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Novel Biological Molecules for Cancer Treatments
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Novel Biological Molecules for Cancer Treatments

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

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 53179

Special Issue Editor

Prof. Dr. Lina Sabatino

E-Mail Website
Guest Editor
Department of Sciences and Technologies, University of Sannio, Via Francesco de Sanctis, 82100 Benevento, Italy
Interests: gene expression; miRNAs and cancer; metabolism and cancer; natural products and impact on cell functions; polyphenols’ activities; PPARs and nuclear receptors; immunogenic cell death; cell stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

One of the cutting-edge topics in cancer biology is the search for new biological molecules for cancer treatments. Biological therapy has represented a breakthrough in the therapy of many types of cancer, as it not only prevents or slows tumor growth and prevents its spread but also causes fewer toxic side effects. The spectrum of this innovative approach is widening every day due to new molecules or antibodies directed against selected molecules expressed mainly or exclusively by cancer cells or to means to stimulate an active response of the immune system against cancer cells. This Special Issue is aimed at providing a survey of molecules employed in cancer treatment acting on different molecular oncogenic pathways or in stimulating an active immune response to improve our therapeutic armamentarium against cancer and support a better prognosis.

Prof. Dr. Lina Sabatino
Guest Editor

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Keywords

  • cancer treatment
  • cancer biology
  • biological molecule
  • cancer cell
  • new molecules or antibodies

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Published Papers (20 papers)

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17 pages, 5197 KiB  
Article
Resveratrol Derivative Exhibits Marked Antiproliferative Actions, Affecting Stemness in Pancreatic Cancer Cells
by Rosalba Florio, Barbara De Filippis, Serena Veschi, Viviana di Giacomo, Paola Lanuti, Giulia Catitti, Davide Brocco, Annalisa di Rienzo, Amelia Cataldi, Ivana Cacciatore, Rosa Amoroso, Alessandro Cama and Laura De Lellis
Int. J. Mol. Sci. 2023, 24(3), 1977; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031977 - 19 Jan 2023
Cited by 4 | Viewed by 1382
Abstract
Pancreatic cancer (PC) is one of the deadliest malignancies, with an increasing incidence and limited response to current therapeutic options. Therefore, more effective and low-toxic agents are needed to improve PC patients’ outcomes. Resveratrol (RSV) is a natural polyphenol with multiple biological properties, [...] Read more.
Pancreatic cancer (PC) is one of the deadliest malignancies, with an increasing incidence and limited response to current therapeutic options. Therefore, more effective and low-toxic agents are needed to improve PC patients’ outcomes. Resveratrol (RSV) is a natural polyphenol with multiple biological properties, including anticancer effects. In this study, we explored the antiproliferative activities of newly synthetized RSV analogues in a panel of PC cell lines and evaluated the physicochemical properties of the most active compound. This derivative exhibited marked antiproliferative effects in PC cells through mechanisms involving DNA damage, apoptosis induction, and interference in cell cycle progression, as assessed using flow cytometry and immunoblot analysis of cell cycle proteins, PARP cleavage, and H2AX phosphorylation. Notably, the compound induced a consistent reduction in the PC cell subpopulation with a CD133+EpCAM+ stem-like phenotype, paralleled by dramatic effects on cell clonogenicity. Moreover, the RSV derivative had negligible toxicity against normal HFF-1 cells and, thus, good selectivity index values toward PC cell lines. Remarkably, its higher lipophilicity and stability in human plasma, as compared to RSV, might ensure a better permeation along the gastrointestinal tract. Our results provide insights into the mechanisms of action contributing to the antiproliferative activity of a synthetic RSV analogue, supporting its potential value in the search for effective and safe agents in PC treatment. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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17 pages, 5201 KiB  
Article
The Silkworm Carboxypeptidase Inhibitor Prevents Gastric Cancer Cells’ Proliferation through the EGF/EGFR Signaling Pathway
by Junhong Ye, Jifu Li and Ping Zhao
Int. J. Mol. Sci. 2023, 24(2), 1078; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021078 - 05 Jan 2023
Cited by 3 | Viewed by 1717
Abstract
Gastric cancer is a common malignant tumor originating from the gastric mucosa epithelium. Studies have shown that bioactive substances such as antimicrobial peptides and cantharidin contained in a variety of insects can exert anti-cancer functions; when compared with chemotherapy drugs, these bioactive substances [...] Read more.
