subgroups by using the CIBERSORT algorithm to infer the relative proportion of various immune infiltrating cells, and Spearman correlation analysis was performed to determine the gene expression and immune cell content. In addition, this study utilized drug trial data from the GDSC database. The IC50 estimates for each specific targeted therapy were obtained by using a regression method, and the regression and prediction accuracy were tested via ten cross-validations with the GDSC training set. An immunohistochemical test was performed on the samples of 20 patients with lung adenocarcinoma in the subcomponent analysis of immune cells, and the protein expression of RBM10 in lung adenocarcinoma tissues was verified by cellular immunofluorescence assays. Nucleic acids were extracted at low temperatures, and qRT-PCR was used to verify the expression levels of the mRNA of RBM10 in lung adenocarcinoma tissues and normal tissues (p < 0.05). Results: After screening and inclusion using a machine language, the results showed that RBM10 was significantly highly expressed in the lung adenocarcinoma tissues. The related signaling pathways were mainly concentrated in ncRNA processing, rRNA metabolic processes, ribosome biogenesis, and the regulation of translation. The qRT-PCR for 20 lung adenocarcinoma tissues showed that the expression of RBM10 in these tissues was significantly different from that in normal tissues (p = 0.0255). Immunohistochemistry analysis and cell immunofluorescence staining also confirmed that RBM10 was involved in the immune regulation of lung adenocarcinoma tissues, and the number of immune cell aggregations was significantly higher than that of the control group. RBM10 regulates B cell memory-CIBERSORT (p = 0.042) and B cell memory-CIBERSOTRT-abs (p = 0.027), cancer-associated fibroblast-EPIC (p = 0.001), cancer-associated fibroblast- MCPCounter (p = 0.0037), etc. The risk score was significantly associated with the sensitivity of patients to lapatinib (p = 0.049), nilotinib (p = 0.015), pazopanib (p = 0.001), and sorafenib (p = 0.048). Conclusions: RBM10 can inhibit the proliferation and invasion of lung adenocarcinoma cells through negative regulation and promote the apoptosis of lung adenocarcinoma cells through immunomodulatory mechanisms. The expression level of RBM10 affects the efficacy of targeted drug therapy and the survival prognosis of lung adenocarcinoma patients, which has a certain guiding significance for the clinical treatment of these patients. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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23 pages, 46660 KiB  
Article
Arsenic Inhibits Proliferation and Induces Autophagy of Tumor Cells in Pleural Effusion of Patients with Non-Small Cell Lung Cancer Expressing EGFR with or without Mutations via PI3K/AKT/mTOR Pathway
by Jianhua Mao, Xiaoqian Shi, Li Hua, Menghang Yang, Yan Shen, Zheng Ruan, Bing Li and Xiaodong Xi
Biomedicines 2023, 11(6), 1721; https://doi.org/10.3390/biomedicines11061721 - 15 Jun 2023
Cited by 5 | Viewed by 1231
Abstract
To clarify whether arsenic could exert inhibitory effects on tumor cells in pleural effusions of patients with non-small cell lung cancer (NSCLC), 36 NSCLC pleural effusion samples were collected from Changzheng Hospital and Ruijin Hospital, from 2019 to 2022. The genotype of epidermal [...] Read more.
To clarify whether arsenic could exert inhibitory effects on tumor cells in pleural effusions of patients with non-small cell lung cancer (NSCLC), 36 NSCLC pleural effusion samples were collected from Changzheng Hospital and Ruijin Hospital, from 2019 to 2022. The genotype of epidermal growth factor receptor (EGFR) was identified. Tumor cells were isolated and treated with arsenic trioxide (ATO) or/and gefitinib. Additionally, six patients were intrapleurally administrated with ATO. Results showed that 25 samples bore EGFR wild type (WT) and 11 harbored EGFR mutations, including 6 with L858R, 3 with ΔE746-A750, and 2 with T790M. ATO diminished the number of tumor cells from patients with WT and mutant EGFR, down-regulated the expression or phosphorylation of EGFR, pmTOR, PI3K, PTEN, and p4E-BP1, and up-regulated the expression of LC3. Immunofluorescent experiments showed that ATO enhanced LC3 and P62. By contrast, gefitinib was only effective in those harboring EGFR sensitizing mutations. Notably, in patients with intrapleural ATO injection, the pleural effusion underwent a bloody to pale yellow color change, the volume of the pleural effusion was reduced, and the number of the tumor cells was significantly reduced. In conclusion, arsenic is effective against NSCLC with various EGFR genotypes in vitro and in vivo, and potentially circumvents gefitinib resistance. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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20 pages, 2264 KiB  
Article
A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma
by Guilherme Freimann Wermelinger, Lucas Rubini, Anna Carolina Carvalho da Fonseca, Gabriel Ouverney, Rafael P. R. F. de Oliveira, Acácio S. de Souza, Luana S. M. Forezi, Gabriel Limaverde-Sousa, Sergio Pinheiro and Bruno Kaufmann Robbs
Biomedicines 2023, 11(6), 1711; https://doi.org/10.3390/biomedicines11061711 - 14 Jun 2023
Cited by 1 | Viewed by 1337
Abstract
Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an [...] Read more.
Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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19 pages, 3638 KiB  
Article
Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification
by Aideen C. Roddy, Caitríona E. McInerney, Tom Flannery, Estelle G. Healy, James P. Stewart, Veronica J. Spence, Jamie Walsh, Manuel Salto-Tellez, Darragh G. McArt and Kevin M. Prise
Biomedicines 2023, 11(4), 1219; https://doi.org/10.3390/biomedicines11041219 - 19 Apr 2023
Viewed by 2980
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are [...] Read more.
Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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14 pages, 2137 KiB  
Article
Targeting RNA Polymerase I Transcription Activity in Osteosarcoma: Pre-Clinical Molecular and Animal Treatment Studies
by Chang-Won Kang, Anneke C. Blackburn, Amos Hong Pheng Loh, Kuick Chick Hong, Jian Yuan Goh, Nadine Hein, Denis Drygin, Chris R. Parish, Ross D. Hannan, Katherine M. Hannan and Lucy A. Coupland
Biomedicines 2023, 11(4), 1133; https://doi.org/10.3390/biomedicines11041133 - 9 Apr 2023
Cited by 1 | Viewed by 1710
Abstract
The survival rate of patients with osteosarcoma (OS) has not improved over the last 30 years. Mutations in the genes TP53, RB1 and c-Myc frequently occur in OS and enhance RNA Polymerase I (Pol I) activity, thus supporting uncontrolled cancer cell proliferation. [...] Read more.
The survival rate of patients with osteosarcoma (OS) has not improved over the last 30 years. Mutations in the genes TP53, RB1 and c-Myc frequently occur in OS and enhance RNA Polymerase I (Pol I) activity, thus supporting uncontrolled cancer cell proliferation. We therefore hypothesised that Pol I inhibition may be an effective therapeutic strategy for this aggressive cancer. The Pol I inhibitor CX-5461 has demonstrated therapeutic efficacy in different cancers in pre-clinical and phase I clinical trials; thus, the effects were determined on ten human OS cell lines. Following characterisation using genome profiling and Western blotting, RNA Pol I activity, cell proliferation and cell cycle progression were evaluated in vitro, and the growth of TP53 wild-type and mutant tumours was measured in a murine allograft model and in two human xenograft OS models. CX-5461 treatment resulted in reduced ribosomal DNA (rDNA) transcription and Growth 2 (G2)-phase cell cycle arrest in all OS cell lines. Additionally, tumour growth in all allograft and xenograft OS models was effectively suppressed without apparent toxicity. Our study demonstrates the efficacy of Pol I inhibition against OS with varying genetic alterations. This study provides pre-clinical evidence to support this novel therapeutic approach in OS. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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17 pages, 5971 KiB  
Article
Exploring the Role of Hypoxia-Inducible Carbonic Anhydrase IX (CAIX) in Circulating Tumor Cells (CTCs) of Breast Cancer
by Julianne D. Twomey and Baolin Zhang
Biomedicines 2023, 11(3), 934; https://doi.org/10.3390/biomedicines11030934 - 17 Mar 2023
Cited by 1 | Viewed by 2129
Abstract
Circulating tumor cells (CTCs) in the peripheral blood are believed to be the source of metastasis and can be used as a liquid biopsy to monitor cancer progression and therapeutic response. However, it has been challenging to accurately detect CTCs because of their [...] Read more.
