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Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression
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Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 62983

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Angela Stefanachi

E-Mail Website
Guest Editor
Department of Pharmacy-Drug Sciences, University of Bari, 70125 Bari, Italy
Interests: BCR-ABL inhibitors; HDAC inhibitors; CB2 modulators
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Classical chemotherapy is often associated with tumoral cell resistance phenomena or with systemic toxicity in patients, and for this reason, new strategies have been developed to overcome these issues. Some initial approaches consisted in the combination of drugs, endowed with a diverse mechanism of action, to overcome tumor resistance to antineoplastic drugs, while more recently, thanks to the target therapy approach, drugs able to selectively hit a specific molecular mechanism of the tumor cells have been developed, with a convenient improvement of their therapeutic index. The last strategy includes, among others, the development of tyrosine kinases inhibitors, monoclonal antibodies, antibody drug conjugates (ADC), antisense, and siRNA.

Moreover, the complexity of cancer progression has demonstrated that single-target drugs are often unable to gain a complete therapeutic effect, and so, the development of multi-target drugs, directed at more than one target, has been demonstrated to be of high interest. Computational studies have helped scientists in this challenge against tumor disease, as well as all the drug delivery technologies, with particular attention to site-directed ones.

The aim of this Special Issue is to collect reports regarding all the recent strategies, directed at the improvement of antineoplastic activity of drugs in cancer progression, engaging all the expertise needed for the development of new anticancer drugs: medicinal chemistry, pharmacology, molecular biology, and computational and drug delivery studies. Original research, reviews, opinion papers, or short communications are welcome.

Dr. Angela Stefanachi
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cancer
  • Antineoplastic drugs
  • Target therapy
  • Drug delivery
  • Computational studies
  • MDR
  • Multitarget drugs

Published Papers (23 papers)

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15 pages, 1075 KiB  
Article
Aminopeptidase N Inhibitors as Pointers for Overcoming Antitumor Treatment Resistance
by Oldřich Farsa, Veronika Ballayová, Radka Žáčková, Peter Kollar, Tereza Kauerová and Peter Zubáč
Int. J. Mol. Sci. 2022, 23(17), 9813; https://doi.org/10.3390/ijms23179813 - 29 Aug 2022
Cited by 2 | Viewed by 1508
Abstract
Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), [...] Read more.
Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), a stress response characterized by the upregulation of amino acid transporters and synthetic enzymes and activation of stress-related pathways such as nuclear factor kB (NFkB) and other pro-apoptotic regulators, which leads to cancer cell death by apoptosis. Recently, APN inhibition has been shown to augment DR4-induced tumor cell death and thus overcome resistance to cancer treatment with DR4-ligand TRAIL, which is available as a recombinant soluble form dulanermin. This implies that APN inhibitors could serve as potential weapons for overcoming cancer treatment resistance. In this study, a series of basically substituted acetamidophenones and the semicarbazones and thiosemicarbazones derived from them were prepared, for which APN inhibitory activity was determined. In addition, a selective anti-proliferative activity against cancer cells expressing APN was demonstrated. Our semicarbazones and thiosemicarbazones are the first compounds of these structural types of Schiff bases that were reported to inhibit not only a zinc-dependent aminopeptidase of the M1 family but also a metalloenzyme. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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26 pages, 26993 KiB  
Article
Isothiocyanates (ITCs) 1-(Isothiocyanatomethyl)-4-phenylbenzene and 1-Isothiocyanato-3,5-bis(trifluoromethyl)benzene—Aldehyde Dehydrogenase (ALDH) Inhibitors, Decreases Cisplatin Tolerance and Migratory Ability of NSCLC
by Jolanta Kryczka, Jakub Kryczka, Łukasz Janczewski, Anna Gajda, Andrzej Frączyk, Joanna Boncela, Beata Kolesińska and Ewa Brzeziańska-Lasota
Int. J. Mol. Sci. 2022, 23(15), 8644; https://doi.org/10.3390/ijms23158644 - 3 Aug 2022
Cited by 2 | Viewed by 2740
Abstract
One of the main treatment modalities for non-small-cell lung cancer (NSCLC) is cisplatin-based chemotherapy. However, the acquisition of cisplatin resistance remains a major problem. Existing chemotherapy regimens are often ineffective against cancer cells expressing aldehyde dehydrogenase (ALDH). As such, there is an urgent [...] Read more.