Gastric cancer is a common malignant tumor originating from the gastric mucosa epithelium. Studies have shown that bioactive substances such as antimicrobial peptides and cantharidin contained in a variety of insects can exert anti-cancer functions; when compared with chemotherapy drugs, these bioactive substances have less toxicity and reduced side effects. Here, we report the first Bombyx mori carboxypeptidase inhibitor that is specifically and highly expressed in silk glands, which can significantly prevent the proliferation of gastric cancer cells by inhibiting the MAPK/ERK pathway initiated by EGF/EGFR through the promotion of expression of the proto-oncogene c-Myc, thereby affecting the expression of related cyclins. Through molecular docking and virtual screening of silkworm carboxypeptidase inhibitors and epidermal growth factor receptors, we identified a polypeptide that overlapped with existing small-molecule inhibitors of the receptor. In the present work, we explore the medicinal potential and application of silkworm carboxypeptidase inhibitors to promote the development of anti-tumor drugs from insect-derived substances. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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20 pages, 3517 KiB  
Article
Newly Synthesized Melphalan Analogs Induce DNA Damage and Mitotic Catastrophe in Hematological Malignant Cancer Cells
by Anastazja Poczta, Piotr Krzeczyński, Maksim Ionov, Aneta Rogalska, Udo S. Gaipl, Agnieszka Marczak and Dorota Lubgan
Int. J. Mol. Sci. 2022, 23(22), 14258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214258 - 17 Nov 2022
Cited by 1 | Viewed by 1218
Abstract
Myeloablative therapy with highdoses of the cytostatic drug melphalan (MEL) in preparation for hematopoietic cell transplantation is the standard of care for multiple myeloma (MM) patients. Melphalan is a bifunctional alkylating agent that covalently binds to nucleophilic sites in the DNA and effective [...] Read more.
Myeloablative therapy with highdoses of the cytostatic drug melphalan (MEL) in preparation for hematopoietic cell transplantation is the standard of care for multiple myeloma (MM) patients. Melphalan is a bifunctional alkylating agent that covalently binds to nucleophilic sites in the DNA and effective in the treatment, but unfortunately has limited therapeutic benefit. Therefore, new approaches are urgently needed for patients who are resistant to existing standard treatment with MEL. Regulating the pharmacological activity of drug molecules by modifying their structure is one method for improving their effectiveness. The purpose of this work was to analyze the physicochemical and biological properties of newly synthesized melphalan derivatives (EE-MEL, EM-MEL, EM-MOR-MEL, EM-I-MEL, EM-T-MEL) obtained through the esterification of the carboxyl group and the replacement of the the amino group with an amidine group. Compounds were selected based on our previous studies for their improved anticancer properties in comparison with the original drug. For this, we first evaluated the physicochemical properties using the circular dichroism technique, then analyzed the zeta potential and the hydrodynamic diameters of the particles. Then, the in vitro biological properties of the analogs were tested on multiple myeloma (RPMI8226), acute monocytic leukemia (THP1), and promyelocytic leukemia (HL60) cells as model systems for hematological malignant cells. DNA damage was assessed by immunostaining γH2AX, cell cycle distribution changes by propidium iodide (PI) staining, and cell death by the activation of caspase 2. We proved that the newly synthesized derivatives, in particular EM-MOR-MEL and EM-T-MEL, affected the B-DNA conformation, thus increasing the DNA damage. As a result of the DNA changes, the cell cycle was arrested in the S and G2/M phases. The cell death occurred by activating a mitotic catastrophe. Our investigations suggest that the analogs EM-MOR-MEL and EM-T-MEL have better anti-cancer activity in multiple myeloma cells than the currently used melphalan. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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20 pages, 11848 KiB  
Article
Potential Therapeutic Effects of Thiazolidinedione on Malignant Glioma
by Meei-Ling Sheu, Liang-Yi Pan, Huai-Yun Hu, Hong-Lin Su, Jason Sheehan, Hsi-Kai Tsou and Hung-Chuan Pan
Int. J. Mol. Sci. 2022, 23(21), 13510; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113510 - 04 Nov 2022
Cited by 3 | Viewed by 1421
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and reaching merely a median of ~15 months even with aggressive treatments. PPARγ (Peroxisome proliferator- activated receptor gamma) [...] Read more.
Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and reaching merely a median of ~15 months even with aggressive treatments. PPARγ (Peroxisome proliferator- activated receptor gamma) agonists (ciglitazone), while being widely used on patients of type 2 diabetes mellitus, also have approved anticancer effects. Their action mechanisms on malignant glioma are not fully understood. The aim of this study is to investigate the potential therapeutic effect of PPARγ agonists on maligant glioma. Glioma cell line and in-vivo/ex-vivo animal model intervened by ciglitazone were used to assess the associated mechanism and therapeutic effect. Our results from in vivo and ex vivo experiments showed that ciglitazone not only inhibited tumor growth and its associated angiogenesis, but it also reduced colony formation and migration of tumors. Ciglitazone inhibited the phosphorylation of STAT3 (signal transducer and activator of transcription 3) (at the point of tyrosine 705 by increasing both the amount and activity of SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2) proteins, based on evidence obtained from immunoprecipitation and immunohistochemistry. Furthermore, ciglitazone activated proteasomes and lysosomes to degrade cell-cycle-related proteins like Cyclin D1, Cyclin E, CDK2 (Cyclin-dependent kinase 2), and CDK4 (Cyclin-dependent kinase 4). Ciglitazone triggered expressions of LC3 (Microtubule-associated protein 1A/1B-light chain 3) and formation of acidic vesicular organelles (AVOs), both of which were implicated in the autophagy pathway. In conclusion, ciglitazone showed the multiple actions to regulate the growth of glioma, which appeared to be a potential candidate for treating malignant glioma. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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28 pages, 33206 KiB  
Article
Potent Chlorambucil-Platinum(IV) Prodrugs
by Angelico D. Aputen, Maria George Elias, Jayne Gilbert, Jennette A. Sakoff, Christopher P. Gordon, Kieran F. Scott and Janice R. Aldrich-Wright
Int. J. Mol. Sci. 2022, 23(18), 10471; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810471 - 09 Sep 2022
Cited by 10 | Viewed by 2799
Abstract
The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL [...] Read more.