Circulating tumor cells (CTCs) in the peripheral blood are believed to be the source of metastasis and can be used as a liquid biopsy to monitor cancer progression and therapeutic response. However, it has been challenging to accurately detect CTCs because of their low frequency and the heterogeneity of the population. In this study, we have developed an in vitro model of CTCs by using non-adherent suspension culture. We used this model to study a group of breast cancer cell lines with distinct molecular subtypes (TNBC, HER2+, and ER+/PR+). We found that, when these breast cancer cell lines lost their attachment to the extracellular matrix, they accumulated a subtype of cancer stem cells (CSC) that expressed the surface markers of stem cells (e.g., CD44+CD24). These stem-like CTCs also showed high expressions of hypoxia-inducible gene products, particularly the hypoxia-inducible carbonic anhydrase IX (CAIX). Inhibition of CAIX activity was found to reduce CAIX expression and stem cell phenotypes in the targeted CTCs. Further studies are needed, using CTC samples from breast cancer patients, to determine the role of CAIX in CTC survival, CSC transition, and metastasis. CAIX may be a useful surface marker for the detection of CSCs in the blood, and a potential target for treating metastatic breast cancers. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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17 pages, 5900 KiB  
Article
Mesenchymal Stem Cells Genetically Modified by Lentivirus-Express Soluble TRAIL and Interleukin-12 Inhibit Growth and Reduced Metastasis-Relate Changes in Lymphoma Mice Model
by Adriana G. Quiroz-Reyes, Carlos A. Gonzalez-Villarreal, Alberto Y. Limon-Flores, Paulina Delgado-Gonzalez, Herminia G. Martinez-Rodriguez, Salvador L. Said-Fernandez, Adolfo Soto-Dominguez, Ana M. Rivas-Estilla, Jose F. Islas, Juan F. Molina-De la Garza and Elsa N. Garza-Treviño
Biomedicines 2023, 11(2), 595; https://doi.org/10.3390/biomedicines11020595 - 17 Feb 2023
Cited by 2 | Viewed by 2594
Abstract
Background: Cancer treatment has many side effects; therefore, more efficient treatments are needed. Mesenchymal stem cells (MSC) have immunoregulatory properties, tumor site migration and can be genetically modified. Some proteins, such as soluble TRAIL (sTRAIL) and interleukin-12 (IL-12), have shown antitumoral potential, thus [...] Read more.
Background: Cancer treatment has many side effects; therefore, more efficient treatments are needed. Mesenchymal stem cells (MSC) have immunoregulatory properties, tumor site migration and can be genetically modified. Some proteins, such as soluble TRAIL (sTRAIL) and interleukin-12 (IL-12), have shown antitumoral potential, thus its combination in solid tumors could increase their activity. Materials and Methods: Lentiviral transduction of bone marrow MSC with green fluorescent protein (GFP) and transgenes (sTRAIL and IL-12) was confirmed by fluorescence microscopy and Western blot. Soluble TRAIL levels were quantified by ELISA. Lymphoma L5178Y cells express a reporter gene (GFP/mCherry), and TRAIL receptor (DR5). Results: An in vivo model showed that combined treatment with MSC expressing sTRAIL+IL-12 or IL-12 alone significantly reduced tumor volume and increased survival in BALB/c mice (p < 0.05) with only one application. However, at the histological level, only MSC expressing IL-12 reduced tumor cell infiltration significantly in the right gastrocnemius compared with the control group (p < 0.05). It presented less tissue dysplasia confirmed by fluorescence and hematoxylin–eosin dye; nevertheless, treatment not inhibited hepatic metastasis. Conclusions: MSC expressing IL-12, is or combination with BM-MSC expressing sTRAIL represents an antitumor strategy for lymphoma tumors since they increase survival and reduce tumor development. However, the combination did not show significative additive effect. The localized application did not inhibit metastasis but reduced morphological alterations of tissue associated with liver metastasis. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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Review

Jump to: Editorial, Research, Other

19 pages, 718 KiB  
Review
ATP-Binding Cassette Subfamily G Member 2 in Acute Myeloid Leukemia: A New Molecular Target?
by Daniela Damiani and Mario Tiribelli
Biomedicines 2024, 12(1), 111; https://doi.org/10.3390/biomedicines12010111 - 5 Jan 2024
Viewed by 1167
Abstract
Despite the progress in the knowledge of disease pathogenesis and the identification of many molecular markers as potential targets of new therapies, the cure of acute myeloid leukemia remains challenging. Disease recurrence after an initial response and the development of resistance to old [...] Read more.