One of the main treatment modalities for non-small-cell lung cancer (NSCLC) is cisplatin-based chemotherapy. However, the acquisition of cisplatin resistance remains a major problem. Existing chemotherapy regimens are often ineffective against cancer cells expressing aldehyde dehydrogenase (ALDH). As such, there is an urgent need for therapies targeting ALDH-positive cancer cells. The present study compares the anticancer properties of 36 structurally diverse isothiocyanates (ITCs) against NSCLC cells with the ALDH inhibitor disulfiram (DSF). Their potential affinity to ALDH isoforms and ABC proteins was assessed using AutoDockTools, allowing for selection of three compounds presenting the strongest affinity to all tested proteins. The selected ITCs had no impact on NSCLC cell viability (at tested concentrations), but significantly decreased the cisplatin tolerance of cisplatin-resistant variant of A549 (A549CisR) and advanced (stage 4) NSCLC cell line H1581. Furthermore, long-term supplementation with ITC 1-(isothiocyanatomethyl)-4-phenylbenzene reverses the EMT phenotype and migratory potential of A549CisR to the level presented by parental A549 cells, increasing E-Cadherin expression, followed by decreased expression of ABCC1 and ALDH3A1. Our data indicates that the ALDH inhibitors DSF and ITCs are potential adjuvants of cisplatin chemotherapy. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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16 pages, 2720 KiB  
Article
Ketoconazole Reverses Imatinib Resistance in Human Chronic Myelogenous Leukemia K562 Cells
by Omar Prado-Carrillo, Abner Arenas-Ramírez, Monserrat Llaguno-Munive, Rafael Jurado, Jazmin Pérez-Rojas, Eduardo Cervera-Ceballos and Patricia Garcia-Lopez
Int. J. Mol. Sci. 2022, 23(14), 7715; https://doi.org/10.3390/ijms23147715 - 13 Jul 2022
Cited by 6 | Viewed by 2291
Abstract
Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the oncogene BCR-ABL1, which encodes an oncoprotein with tyrosine kinase activity. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor, performs exceptionally well with minimal toxicity in CML chemotherapy. According to clinical trials, however, 20–30% of [...] Read more.
Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the oncogene BCR-ABL1, which encodes an oncoprotein with tyrosine kinase activity. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor, performs exceptionally well with minimal toxicity in CML chemotherapy. According to clinical trials, however, 20–30% of CML patients develop resistance to imatinib. Although the best studied resistance mechanisms are BCR-ABL1-dependent, P-glycoprotein (P-gp, a drug efflux transporter) may also contribute significantly. This study aimed to establish an imatinib-resistant human CML cell line, evaluate the role of P-gp in drug resistance, and assess the capacity of ketoconazole to reverse resistance by inhibiting P-gp. The following parameters were determined in both cell lines: cell viability (as the IC50) after exposure to imatinib and imatinib + ketoconazole, P-gp expression (by Western blot and immunofluorescence), the intracellular accumulation of a P-gp substrate (doxorubicin) by flow cytometry, and the percentage of apoptosis (by the Annexin method). In the highly resistant CML cell line obtained, P-gp was overexpressed, and the level of intracellular doxorubicin was low, representing high P-gp activity. Imatinib plus a non-toxic concentration of ketoconazole (10 μM) overcame drug resistance, inhibited P-gp overexpression and its efflux function, increased the intracellular accumulation of doxorubicin, and favored greater apoptosis of CML cells. P-gp contributes substantially to imatinib resistance in CML cells. Ketoconazole reversed CML cell resistance to imatinib by targeting P-gp-related pathways. The repurposing of ketoconazole for CML treatment will likely help patients resistant to imatinib. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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21 pages, 6995 KiB  
Article
The Multidirectional Effect of Azelastine Hydrochloride on Cervical Cancer Cells
by Ewa Trybus, Teodora Król and Wojciech Trybus
Int. J. Mol. Sci. 2022, 23(11), 5890; https://doi.org/10.3390/ijms23115890 - 24 May 2022
Cited by 5 | Viewed by 2059
Abstract
A major cause of cancer cell resistance to chemotherapeutics is the blocking of apoptosis and induction of autophagy in the context of cell adaptation and survival. Therefore, new compounds are being sought, also among drugs that are commonly used in other therapies. Due [...] Read more.