The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB, 5CLB, and 56CLB, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, PHENSS, 5MESS, and 56MESS. Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI50 values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with PCLB, 5CLB, and 56CLB up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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13 pages, 3504 KiB  
Article
Synthesis of Four Steroidal Carbamates with Antitumor Activity against Mouse Colon Carcinoma CT26WT Cells: In Vitro and In Silico Evidence
by Daylin Fernández Pacheco, Dayana Alonso, Leonardo González Ceballos, Armando Zaldo Castro, Sheila Brown Roldán, Mairelys García Díaz, Anabel Villa Testa, Sarah Fuentes Wagner, Janet Piloto-Ferrer, Yamilet Coll García, Andrés F. Olea and Luis Espinoza
Int. J. Mol. Sci. 2022, 23(15), 8775; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158775 - 07 Aug 2022
Viewed by 1533
Abstract
Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in [...] Read more.
Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in CRC control. Moreover, the lack of selectivity of current anticancer drugs, plus mutations that occur in cancerous cells, demands the development of new chemotherapeutic agents. Several steroids have shown their potentiality as anticancer agents, while some other compounds, such as Taxol and its derivatives bearing a carbamate functionality, have reached the market. In this article, the synthesis, characterization, and antiproliferative activity of four steroidal carbamates on mouse colon carcinoma CT26WT cells are described. Carbamate synthesis occurred via direct reaction between diosgenin, its B-ring modified derivative, and testosterone with phenyl isocyanate under a Brønsted acid catalysis. All obtained compounds were characterized by 1H and 13C Nuclear Magnetic Resonance (NMR), High Resolution Mass Spectroscopy (HRMS); their melting points are also reported. Results obtained from antiproliferative activity assays indicated that carbamates compounds have inhibitory effects on the growth of this colon cancer cell line. A molecular docking study carried out on Human Prostaglandin E Receptor (EP4) showed a high affinity between carbamates and protein, thus providing a valuable theoretical explanation of the in vitro results. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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20 pages, 4298 KiB  
Article
JIB-04, a Pan-Inhibitor of Histone Demethylases, Targets Histone-Lysine-Demethylase-Dependent AKT Pathway, Leading to Cell Cycle Arrest and Inhibition of Cancer Stem-Like Cell Properties in Hepatocellular Carcinoma Cells
by Jina Lee, Ji-Soo Kim, Hye-In Cho, So-Ra Jo and Yeun-Kyu Jang
Int. J. Mol. Sci. 2022, 23(14), 7657; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147657 - 11 Jul 2022
Cited by 3 | Viewed by 2195
Abstract
JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of [...] Read more.
JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of hepatocellular carcinoma (HCC) has not been elucidated yet. Here, we showed that JIB-04 targeted KDMs, leading to the growth inhibition and cell cycle arrest of HCC, and abolished the viability of LCSCs. JIB-04 significantly attenuated CSC tumorsphere formation, growth, relapse, migration, and invasion in vitro. Among KDMs, the deficiency of KDM4B, KDM4D, and KDM6B reduced the viability of the tumorspheres, suggesting their roles in the function of LCSCs. RNA sequencing revealed that JIB-04 affected various cancer-related pathways, especially the PI3K/AKT pathway, which is crucial for HCC malignancy and the maintenance of LCSCs. Our results revealed KDM6B-dependent AKT2 expression and the downregulation of E2F-regulated genes via JIB-04-induced inhibition of the AKT2/FOXO3a/p21/RB axis. A ChIP assay demonstrated JIB-04-induced reduction in H3K27me3 at the AKT2 promoter and the enrichment of KDM6B within this promoter. Overall, our results strongly suggest that the inhibitory effect of JIB-04 on HCC malignancy and the maintenance of LCSCs is mediated via targeting the KDM6B-AKT2 pathway, indicating the therapeutic potential of JIB-04. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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16 pages, 3765 KiB  
Article
Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration
by Tsugumasa Toma, Hiroshi Tateishi, Kensaku Kawakami, Taha F. S. Ali, Masahiro Kamo, Kazuaki Monde, Yuta Nakashima, Mikako Fujita and Masami Otsuka
Int. J. Mol. Sci. 2022, 23(9), 5047; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095047 - 02 May 2022
Cited by 5 | Viewed by 2998
Abstract
Cancer metastasis accounts for most of the mortality associated with solid tumors. However, antimetastatic drugs are not available on the market. One of the important biological events leading to metastasis is the epithelial to mesenchymal transition (EMT) induced by cytokines, namely transforming growth-factor-β [...] Read more.