Despite the progress in the knowledge of disease pathogenesis and the identification of many molecular markers as potential targets of new therapies, the cure of acute myeloid leukemia remains challenging. Disease recurrence after an initial response and the development of resistance to old and new therapies account for the poor survival rate and still make allogeneic stem cell transplantation the only curative option. Multidrug resistance (MDR) is a multifactorial phenomenon resulting from host-related characteristics and leukemia factors. Among these, the overexpression of membrane drug transporter proteins belonging to the ABC (ATP-Binding Cassette)-protein superfamily, which diverts drugs from their cellular targets, plays an important role. Moreover, a better understanding of leukemia biology has highlighted that, at least in cancer, ABC protein’s role goes beyond simple drug transport and affects many other cell functions. In this paper, we summarized the current knowledge of ABCG2 (formerly Breast Cancer Resistance Protein, BCRP) in acute myeloid leukemia and discuss the potential ways to overcome its efflux function and to revert its ability to confer stemness to leukemia cells, favoring the persistence of leukemia progenitors in the bone marrow niche and justifying relapse also after therapy intensification with allogeneic stem cell transplantation. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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27 pages, 4477 KiB  
Review
Novel Para-Aminobenzoic Acid Analogs and Their Potential Therapeutic Applications
by Faisal Haroon, Umme Farwa, Maimoona Arif, Muhammad Asam Raza, Zeshan Ali Sandhu, Mohamed El Oirdi, Mohd Farhan and Mohammed Ahmed Ismail Alhasawi
Biomedicines 2023, 11(10), 2686; https://doi.org/10.3390/biomedicines11102686 - 30 Sep 2023
Viewed by 2260
Abstract
A “building block” is a key component that plays a substantial and critical function in the pharmaceutical research and development industry. Given its structural versatility and ability to undergo substitutions at both the amino and carboxyl groups, para-aminobenzoic acid (PABA) is a commonly [...] Read more.
A “building block” is a key component that plays a substantial and critical function in the pharmaceutical research and development industry. Given its structural versatility and ability to undergo substitutions at both the amino and carboxyl groups, para-aminobenzoic acid (PABA) is a commonly used building block in pharmaceuticals. Therefore, it is great for the development of a wide range of novel molecules with potential medical applications. Anticancer, anti-Alzheimer’s, antibacterial, antiviral, antioxidant, and anti-inflammatory properties have been observed in PABA compounds, suggesting their potential as therapeutic agents in future clinical trials. PABA-based therapeutic chemicals as molecular targets and their usage in biological processes are the primary focus of this review study. PABA’s unique features make it a strong candidate for inclusion in a massive chemical database of molecules having drug-like effects. Based on the current literature, further investigation is needed to evaluate the safety and efficacy of PABA derivatives in clinical investigations and better understand the specific mechanism of action revealed by these compounds. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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19 pages, 1936 KiB  
Review
RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy
by Hae Ryung Chang
Biomedicines 2023, 11(9), 2527; https://doi.org/10.3390/biomedicines11092527 - 13 Sep 2023
Viewed by 1377
Abstract
Ubiquitination is a post-translational modification (PTM) that is involved in proteolysis, protein–protein interaction, and signal transduction. Accumulation of mutations and genomic instability are characteristic of cancer cells, and dysfunction of the ubiquitin pathway can contribute to abnormal cell physiology. Because mutations can be [...] Read more.