A major cause of cancer cell resistance to chemotherapeutics is the blocking of apoptosis and induction of autophagy in the context of cell adaptation and survival. Therefore, new compounds are being sought, also among drugs that are commonly used in other therapies. Due to the involvement of histamine in the regulation of processes occurring during the development of many types of cancer, antihistamines are now receiving special attention. Our study concerned the identification of new mechanisms of action of azelastine hydrochloride, used in antiallergic treatment. The study was performed on HeLa cells treated with different concentrations of azelastine (15–90 µM). Cell cycle, level of autophagy (LC3 protein activity) and apoptosis (annexin V assay), activity of caspase 3/7, anti-apoptotic protein of Bcl-2 family, ROS concentration, measurement of mitochondrial membrane potential (Δψm), and level of phosphorylated H2A.X in response to DSB were evaluated by cytometric method. Cellular changes were also demonstrated at the level of transmission electron microscopy and optical and fluorescence microscopy. Lysosomal enzyme activities-cathepsin D and L and cell viability (MTT assay) were assessed spectrophotometrically. Results: Azelastine in concentrations of 15–25 µM induced degradation processes, vacuolization, increase in cathepsin D and L activity, and LC3 protein activation. By increasing ROS, it also caused DNA damage and blocked cells in the S phase of the cell cycle. At the concentrations of 45–90 µM, azelastine clearly promoted apoptosis by activation of caspase 3/7 and inactivation of Bcl-2 protein. Fragmentation of cell nucleus was confirmed by DAPI staining. Changes were also found in the endoplasmic reticulum and mitochondria, whose damage was confirmed by staining with rhodamine 123 and in the MTT test. Azelastine decreased the mitotic index and induced mitotic catastrophe. Studies demonstrated the multidirectional effects of azelastine on HeLa cells, including anti-proliferative, cytotoxic, autophagic, and apoptotic properties, which were the predominant mechanism of death. The revealed novel properties of azelastine may be practically used in anti-cancer therapy in the future. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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11 pages, 5801 KiB  
Article
Arylquin 1 (Potent Par-4 Secretagogue) Inhibits Tumor Progression and Induces Apoptosis in Colon Cancer Cells
by Yi-Ting Chen, Tzu-Ting Tseng, Hung-Pei Tsai and Ming-Yii Huang
Int. J. Mol. Sci. 2022, 23(10), 5645; https://doi.org/10.3390/ijms23105645 - 18 May 2022
Cited by 2 | Viewed by 1550
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. Current therapeutic strategies mainly involve surgery and chemoradiotherapy; however, novel antitumor compounds are needed to avoid drug resistance in CRC, as well as the severe side effects of current treatments. In [...] Read more.
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. Current therapeutic strategies mainly involve surgery and chemoradiotherapy; however, novel antitumor compounds are needed to avoid drug resistance in CRC, as well as the severe side effects of current treatments. In this study, we investigated the anticancer effects and underlying mechanisms of Arylquin 1 in CRC. The MTT assay was used to detect the viability of SW620 and HCT116 cancer cells treated with Arylquin 1 in a dose-dependent manner in vitro. Further, wound-healing and transwell migration assays were used to evaluate the migration and invasion abilities of cultured cells, and Annexin V was used to detect apoptotic cells. Additionally, Western blot was used to identify the expression levels of N-cadherin, caspase-3, cyclin D1, p-extracellular signal-regulated kinase (ERK), p-c-JUN N-terminal kinase (JNK), and phospho-p38, related to key signaling proteins, after administration of Arylquin 1. Xenograft experiments further confirmed the effects of Arylquin 1 on CRC cells in vivo. Arylquin 1 exhibited a dose-dependent reduction in cell viability in cultured CRC cells. It also inhibited cell proliferation, migration, and invasion, and induced apoptosis. Mechanistic analysis demonstrated that Arylquin 1 increased phosphorylation levels of ERK, JNK, and p38. In a mouse xenograft model, Arylquin 1 treatment diminished the growth of colon tumors after injection of cultured cancer cells. Arylquin 1 may have potential anticancer effects and translational significance in the treatment of CRC. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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15 pages, 2576 KiB  
Article
Sulforaphane Suppresses the Nicotine-Induced Expression of the Matrix Metalloproteinase-9 via Inhibiting ROS-Mediated AP-1 and NF-κB Signaling in Human Gastric Cancer Cells
by Shinan Li, Pham Ngoc Khoi, Hong Yin, Dhiraj Kumar Sah, Nam-Ho Kim, Sen Lian and Young-Do Jung
Int. J. Mol. Sci. 2022, 23(9), 5172; https://doi.org/10.3390/ijms23095172 - 5 May 2022
Cited by 11 | Viewed by 2126
Abstract
Sulforaphane, a natural phytochemical compound found in various cruciferous vegetables, has been discovered to present anti-cancer properties. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in gastric cancer metastasis. However, the role of sulforaphane in MMP-9 expression in gastric cancer is not yet defined. [...] Read more.