Cancer metastasis accounts for most of the mortality associated with solid tumors. However, antimetastatic drugs are not available on the market. One of the important biological events leading to metastasis is the epithelial to mesenchymal transition (EMT) induced by cytokines, namely transforming growth-factor-β (TGF-β). Although several classes of inhibitors targeting TGF-β and its receptor have been developed, they have shown profound clinical side effects. We focused on our synthetic compound, HPH-15, which has shown anti-fibrotic activity via the blockade of the TGF-β Smad-dependent signaling. In this study, 10 μM of HPH-15 was found to exhibit anti-cell migration and anti-EMT activities in non-small-cell lung cancer (NSCLC) cells. Although higher concentrations are required, the anti-EMT activity of HPH-15 has also been observed in 3D-cultured NSCLC cells. A mechanistic study showed that HPH-15 inhibits downstream TGF-β signaling. This downstream inhibition blocks the expression of cytokines such as TGF-β, leading to the next cycle of Smad-dependent and -independent signaling. HPH-15 has AMPK-activation activity, but a relationship between AMPK activation and anti-EMT/cell migration was not observed. Taken together, HPH-15 may lead to the development of antimetastatic drugs with a new mechanism of action. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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17 pages, 1613 KiB  
Article
Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines
by Yixuan Ma, Sina Sender, Anett Sekora, Weibo Kong, Peter Bauer, Najim Ameziane, Susann Krake, Mandy Radefeldt, Ruslan Al-Ali, Frank Ulrich Weiss, Markus M. Lerch, Alisha Parveen, Dietmar Zechner, Christian Junghanss and Hugo Murua Escobar
Int. J. Mol. Sci. 2022, 23(8), 4409; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084409 - 16 Apr 2022
Cited by 3 | Viewed by 2498
Abstract
Casein kinase II (CK2) and cyclin-dependent kinases (CDKs) frequently interact within multiple pathways in pancreatic ductal adenocarcinoma (PDAC). Application of CK2- and CDK-inhibitors have been considered as a therapeutic option, but are currently not part of routine chemotherapy regimens. We investigated ten PDAC [...] Read more.
Casein kinase II (CK2) and cyclin-dependent kinases (CDKs) frequently interact within multiple pathways in pancreatic ductal adenocarcinoma (PDAC). Application of CK2- and CDK-inhibitors have been considered as a therapeutic option, but are currently not part of routine chemotherapy regimens. We investigated ten PDAC cell lines exposed to increasing concentrations of silmitasertib and dinaciclib. Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated, and bioinformatic clustering was used to classify cell lines into sensitive groups based on their response to inhibitors. Furthermore, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) was conducted to assess recurrent mutations and the expression profile of inhibitor targets and genes frequently mutated in PDAC, respectively. Dinaciclib and silmitasertib demonstrated pronounced and limited cell line specific effects in cell death induction, respectively. WES revealed no genomic variants causing changes in the primary structure of the corresponding inhibitor target proteins. RNA-Seq demonstrated that the expression of all inhibitor target genes was higher in the PDAC cell lines compared to non-neoplastic pancreatic tissue. The observed differences in PDAC cell line sensitivity to silmitasertib or dinaciclib did not depend on target gene expression or the identified gene variants. For the PDAC hotspot genes kirsten rat sarcoma virus (KRAS) and tumor protein p53 (TP53), three and eight variants were identified, respectively. In conclusion, both inhibitors demonstrated in vitro efficacy on the PDAC cell lines. However, aberrations and expression of inhibitor target genes did not appear to affect the efficacy of the corresponding inhibitors. In addition, specific aberrations in TP53 and KRAS affected the efficacy of both inhibitors. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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23 pages, 4156 KiB  
Article
Effect of ALDH1A1 Gene Knockout on Drug Resistance in Paclitaxel and Topotecan Resistant Human Ovarian Cancer Cell Lines in 2D and 3D Model
by Marta Nowacka, Barbara Ginter-Matuszewska, Monika Świerczewska, Karolina Sterzyńska, Michał Nowicki and Radosław Januchowski
Int. J. Mol. Sci. 2022, 23(6), 3036; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063036 - 11 Mar 2022
Cited by 10 | Viewed by 2969
Abstract
Ovarian cancer is the most common cause of gynecological cancer death. Cancer Stem Cells (CSCs) characterized by drug transporters and extracellular matrix (ECM) molecules expression are responsible for drug resistance development. The goal of our study was to examine the role of aldehyde [...] Read more.