Ubiquitination is a post-translational modification (PTM) that is involved in proteolysis, protein–protein interaction, and signal transduction. Accumulation of mutations and genomic instability are characteristic of cancer cells, and dysfunction of the ubiquitin pathway can contribute to abnormal cell physiology. Because mutations can be critical for cells, DNA damage repair, cell cycle regulation, and apoptosis are pathways that are in close communication to maintain genomic integrity. Uncontrolled cell proliferation due to abnormal processes is a hallmark of cancer, and mutations, changes in expression levels, and other alterations of ubiquitination factors are often involved. Here, three E3 ubiquitin ligases will be reviewed in detail. RNF126, RNF168 and CUL1 are involved in DNA damage response (DDR), DNA double-strand break (DSB) repair, cell cycle regulation, and ultimately, cancer cell proliferation control. Their involvement in multiple cellular pathways makes them an attractive candidate for cancer-targeting therapy. Functional studies of these E3 ligases have increased over the years, and their significance in cancer is well reported. There are continuous efforts to develop drugs targeting the ubiquitin pathway for anticancer therapy, which opens up the possibility for these E3 ligases to be evaluated for their potential as a target protein for anticancer therapy. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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19 pages, 1829 KiB  
Review
Current Understanding of Polyphenols to Enhance Bioavailability for Better Therapies
by Mohammad Aatif
Biomedicines 2023, 11(7), 2078; https://doi.org/10.3390/biomedicines11072078 - 24 Jul 2023
Cited by 11 | Viewed by 2116
Abstract
In recent years, plant polyphenols have become a popular focus for the development of novel functional foods. Polyphenols, a class of bioactive compounds, including flavonoids, phenolic acids, and lignans, are commonly found in plant-based diets with a variety of biological actions, including antioxidant, [...] Read more.
In recent years, plant polyphenols have become a popular focus for the development of novel functional foods. Polyphenols, a class of bioactive compounds, including flavonoids, phenolic acids, and lignans, are commonly found in plant-based diets with a variety of biological actions, including antioxidant, anti-inflammatory, and anticancer effects. Unfortunately, polyphenols are not widely used in nutraceuticals since many of the chemicals in polyphenols possess poor oral bioavailability. Thankfully, polyphenols can be encapsulated and transported using bio-based nanocarriers, thereby increasing their bioavailability. Polyphenols’ limited water solubility and low bioavailability are limiting factors for their practical usage, but this issue can be resolved if suitable delivery vehicles are developed for encapsulating and delivering polyphenolic compounds. This paper provides an overview of the study of nanocarriers for the enhancement of polyphenol oral bioavailability, as well as a summary of the health advantages of polyphenols in the prevention and treatment of several diseases. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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31 pages, 1249 KiB  
Review
Insights on the Role of Polyphenols in Combating Cancer Drug Resistance
by Mohd Farhan
Biomedicines 2023, 11(6), 1709; https://doi.org/10.3390/biomedicines11061709 - 14 Jun 2023
Cited by 5 | Viewed by 2467
Abstract
Chemotherapy resistance is still a serious problem in the treatment of most cancers. Many cellular and molecular mechanisms contribute to both inherent and acquired drug resistance. They include the use of unaffected growth-signaling pathways, changes in the tumor microenvironment, and the active transport [...] Read more.
Chemotherapy resistance is still a serious problem in the treatment of most cancers. Many cellular and molecular mechanisms contribute to both inherent and acquired drug resistance. They include the use of unaffected growth-signaling pathways, changes in the tumor microenvironment, and the active transport of medicines out of the cell. The antioxidant capacity of polyphenols and their potential to inhibit the activation of procarcinogens, cancer cell proliferation, metastasis, and angiogenesis, as well as to promote the inhibition or downregulation of active drug efflux transporters, have been linked to a reduced risk of cancer in epidemiological studies. Polyphenols also have the ability to alter immunological responses and inflammatory cascades, as well as trigger apoptosis in cancer cells. The discovery of the relationship between abnormal growth signaling and metabolic dysfunction in cancer cells highlights the importance of further investigating the effects of dietary polyphenols, including their ability to boost the efficacy of chemotherapy and avoid multidrug resistance (MDR). Here, it is summarized what is known regarding the effectiveness of natural polyphenolic compounds in counteracting the resistance that might develop to cancer drugs as a result of a variety of different mechanisms. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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25 pages, 1831 KiB  
Review
Mechanisms of Action and Limitations of Monoclonal Antibodies and Single Chain Fragment Variable (scFv) in the Treatment of Cancer
by Cynthia Rodríguez-Nava, Carlos Ortuño-Pineda, Berenice Illades-Aguiar, Eugenia Flores-Alfaro, Marco Antonio Leyva-Vázquez, Isela Parra-Rojas, Oscar del Moral-Hernández, Amalia Vences-Velázquez, Karen Cortés-Sarabia and Luz del Carmen Alarcón-Romero
Biomedicines 2023, 11(6), 1610; https://doi.org/10.3390/biomedicines11061610 - 1 Jun 2023
Cited by 6 | Viewed by 6167
Abstract
Monoclonal antibodies are among the most effective tools for detecting tumor-associated antigens. The U.S. Food and Drug Administration (FDA) has approved more than 36 therapeutic antibodies for developing novel alternative therapies that have significant success rates in fighting cancer. However, some functional limitations [...] Read more.