Sulforaphane, a natural phytochemical compound found in various cruciferous vegetables, has been discovered to present anti-cancer properties. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in gastric cancer metastasis. However, the role of sulforaphane in MMP-9 expression in gastric cancer is not yet defined. Nicotine, a psychoactive alkaloid found in tobacco, is associated with the development of gastric cancer. Here, we found that sulforaphane suppresses the nicotine-mediated induction of MMP-9 in human gastric cancer cells. We discovered that reactive oxygen species (ROS) and MAPKs (p38 MAPK, Erk1/2) are involved in nicotine-induced MMP-9 expression. AP-1 and NF-κB are the critical transcription factors in MMP-9 expression. ROS/MAPK (p38 MAPK, Erk1/2) and ROS functioned as upstream signaling of AP-1 and NF-κB, respectively. Sulforaphane suppresses the nicotine-induced MMP-9 by inhibiting ROS-mediated MAPK (p38 MAPK, Erk1/2)/AP-1 and ROS-mediated NF-κB signaling axes, which in turn inhibit cell invasion in human gastric cancer AGS cells. Therefore, the current study provides valuable evidence for developing sulforaphane as a new anti-invasion strategy for human gastric cancer therapy. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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13 pages, 2013 KiB  
Article
Pancreatic Ductal Cell-Derived Extracellular Vesicles Are Effective Drug Carriers to Enhance Paclitaxel’s Efficacy in Pancreatic Cancer Cells through Clathrin-Mediated Endocytosis
by Haoyao Sun, Kritisha Bhandari, Stephanie Burrola, Jinchang Wu and Wei-Qun Ding
Int. J. Mol. Sci. 2022, 23(9), 4773; https://doi.org/10.3390/ijms23094773 - 26 Apr 2022
Cited by 5 | Viewed by 1835
Abstract
Chemo-resistance challenges the clinical management of pancreatic ductal adenocarcinoma (PDAC). A limited admittance of chemotherapeutics to PDAC tissues is a key obstacle in chemotherapy of the malignancy. An enhanced uptake of drugs into PDAC cells is required for a more effective treatment. Extracellular [...] Read more.
Chemo-resistance challenges the clinical management of pancreatic ductal adenocarcinoma (PDAC). A limited admittance of chemotherapeutics to PDAC tissues is a key obstacle in chemotherapy of the malignancy. An enhanced uptake of drugs into PDAC cells is required for a more effective treatment. Extracellular vesicles (EVs), especially small EVs (sEVs), have emerged as drug carriers for delivering chemotherapeutics due to their low immunogenicity and propensity for homing toward tumor cells. The present study evaluated sEVs derived from six different human cell lines as carriers for paclitaxel (PTX). The encapsulation of the chemotherapeutics was achieved using incubation, sonication and electroporation. The cytotoxicity of the EV drugs was evaluated by MTS assay. While sonication led to a higher efficiency of drug loading than incubation and electroporation, PTX loaded through incubation with HPNE-derived sEVs (HI-PTX) was the most efficacious in killing PDAC cells. Furthermore, HI-PTX was taken up by PDAC cells more efficiently than other EV drugs, implying that the efficacy of HI-PTX is associated with its efficient uptake. This was supported by the observation that the cytotoxicity and uptake of HI-PTX is mediated via the clathrin-dependent endocytosis. Our results indicate that the hTERT-HPNE cell-derived EVs are effective drug carriers to enhance paclitaxel’s efficacy in PDAC cells. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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20 pages, 4649 KiB  
Article
Indomethacin and Diclofenac Hybrids with Oleanolic Acid Oximes Modulate Key Signaling Pathways in Pancreatic Cancer Cells
by Maria Narożna, Violetta Krajka-Kuźniak, Robert Kleszcz and Wanda Baer-Dubowska
Int. J. Mol. Sci. 2022, 23(3), 1230; https://doi.org/10.3390/ijms23031230 - 22 Jan 2022
Cited by 3 | Viewed by 2861
Abstract
Our earlier studies showed that coupling nonsteroidal anti-inflammatory drugs (NSAIDs) with oleanolic acid derivatives increased their anti-inflammatory activity in human hepatoma cells. The aim of this study was to evaluate their effect on the signaling pathways involved in inflammation processes in human pancreatic [...] Read more.
Our earlier studies showed that coupling nonsteroidal anti-inflammatory drugs (NSAIDs) with oleanolic acid derivatives increased their anti-inflammatory activity in human hepatoma cells. The aim of this study was to evaluate their effect on the signaling pathways involved in inflammation processes in human pancreatic cancer (PC) cells. Cultured PSN-1 cells were exposed for 24 h (30 µM) to OA oxime (OAO) derivatives substituted with benzyl or morpholide groups and their conjugates with indomethacin (IND) or diclofenac (DCL). The activation of NF-κB and Nrf2 was assessed by the evaluation of the translocation of their active forms into the nucleus and their binding to specific DNA sequences via the ELISA assay. The expression of NF-κB and Nrf2 target genes was evaluated by R-T PCR and Western blot analysis. The conjugation of IND or DCL with OAO derivatives increased cytotoxicity and their effect on the tested signaling pathways. The most effective compound was the DCL hybrid with OAO morpholide (4d). This compound significantly reduced the activation and expression of NF-κB and enhanced the activation and expression of Nrf2. Increased expression of Nrf2 target genes led to reduced ROS production. Moreover, MAPKs and the related pathways were also affected. Therefore, conjugate 4d deserves more comprehensive studies as a potential PC therapeutic agent. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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27 pages, 51994 KiB  
Article
Biotin Transport-Targeting Polysaccharide-Modified PAMAM G3 Dendrimer as System Delivering α-Mangostin into Cancer Cells and C. elegans Worms
by Joanna Markowicz, Łukasz Uram, Stanisław Wołowiec and Wojciech Rode
Int. J. Mol. Sci. 2021, 22(23), 12925; https://doi.org/10.3390/ijms222312925 - 29 Nov 2021
Cited by 8 | Viewed by 2295
Abstract
The natural xanthone α-mangostin (αM) exhibits a wide range of pharmacological activities, including antineoplastic and anti-nematode properties, but low water solubility and poor selectivity of the drug prevent its potential clinical use. Therefore, the targeted third-generation poly(amidoamine) dendrimer (PAMAM G3) delivery system was [...] Read more.