Ovarian cancer is the most common cause of gynecological cancer death. Cancer Stem Cells (CSCs) characterized by drug transporters and extracellular matrix (ECM) molecules expression are responsible for drug resistance development. The goal of our study was to examine the role of aldehyde dehydrogenase 1A1 (ALDH1A1) expression in paclitaxel (PAC) and topotecan (TOP) resistant ovarian cancer cell lines. In both cell lines, we knocked out the ALDH1A1 gene using the CRISPR/Cas9 technique. Additionally, we derived an ALDH1A1 positive TOP-resistant cell line with ALDH1A1 expression in all cells via clonal selection. The effect of ALDH1A1 gene knockout or clonal selection on the expression of ALDH1A1, drug transporters (P-gp and BCRP), and ECM (COL3A1) was determined by Q-PCR, Western blot and immunofluorescence. Using MTT assay, we compared drug resistance in two-dimensional (2D) and three-dimensional (3D) cell culture conditions. We did not observe any effect of ALDH1A1 gene knockout on MDR1/P-gp expression and drug resistance in the PAC-resistant cell line. The knockout of ALDH1A1 in the TOP-resistant cell line resulted in a moderate decrease of BCRP and COL3A1 expression and weakened TOP resistance. The clonal selection of ALDH1A1 cells resulted in very strong downregulation of BCPR and COL3A1 expression and overexpression of MDR1/P-gp. This finally resulted in decreased resistance to TOP but increased resistance to PAC. All spheroids were more resistant than cells growing as monolayers, but the resistance mechanism differs. The spheroids’ resistance may result from the presence of cell zones with different proliferation paces, the density of the spheroid, ECM expression, and drug capacity to diffuse into the spheroid. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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26 pages, 9687 KiB  
Article
Bivalent EGFR-Targeting DARPin-MMAE Conjugates
by Lennard Karsten, Nils Janson, Vadim Le Joncour, Sarfaraz Alam, Benjamin Müller, Jayendrakishore Tanjore Ramanathan, Pirjo Laakkonen, Norbert Sewald and Kristian M. Müller
Int. J. Mol. Sci. 2022, 23(5), 2468; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052468 - 23 Feb 2022
Cited by 9 | Viewed by 3622
Abstract
Epidermal growth factor receptor (EGFR) is a validated tumor marker overexpressed in various cancers such as squamous cell carcinoma (SSC) of the head and neck and gliomas. We constructed protein-drug conjugates based on the anti-EGFR Designed Ankyrin Repeat Protein (DARPin) E01, and compared [...] Read more.
Epidermal growth factor receptor (EGFR) is a validated tumor marker overexpressed in various cancers such as squamous cell carcinoma (SSC) of the head and neck and gliomas. We constructed protein-drug conjugates based on the anti-EGFR Designed Ankyrin Repeat Protein (DARPin) E01, and compared the bivalent DARPin dimer (DD1) and a DARPin-Fc (DFc) to the monomeric DARPin (DM) and the antibody derived scFv425-Fc (scFvFc) in cell culture and a mouse model. The modular conjugation system, which was successfully applied for the preparation of protein-drug and -dye conjugates, uses bio-orthogonal protein-aldehyde generation by the formylglycine-generating enzyme (FGE). The generated carbonyl moiety is addressed by a bifunctional linker with a pyrazolone for a tandem Knoevenagel reaction and an azide for strain-promoted azide-alkyne cycloaddition (SPAAC). The latter reaction with a PEGylated linker containing a dibenzocyclooctyne (DBCO) for SPAAC and monomethyl auristatin E (MMAE) as the toxin provided the stable conjugates DD1-MMAE (drug-antibody ratio, DAR = 2.0) and DFc-MMAE (DAR = 4.0) with sub-nanomolar cytotoxicity against the human squamous carcinoma derived A431 cells. In vivo imaging of Alexa Fluor 647-dye conjugates in A431-xenografted mice bearing subcutaneous tumors as the SCC model revealed unspecific binding of bivalent DARPins to the ubiquitously expressed EGFR. Tumor-targeting was verified 6 h post-injection solely for DD1 and scFvFc. The total of four administrations of 6.5 mg/kg DD1-MMAE or DFc-MMAE twice weekly did not cause any sequela in mice. MMAE conjugates showed no significant anti-tumor efficacy in vivo, but a trend towards increased necrotic areas (p = 0.2213) was observed for the DD1-MMAE (n = 5). Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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16 pages, 3686 KiB  
Article
BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells
by Weibo Kong, Sina Sender, Leila Taher, Simon Villa-Perez, Yixuan Ma, Anett Sekora, Barbara C. Ruetgen, Bertram Brenig, Julia Beck, Ekkehard Schuetz, Christian Junghanss, Ingo Nolte and Hugo Murua Escobar
Int. J. Mol. Sci. 2021, 22(23), 12673; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312673 - 24 Nov 2021
Cited by 5 | Viewed by 2322
Abstract
Bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) in the B-cell receptor (BCR) signaling pathway are considered potential therapeutic targets for the treatment of B-cell lymphomas, among which, diffuse large B-cell lymphoma (DLBCL) is the most common type. Herein, we comparatively evaluated the [...] Read more.
Bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) in the B-cell receptor (BCR) signaling pathway are considered potential therapeutic targets for the treatment of B-cell lymphomas, among which, diffuse large B-cell lymphoma (DLBCL) is the most common type. Herein, we comparatively evaluated the single and combined application of the BTK inhibitor ibrutinib and the selective PI3Kγ inhibitor AS-605240 in the canine DLBCL cell line CLBL-1. For further comparison, key findings were additionally analyzed in canine B-cell leukemia GL-1 and human DLBCL cell line SU-DHL-4. While ibrutinib alone induced significant anti-proliferative effects on all cell lines in a dose-dependent manner, AS-605240 only induced anti-proliferative effects at high concentrations. Interestingly, ibrutinib and AS-605240 acted synergistically, reducing cell proliferation and increasing apoptosis/necrosis in all cell lines and inducing morphological changes in CLBL-1. Moreover, the combined application of ibrutinib and AS-605240 reduced relative phosphorylation and, in some instances, the levels of the BTK, AKT, GSK3β, and ERK proteins. Comparative variant analysis of RNA-seq data among canine B- and T-lymphoid cell lines and primary B-cell lymphoma samples revealed potentially high-impact somatic variants in the genes that encode PI3K, which may explain why AS-605240 does not singly inhibit the proliferation of cell lines. The combination of ibrutinib and AS-605240 represents a promising approach that warrants further in vivo evaluation in dogs, potentially bearing significant value for the treatment of human DLBCL. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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18 pages, 4635 KiB  
Article
Modulation of Cellular NAD+ Attenuates Cancer-Associated Hypercoagulability and Thrombosis via the Inhibition of Tissue Factor and Formation of Neutrophil Extracellular Traps
by Wa Cao, Meng-Yu Zhu, Seung-Hoon Lee, Su-Bin Lee, Hyung-Jin Kim, Byung-Ouk Park, Cheol-Hwan Yoon, Dipendra Khadka, Gi-Su Oh, Hyeok Shim, Tae-Hwan Kwak and Hong-Seob So
Int. J. Mol. Sci. 2021, 22(21), 12085; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222112085 - 08 Nov 2021
Cited by 8 | Viewed by 3221
Abstract
Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD+) levels by accelerating the oxidation [...] Read more.
Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD+) levels by accelerating the oxidation of NADH to NAD+, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD+ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD+ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD+ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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15 pages, 15510 KiB  
Article
Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line
by Ha-yeon Jee, Yoon-Gyeong Lee, Sol Lee, Rosalie Elvira, Hye-eun Seo, Ji-Yeon Lee, Jaeseok Han and Kyungho Lee
Int. J. Mol. Sci. 2021, 22(21), 11824; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111824 - 30 Oct 2021
Cited by 2 | Viewed by 1932
Abstract
Protein synthesis is important for maintaining cellular homeostasis under various stress responses. In this study, we screened an anticancer drug library to select compounds with translational repression functions. AZD8055, an ATP-competitive mechanistic target of rapamycin complex 1/2 (mTORC1/2) inhibitor, was selected as a [...] Read more.
Protein synthesis is important for maintaining cellular homeostasis under various stress responses. In this study, we screened an anticancer drug library to select compounds with translational repression functions. AZD8055, an ATP-competitive mechanistic target of rapamycin complex 1/2 (mTORC1/2) inhibitor, was selected as a translational suppressor. AZD8055 inhibited protein synthesis in mouse embryonic fibroblasts and hepatocellular carcinoma HepG2 cells. Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) were activated during the early phase of mTORC1/2 inhibition by AZD8055 treatment. Combined treatment of AZD8055 with the MAPK kinase1/2 (MEK1/2) inhibitor refametinib or the p38 inhibitor SB203580 markedly decreased translation in HepG2 cells. Thus, the inhibition of ERK1/2 or p38 may enhance the efficacy of AZD8055-mediated inhibition of protein synthesis. In addition, AZD8055 down-regulated the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and AZD8055-induced phosphorylation of ERK1/2 and p38 had no effect on phosphorylation status of 4E-BP1. Interestingly, AZD8055 modulated the 4E-BP1 mRNA pool by up-regulating ERK1/2 and p38 pathways. Together, these results suggest that AZD8055-induced activation of MAPKs interferes with inhibition of protein synthesis at an early stage of mTORC1/2 inhibition, and that it may contribute to the development of resistance to mTORC1/2 inhibitors. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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13 pages, 2583 KiB  
Article
An Attenuated Targeted-TNF Localizes to Tumors In Vivo and Regains Activity at the Site of Disease
by Sheila Dakhel, Christian Lizak, Mattia Matasci, Jacqueline Mock, Alessandra Villa, Dario Neri and Samuele Cazzamalli
Int. J. Mol. Sci. 2021, 22(18), 10020; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810020 - 16 Sep 2021
Cited by 8 | Viewed by 2281
Abstract
Antibody-cytokine fusion proteins (immunocytokines) are gaining importance for cancer therapy, but those products are often limited by systemic toxicity related to the activity of the cytokine payload in circulation and in secondary lymphoid organs. Tumor necrosis factor (TNF) is used as a pro-inflammatory [...] Read more.