Monoclonal antibodies are among the most effective tools for detecting tumor-associated antigens. The U.S. Food and Drug Administration (FDA) has approved more than 36 therapeutic antibodies for developing novel alternative therapies that have significant success rates in fighting cancer. However, some functional limitations have been described, such as their access to solid tumors and low interaction with the immune system. Single-chain variable fragments (scFv) are versatile and easy to produce, and being an attractive tool for use in immunotherapy models. The small size of scFv can be advantageous for treatment due to its short half-life and other characteristics related to the structural and functional aspects of the antibodies. Therefore, the main objective of this review was to describe the current situation regarding the mechanisms of action, applications, and limitations of monoclonal antibodies and scFv in the treatment of cancer. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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16 pages, 8887 KiB  
Review
Biological Role and Aberrant Overexpression of Syntenin-1 in Cancer: Potential Role as a Biomarker and Therapeutic Target
by Valeria Guadalupe Pintor-Romero, Edgar Hurtado-Ortega, María Lilia Nicolás-Morales, Mayralina Gutiérrez-Torres, Amalia Vences-Velázquez, Carlos Ortuño-Pineda, Mónica Espinoza-Rojo, Napoleón Navarro-Tito and Karen Cortés-Sarabia
Biomedicines 2023, 11(4), 1034; https://doi.org/10.3390/biomedicines11041034 - 27 Mar 2023
Cited by 1 | Viewed by 2427
Abstract
Syntenin-1 is a 298 amino acid protein codified by the melanoma differentiation-associated gene-9 (MDA-9). Structurally, it is composed of four domains: N-terminal, PDZ1, PDZ2, and C-terminal. The PDZ domains of syntenin-1 are involved in the stability and interaction with other molecules [...] Read more.
Syntenin-1 is a 298 amino acid protein codified by the melanoma differentiation-associated gene-9 (MDA-9). Structurally, it is composed of four domains: N-terminal, PDZ1, PDZ2, and C-terminal. The PDZ domains of syntenin-1 are involved in the stability and interaction with other molecules such as proteins, glycoproteins, and lipids. Domains are also associated with several biological functions such as the activation of signaling pathways related to cell-to-cell adhesion, signaling translation, and the traffic of intracellular lipids, among others. The overexpression of syntenin-1 has been reported in glioblastoma, colorectal, melanoma, lung, prostate, and breast cancer, which promotes tumorigenesis by regulating cell migration, invasion, proliferation, angiogenesis, apoptosis, and immune response evasion, and metastasis. The overexpression of syntenin-1 in samples has been associated with worst prognostic and recurrence, whereas the use of inhibitors such as shRNA, siRNA, and PDZli showed a diminution of the tumor size and reduction in metastasis and invasion. Syntenin-1 has been suggested as a potential biomarker and therapeutic target in cancer for developing more effective diagnostic/prognostic tests or passive/active immunotherapies. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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11 pages, 271 KiB  
Review
Amivantamab-Vmjw: A Novel Treatment for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutation after Progression on Platinum-Based Chemotherapy
by Vishal Shah, Andrea McNatty, Lacey Simpson, Henry Ofori and Farah Raheem
Biomedicines 2023, 11(3), 950; https://doi.org/10.3390/biomedicines11030950 - 20 Mar 2023
Cited by 2 | Viewed by 2867
Abstract
Objective: This study is a comprehensive review of the clinical pharmacology, pharmacokinetics, efficacy, safety, and clinical applicability of amivantamab-vmjw for metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutation. Data Synthesis: The literature search to [...] Read more.