The natural xanthone α-mangostin (αM) exhibits a wide range of pharmacological activities, including antineoplastic and anti-nematode properties, but low water solubility and poor selectivity of the drug prevent its potential clinical use. Therefore, the targeted third-generation poly(amidoamine) dendrimer (PAMAM G3) delivery system was proposed, based on hyperbranched polymer showing good solubility, high biocompatibility and low immunogenicity. A multifunctional nanocarrier was prepared by attaching αM to the surface amine groups of dendrimer via amide bond in the ratio 5 (G32B12gh5M) or 17 (G32B10gh17M) residues per one dendrimer molecule. Twelve or ten remaining amine groups were modified by conjugation with D-glucoheptono-1,4-lactone (gh) to block the amine groups, and two biotin (B) residues as targeting moieties. The biological activity of the obtained conjugates was studied in vitro on glioma U-118 MG and squamous cell carcinoma SCC-15 cancer cells compared to normal fibroblasts (BJ), and in vivo on a model organism Caenorhabditis elegans. Dendrimer vehicle G32B12gh at concentrations up to 20 µM showed no anti-proliferative effect against tested cell lines, with a feeble cytotoxicity of the highest concentration seen only with SCC-15 cells. The attachment of αM to the vehicle significantly increased cytotoxic effect of the drug, even by 4- and 25-fold for G32B12gh5M and G32B10gh17M, respectively. A stronger inhibition of cells viability and influence on other metabolic parameters (proliferation, adhesion, ATP level and Caspase-3/7 activity) was observed for G32B10gh17M than for G32B12gh5M. Both bioconjugates were internalized efficiently into the cells. Similarly, the attachment of αM to the dendrimer vehicle increased its toxicity for C. elegans. Thus, the proposed α-mangostin delivery system allowed the drug to be more effective in the dendrimer-bound as compared to free state against both cultured the cancer cells and model organism, suggesting that this treatment is promising for anticancer as well as anti-nematode chemotherapy. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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26 pages, 2735 KiB  
Article
Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs
by Heba E. Elnakib, Marian M. Ramsis, Nouran O. Albably, Merna A. Vector, Jan J. Weigand, Kai Schwedtmann, Jannette Wober, Oliver Zierau, Günter Vollmer, Ashraf H. Abadi and Nermin S. Ahmed
Int. J. Mol. Sci. 2021, 22(22), 12575; https://doi.org/10.3390/ijms222212575 - 22 Nov 2021
Cited by 3 | Viewed by 2159
Abstract
Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ERα) agonists or antagonists depending on the target issue. Tamoxifen (TAM) (a non-steroidal triphenylethylene derivative) was the first SERM approved as anti-estrogen for the treatment of metastatic breast cancer. On the hunt for novel [...] Read more.
Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ERα) agonists or antagonists depending on the target issue. Tamoxifen (TAM) (a non-steroidal triphenylethylene derivative) was the first SERM approved as anti-estrogen for the treatment of metastatic breast cancer. On the hunt for novel SERMs with potential growth inhibitory activity on breast cancer cell lines yet no potential to induce endometrial carcinoma, we designed and synthesized 28 novel TAM analogs. The novel analogs bear a triphenylethylene scaffold. Modifications on rings A, B, and C aim to attenuate estrogenic/anti-estrogenic activities of the novel compounds so they can potentially inhibit breast cancer and provide positive, beneficial estrogenic effects on other tissues with no risk of developing endometrial hyperplasia. Compound 12 (E/Z-1-(2-{4-[1-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-propenyl]-phenoxy}-ethyl)-piperidine) showed an appreciable relative ERα agonistic activity in a yeast estrogen screen (YES) assay. It successfully inhibited the growth of the MCF-7 cell line with GI50 = 0.6 µM, and it was approximately three times more potent than TAM. It showed no potential estrogenicity on Ishikawa endometrial adenocarcinoma cell line via assaying alkaline phosphatase (AlkP) activity. Compound 12 was tested in vivo to assess its estrogenic properties in an uterotrophic assay in an ovariectomized rat model. Compared to TAM, it induced less increase in wet uterine wet weight and showed no uterotrophic effect. Compound 12 is a promising candidate for further development due to its inhibition activity on MCF-7 proliferation with moderate AlkP activity and no potential uterotrophic effects. The in vitro estrogenic activity encourages further investigations toward potential beneficial properties in cardiovascular, bone, and brain tissues. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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16 pages, 7566 KiB  
Article
Molecular Iodine/Cyclophosphamide Synergism on Chemoresistant Neuroblastoma Models
by Winniberg Álvarez-León, Irasema Mendieta, Evangelina Delgado-González, Brenda Anguiano and Carmen Aceves
Int. J. Mol. Sci. 2021, 22(16), 8936; https://doi.org/10.3390/ijms22168936 - 19 Aug 2021
Cited by 7 | Viewed by 2034
Abstract
Neuroblastoma (Nb), the most common extracranial tumor in children, exhibited remarkable phenotypic diversity and heterogeneous clinical behavior. Tumors with MYCN overexpression have a worse prognosis. MYCN promotes tumor progression by inducing cell proliferation, de-differentiation, and dysregulated mitochondrial metabolism. Cyclophosphamide (CFF) at minimum effective [...] Read more.
Neuroblastoma (Nb), the most common extracranial tumor in children, exhibited remarkable phenotypic diversity and heterogeneous clinical behavior. Tumors with MYCN overexpression have a worse prognosis. MYCN promotes tumor progression by inducing cell proliferation, de-differentiation, and dysregulated mitochondrial metabolism. Cyclophosphamide (CFF) at minimum effective oral doses (metronomic therapy) exerts beneficial actions on chemoresistant cancers. Molecular iodine (I2) in coadministration with all-trans retinoic acid synergizes apoptosis and cell differentiation in Nb cells. This work analyzes the impact of I2 and CFF on the viability (culture) and tumor progression (xenografts) of Nb chemoresistant SK-N-BE(2) cells. Results showed that both molecules induce dose-response antiproliferative effects, and I2 increases the sensibility of Nb cells to CFF, triggering PPARγ expression and acting as a mitocan in mitochondrial metabolism. In vivo oral I2/metronomic CFF treatments showed significant inhibition in xenograft growth, decreasing proliferation (Survivin) and activating apoptosis signaling (P53, Bax/Bcl-2). In addition, I2 decreased the expression of master markers of malignancy (MYCN, TrkB), vasculature remodeling, and increased differentiation signaling (PPARγ and TrkA). Furthermore, I2 supplementation prevented loss of body weight and hemorrhagic cystitis secondary to CFF in nude mice. These results allow us to propose the I2 supplement in metronomic CFF treatments to increase the effectiveness of chemotherapy and reduce side effects. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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16 pages, 1990 KiB  
Article
Platelet Microparticles Decrease Daunorubicin-Induced DNA Damage and Modulate Intrinsic Apoptosis in THP-1 Cells
by Daniel Cacic, Oddmund Nordgård, Peter Meyer and Tor Hervig
Int. J. Mol. Sci. 2021, 22(14), 7264; https://doi.org/10.3390/ijms22147264 - 6 Jul 2021
Cited by 3 | Viewed by 2474
Abstract
Platelets can modulate cancer through budding of platelet microparticles (PMPs) that can transfer a plethora of bioactive molecules to cancer cells upon internalization. In acute myelogenous leukemia (AML) this can induce chemoresistance, partially through a decrease in cell activity. Here we investigated if [...] Read more.
Platelets can modulate cancer through budding of platelet microparticles (PMPs) that can transfer a plethora of bioactive molecules to cancer cells upon internalization. In acute myelogenous leukemia (AML) this can induce chemoresistance, partially through a decrease in cell activity. Here we investigated if the internalization of PMPs protected the monocytic AML cell line, THP-1, from apoptosis by decreasing the initial cellular damage inflicted by treatment with daunorubicin, or via direct modulation of the apoptotic response. We examined whether PMPs could protect against apoptosis after treatment with a selection of inducers, primarily associated with either the intrinsic or the extrinsic apoptotic pathway, and protection was restricted to the agents targeting intrinsic apoptosis. Furthermore, levels of daunorubicin-induced DNA damage, assessed by measuring gH2AX, were reduced in both 2N and 4N cells after PMP co-incubation. Measuring different BCL2-family proteins before and after treatment with daunorubicin revealed that PMPs downregulated the pro-apoptotic PUMA protein. Thus, our findings indicated that PMPs may protect AML cells against apoptosis by reducing DNA damage both dependent and independent of cell cycle phase, and via direct modulation of the intrinsic apoptotic pathway by downregulating PUMA. These findings further support the clinical relevance of platelets and PMPs in AML. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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11 pages, 3062 KiB  
Article
Cytotoxic Activity against A549 Human Lung Cancer Cells and ADMET Analysis of New Pyrazole Derivatives
by Agnieszka Czylkowska, Małgorzata Szczesio, Anita Raducka, Bartłomiej Rogalewicz, Paweł Kręcisz, Kamila Czarnecka, Paweł Szymański, Monika Pitucha and Tomasz Pawlak
Int. J. Mol. Sci. 2021, 22(13), 6692; https://doi.org/10.3390/ijms22136692 - 22 Jun 2021
Cited by 5 | Viewed by 2826
Abstract
Two new pyrazole derivatives, namely compound 1 and compound 2, have been synthesized, and their biological activity has been evaluated. Monocrystals of the obtained compounds were thoroughly investigated using single-crystal X-ray diffraction analysis, FTIR spectroscopy, and NMR spectroscopy. The results gathered from all [...] Read more.