Antibody-cytokine fusion proteins (immunocytokines) are gaining importance for cancer therapy, but those products are often limited by systemic toxicity related to the activity of the cytokine payload in circulation and in secondary lymphoid organs. Tumor necrosis factor (TNF) is used as a pro-inflammatory payload to trigger haemorrhagic necrosis and boost anti-cancer immunity at the tumor site. Here we describe a depotentiated version of TNF (carrying the single point mutation I97A), which displayed reduced binding affinity to its cognate receptor tumor necrosis factor receptor 1 (TNFR-1) and lower biocidal activity. The fusion of the TNF(I97A) mutant to the L19 antibody promoted restoration of anti-tumor activity upon accumulation on the cognate antigen, the alternatively spliced EDB domain of fibronectin. In vivo administration of high doses (375 μg/Kg) of the fusion protein showed a potent anti-tumor effect without apparent toxicity compared with the wild type protein. L19-TNFI97A holds promise for the targeted delivery of TNF activity to neoplastic lesions, helping spare normal tissues. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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Review

Jump to: Research

16 pages, 1155 KiB  
Review
Intraoperative Tumor Detection Using Pafolacianine
by Mihaela Elisabeta Dindere, Antoanela Tanca, Mihaela Rusu, Elisa Anamaria Liehn and Octavian Bucur
Int. J. Mol. Sci. 2022, 23(21), 12842; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112842 - 25 Oct 2022
Cited by 14 | Viewed by 2630
Abstract
Cancer is a leading cause of death worldwide, with increasing numbers of new cases each year. For the vast majority of cancer patients, surgery is the most effective procedure for the complete removal of the malignant tissue. However, relapse due to the incomplete [...] Read more.
Cancer is a leading cause of death worldwide, with increasing numbers of new cases each year. For the vast majority of cancer patients, surgery is the most effective procedure for the complete removal of the malignant tissue. However, relapse due to the incomplete resection of the tumor occurs very often, as the surgeon must rely primarily on visual and tactile feedback. Intraoperative near-infrared imaging with pafolacianine is a newly developed technology designed for cancer detection during surgery, which has been proven to show excellent results in terms of safety and efficacy. Therefore, pafolacianine was approved by the U.S. Food and Drug Administration (FDA) on 29 November 2021, as an additional approach that can be used to identify malignant lesions and to ensure the total resection of the tumors in ovarian cancer patients. Currently, various studies have demonstrated the positive effects of pafolacianine’s use in a wide variety of other malignancies, with promising results expected in further research. This review focuses on the applications of the FDA-approved pafolacianine for the accurate intraoperative detection of malignant tissues. The cancer-targeting fluorescent ligands can shift the paradigm of surgical oncology by enabling the visualization of cancer lesions that are difficult to detect by inspection or palpation. The enhanced detection and removal of hard-to-detect cancer tissues during surgery will lead to remarkable outcomes for cancer patients and society, specifically by decreasing the cancer relapse rate, increasing the life expectancy and quality of life, and decreasing future rates of hospitalization, interventions, and costs. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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22 pages, 1709 KiB  
Review
Targeting CXCR4 and CD47 Receptors: An Overview of New and Old Molecules for a Biological Personalized Anticancer Therapy
by Manuela Leo and Lina Sabatino
Int. J. Mol. Sci. 2022, 23(20), 12499; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012499 - 18 Oct 2022
Cited by 1 | Viewed by 2195
Abstract
Biological therapy, with its multifaceted applications, has revolutionized the treatment of tumors, mainly due to its ability to exclusively target cancer cells and reduce the adverse effects on normal tissues. This review focuses on the therapies targeting the CXCR4 and CD47 receptors. We [...] Read more.