Objective: This study is a comprehensive review of the clinical pharmacology, pharmacokinetics, efficacy, safety, and clinical applicability of amivantamab-vmjw for metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutation. Data Synthesis: The literature search to identify clinical trials returned only the CHRYSALIS phase 1 study. In a phase I trial, amivantamab-vmjw was associated with an overall response rate (ORR) of 40% (95% CI, 29–51) in the EGFR exon20ins NSCLC patient population (n = 81) after platinum-based chemotherapy. There were 3 complete responses (CRs) and 29 partial responses (PRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9—not reached; NR). The median progression-free survival (PFS) was 8.3 months (95% CI, 6.5–10.9), and overall survival (OS) was 22.8 months (95% CI, 14.6—NR). Application to Clinical Practice: This review summarizes the pharmacology, clinical evidence, and use of amivantamab-vmjw for patients with locally advanced or metastatic NSCLC with EGFR exon20ins mutation. Conclusion: The FDA approval of amivantamab-vmjw, the first bispecific antibody to target the exon20ins mutation, represents an important advancement in the treatment of patients with NSCLC with limited effective treatment options. The initial findings of the CHRYSALIS trial demonstrate an overall tumor response benefit with an acceptable safety profile. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)

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11 pages, 2515 KiB  
Technical Note
A Simple and Affordable Method to Create Nonsense Mutation Clones of p53 for Studying the Premature Termination Codon Readthrough Activity of PTC124
by Chia-Chi Chen, Ruo-Yu Liao, Fang-Yu Yeh, Yu-Rou Lin, Tze-You Wu, Alexa Escobar Pastor, Danny Danilo Zul, Yun-Chien Hsu, Kuan-Yo Wu, Ke-Fang Liu, Reiji Kannagi, Jang-Yi Chen and Bi-He Cai
Biomedicines 2023, 11(5), 1310; https://doi.org/10.3390/biomedicines11051310 - 28 Apr 2023
Viewed by 1449
Abstract
(1) Background: A premature termination codon (PTC) can be induced by a type of point mutation known as a nonsense mutation, which occurs within the coding region. Approximately 3.8% of human cancer patients have nonsense mutations of p53. However, the non-aminoglycoside drug PTC124 [...] Read more.
(1) Background: A premature termination codon (PTC) can be induced by a type of point mutation known as a nonsense mutation, which occurs within the coding region. Approximately 3.8% of human cancer patients have nonsense mutations of p53. However, the non-aminoglycoside drug PTC124 has shown potential to promote PTC readthrough and rescue full-length proteins. The COSMIC database contains 201 types of p53 nonsense mutations in cancers. We built a simple and affordable method to create different nonsense mutation clones of p53 for the study of the PTC readthrough activity of PTC124. (2) Methods: A modified inverse PCR-based site-directed mutagenesis method was used to clone the four nonsense mutations of p53, including W91X, S94X, R306X, and R342X. Each clone was transfected into p53 null H1299 cells and then treated with 50 μM of PTC124. (3) Results: PTC124 induced p53 re-expression in H1299-R306X and H1299-R342X clones but not in H1299-W91X and H1299-S94X clones. (4) Conclusions: Our data showed that PTC124 more effectively rescued the C-terminal of p53 nonsense mutations than the N-terminal of p53 nonsense mutations. We introduced a fast and low-cost site-directed mutagenesis method to clone the different nonsense mutations of p53 for drug screening. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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6 pages, 213 KiB  
Commentary
Low-Dose Immunotherapy: Is It Just an Illusion?
by Fausto Meriggi, Alberto Zaniboni and Anna Zaltieri
Biomedicines 2023, 11(4), 1032; https://doi.org/10.3390/biomedicines11041032 - 27 Mar 2023
Cited by 2 | Viewed by 2134
Abstract
The development and use of immunotherapy in the last decade have led to a drastic improvement in results in the onco-haematological field. This has implied, on the one hand, the need for clinicians to manage a new type of adverse event and, on [...] Read more.
The development and use of immunotherapy in the last decade have led to a drastic improvement in results in the onco-haematological field. This has implied, on the one hand, the need for clinicians to manage a new type of adverse event and, on the other hand, a significant increase in costs. However, emerging scientific evidence suggests that, as with other drugs in the recent past, the registry dosage can be drastically reduced for immunotherapies without penalizing their effectiveness. This would also lead to an important reduction in costs, expanding the audience of cancer patients who could access immunotherapy-based treatments. In this “Commentary”, we analyze the available evidence of pharmacokinetics and pharmacodynamics and the most recent literature in favor of low-dose immunotherapy. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy)
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