Two new pyrazole derivatives, namely compound 1 and compound 2, have been synthesized, and their biological activity has been evaluated. Monocrystals of the obtained compounds were thoroughly investigated using single-crystal X-ray diffraction analysis, FTIR spectroscopy, and NMR spectroscopy. The results gathered from all three techniques are in good agreement, provide complete information about the structures of 1 and 2, and confirm their high purity. Thermal properties were studied using thermogravimetric analysis; both 1 and 2 are stable at room temperature. In order to better characterize 1 and 2, some physicochemical and biological properties have been evaluated using ADMET analysis. The cytotoxic activity of both compounds was determined using the MTT assay on the A549 cell line in comparison with etoposide. It was determined that compound 2 was effective in the inhibition of human lung adenocarcinoma cell growth and may be a promising compound for the treatment of lung cancer. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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23 pages, 2733 KiB  
Article
New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells
by Marcin Cieślak, Mariola Napiórkowska, Julia Kaźmierczak-Barańska, Karolina Królewska-Golińska, Anna Hawrył, Iwona Wybrańska and Barbara Nawrot
Int. J. Mol. Sci. 2021, 22(9), 4318; https://doi.org/10.3390/ijms22094318 - 21 Apr 2021
Cited by 9 | Viewed by 1899
Abstract
Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side [...] Read more.
Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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17 pages, 5168 KiB  
Article
Biotin-Containing Third Generation Glucoheptoamidated Polyamidoamine Dendrimer for 5-Aminolevulinic Acid Delivery System
by Aleksandra Kaczorowska, Małgorzata Malinga-Drozd, Wojciech Kałas, Marta Kopaczyńska, Stanisław Wołowiec and Katarzyna Borowska
Int. J. Mol. Sci. 2021, 22(4), 1982; https://doi.org/10.3390/ijms22041982 - 17 Feb 2021
Cited by 8 | Viewed by 2338
Abstract
Polyamidoamine PAMAM dendrimer generation 3 (G3) was modified by attachment of biotin via amide bond and glucoheptoamidated by addition of α-D-glucoheptono-1,4-lacton to obtain a series of conjugates with a variable number of biotin residues. The composition of conjugates was determined by detailed 1-D [...] Read more.
Polyamidoamine PAMAM dendrimer generation 3 (G3) was modified by attachment of biotin via amide bond and glucoheptoamidated by addition of α-D-glucoheptono-1,4-lacton to obtain a series of conjugates with a variable number of biotin residues. The composition of conjugates was determined by detailed 1-D and 2-D NMR spectroscopy to reveal the number of biotin residues, which were 1, 2, 4, 6, or 8, while the number of glucoheptoamide residues substituted most of the remaining primary amine groups of PAMAM G3. The conjugates were then used as host molecules to encapsulate the 5-aminolevulinic acid. The solubility of 5-aminolevulinic acid increased twice in the presence of the 5-mM guest in water. The interaction between host and guest was accompanied by deprotonation of the carboxylic group of 5-aminolevulinic acid and proton transfer into internal ternary nitrogen atoms of the guest as evidenced by a characteristic chemical shift of resonances in the 1H NMR spectrum of associates. The guest molecules were most likely encapsulated inside inner shell voids of the host. The number of guest molecules depended on the number of biotin residues of the host, which was 15 for non-biotin-containing glucoheptoamidated G3 down to 6 for glucoheptoamidated G3 with 8 biotin residues on the host surface. The encapsulates were not cytotoxic against Caco-2 cells up to 200-µM concentration in the dark. All encapsulates were able to deliver 5-aminolevulinic acid to cells but aqueous encapsulates were more active in this regard. Simultaneously, the reactive oxygen species were detected by staining with H2DCFDA in Caco-2 cells incubated with encapsulates. The amount of PpIX was sufficient for induction of reactive oxygen species upon 30-s illumination with a 655-nm laser beam. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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11 pages, 1504 KiB  
Article
Cell-Penetrating Doxorubicin Released from Elastin-Like Polypeptide Kills Doxorubicin-Resistant Cancer Cells in In Vitro Study
by Jung Su Ryu, Felix Kratz and Drazen Raucher
Int. J. Mol. Sci. 2021, 22(3), 1126; https://doi.org/10.3390/ijms22031126 - 23 Jan 2021
Cited by 9 | Viewed by 2416
Abstract
Elastin-like polypeptides (ELPs) undergo a characteristic phase transition in response to ambient temperature. Therefore, it has been be used as a thermosensitive vector for the delivery of chemotherapy agents since it can be used to target hyperthermic tumors. This novel strategy introduces unprecedented [...] Read more.