Biological therapy, with its multifaceted applications, has revolutionized the treatment of tumors, mainly due to its ability to exclusively target cancer cells and reduce the adverse effects on normal tissues. This review focuses on the therapies targeting the CXCR4 and CD47 receptors. We surveyed the results of early clinical trials testing compounds classified as nonpeptides, small peptides, CXCR4 antagonists or specific antibodies whose activity reduces or completely blocks the intracellular signaling pathways and cell proliferation. We then examined antibodies and fusion proteins against CD47, the receptor that acts as a “do not eat me” signal to phagocytes escaping immune surveillance. Despite these molecules being tested in early clinical trials, some drawbacks are emerging that impair their use in practice. Finally, we examined the ImmunoGenic Surrender mechanism that involves crosstalk and co-internalization of CXCR4 and CD47 upon engagement of CXCR4 by ligands or other molecules. The favorable effect of such compounds is dual as CD47 surface reduction impact on the immune response adds to the block of CXCR4 proliferative potential. These results suggest that a combination of different therapeutic approaches has more beneficial effects on patients’ survival and may pave the way for new accomplishments in personalized anticancer therapy. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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26 pages, 3989 KiB  
Review
Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones
by Teodora Constantinescu and Alin Grig Mihis
Int. J. Mol. Sci. 2022, 23(19), 11595; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911595 - 30 Sep 2022
Cited by 13 | Viewed by 2282
Abstract
ATP-binding cassette subfamily G and tubulin pharmacological mechanisms decrease the effectiveness of anticancer drugs by modulating drug absorption and by creating tubulin assembly through polymerization. A series of natural and synthetic chalcones have been reported to have very good anticancer activity, with a [...] Read more.
ATP-binding cassette subfamily G and tubulin pharmacological mechanisms decrease the effectiveness of anticancer drugs by modulating drug absorption and by creating tubulin assembly through polymerization. A series of natural and synthetic chalcones have been reported to have very good anticancer activity, with a half-maximal inhibitory concentration lower than 1 µM. By modulation, it is observed in case of the first mechanism that methoxy substituents on the aromatic cycle of acetophenone residue and substitution of phenyl nucleus by a heterocycle and by methoxy or hydroxyl groups have a positive impact. To inhibit tubulin, compounds bind to colchicine binding site. Presence of methoxy groups, amino groups or heterocyclic substituents increase activity. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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17 pages, 1743 KiB  
Review
Bilayer Forming Phospholipids as Targets for Cancer Therapy
by Celine Stoica, Adilson Kleber Ferreira, Kayleigh Hannan and Marica Bakovic
Int. J. Mol. Sci. 2022, 23(9), 5266; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095266 - 09 May 2022
Cited by 19 | Viewed by 3705
Abstract
Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the majority of cell membranes. De novo biosynthesis of phosphatidylcholine and phosphatidylethanolamine occurs via the Kennedy pathway, and perturbations in the regulation of this [...] Read more.
Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the majority of cell membranes. De novo biosynthesis of phosphatidylcholine and phosphatidylethanolamine occurs via the Kennedy pathway, and perturbations in the regulation of this pathway are linked to a variety of human diseases, including cancer. Altered phosphatidylcholine and phosphatidylethanolamine membrane content, phospholipid metabolite levels, and fatty acid profiles are frequently identified as hallmarks of cancer development and progression. This review summarizes the research on how phospholipid metabolism changes over oncogenic transformation, and how phospholipid profiling can differentiate between human cancer and healthy tissues, with a focus on colorectal cancer, breast cancer, and non-small cell lung cancer. The potential for phospholipids to serve as biomarkers for diagnostics, or as anticancer therapy targets, is also discussed. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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31 pages, 2766 KiB  
Review
Biological Therapies in the Treatment of Cancer—Update and New Directions
by Monika A. Papież and Wirginia Krzyściak
Int. J. Mol. Sci. 2021, 22(21), 11694; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111694 - 28 Oct 2021
Cited by 18 | Viewed by 6712
Abstract
Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new therapies that have contributed to the advances in treatment of certain malignancies. Immunotherapy, which has repeatedly proven to [...] Read more.
Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new therapies that have contributed to the advances in treatment of certain malignancies. Immunotherapy, which has repeatedly proven to be a breakthrough therapy in melanoma, as well as B-ALL therapy with CAR T cells, are of great merit in this progress. These therapies are currently being developed by modifying bispecific antibodies and CAR T cells to improve their efficiency and bioavailability. Work on improving the therapy with oncolytic viruses is also progressing, and efforts are being made to improve the immunogenicity and stability of cancer vaccines. Combining various biological therapies, immunotherapy with oncolytic viruses or cancer vaccines is gaining importance in cancer therapy. New therapeutic targets are intensively sought among neoantigens, which are not immunocompromised, or antigens associated with tumor stroma cells. An example is fibroblast activation protein α (FAPα), the overexpression of which is observed in the case of tumor progression. Universal therapeutic targets are also sought, such as the neurotrophic receptor tyrosine kinase (NTRK) gene fusion, a key genetic driver present in many types of cancer. This review also raises the problem of the tumor microenvironment. Stromal cells can protect tumor cells from chemotherapy and contribute to relapse and progression. This publication also addresses the problem of cancer stem cells resistance to treatment and presents attempts to avoid this phenomenon. This review focuses on the most important strategies used to improve the selectivity of biological therapies. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments)
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