Elastin-like polypeptides (ELPs) undergo a characteristic phase transition in response to ambient temperature. Therefore, it has been be used as a thermosensitive vector for the delivery of chemotherapy agents since it can be used to target hyperthermic tumors. This novel strategy introduces unprecedented options for treating cancer with fewer concerns about side effects. In this study, the ELP system was further modified with an enzyme-cleavable linker in order to release drugs within tumors. This system consists of an ELP, a matrix metalloproteinase (MMP) substrate, a cell-penetrating peptide (CPP), and a 6-maleimidocaproyl amide derivative of doxorubicin (Dox). This strategy shows up to a 4-fold increase in cell penetration and results in more death in breast cancer cells compared to ELP-Dox. Even in doxorubicin-resistant cells (NCI/ADR and MES-SA/Dx5), ELP-released cell-penetrating doxorubicin demonstrated better membrane penetration, leading to at least twice the killing of resistant cells compared to ELP-Dox and free Dox. MMP-digested CPP-Dox showed better membrane penetration and induced more cancer cell death in vitro. This CPP-complexed Dox released from the ELP killed even Dox-resistant cells more efficiently than both free doxorubicin and non-cleaved ELP-CPP-Dox. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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17 pages, 2630 KiB  
Article
Transferrin-Bound Doxorubicin Enhances Apoptosis and DNA Damage through the Generation of Pro-Inflammatory Responses in Human Leukemia Cells
by Monika Jedrzejczyk, Katarzyna Wisniewska, Katarzyna Dominika Kania, Agnieszka Marczak and Marzena Szwed
Int. J. Mol. Sci. 2020, 21(24), 9390; https://doi.org/10.3390/ijms21249390 - 10 Dec 2020
Cited by 6 | Viewed by 2738
Abstract
Doxorubicin (DOX) is an effective antineoplastic drug against many solid tumors and hematological malignancies. However, the clinical use of DOX is limited, because of its unspecific mode of action. Since leukemia cells overexpress transferrin (Tf) receptors on their surface, we proposed doxorubicin–transferrin (DOX–Tf) [...] Read more.
Doxorubicin (DOX) is an effective antineoplastic drug against many solid tumors and hematological malignancies. However, the clinical use of DOX is limited, because of its unspecific mode of action. Since leukemia cells overexpress transferrin (Tf) receptors on their surface, we proposed doxorubicin–transferrin (DOX–Tf) conjugate as a new vehicle to increase drug concentration directly in cancer cells. The data obtained after experiments performed on K562 and CCRF-CEM human leukemia cell lines clearly indicate severe cytotoxic and genotoxic properties of the conjugate drug. On the other hand, normal peripheral blood mononuclear cells (PBMCs) were more resistant to DOX–Tf than to DOX. In comparison to free drug, we observed that Tf-bound DOX induced apoptosis in a TRAIL-dependent manner and caused DNA damage typical of programmed cell death. These fatal hallmarks of cell death were confirmed upon morphological observation of cells incubated with DOX or DOX–Tf. Studies of expression of TNF-α, IL-4, and IL-6 at the mRNA and protein levels revealed that the pro-inflammatory response plays an important role in the toxicity of the conjugate. Altogether, the results demonstrated here describe a mechanism of the antitumor activity of the DOX–Tf conjugate. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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16 pages, 27872 KiB  
Article
Ligand-Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamic Studies of Dual Tyrosine Kinase Inhibitor of EGFR and VEGFR2
by Frangky Sangande, Elin Julianti and Daryono Hadi Tjahjono
Int. J. Mol. Sci. 2020, 21(20), 7779; https://doi.org/10.3390/ijms21207779 - 21 Oct 2020
Cited by 30 | Viewed by 5400
Abstract
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) play an important role in cancer growth. Both of them have close relationships. Expression of EGFR will induce an angiogenic factor (VEGF) release for binding with VEGFR2. However, the existence [...] Read more.
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) play an important role in cancer growth. Both of them have close relationships. Expression of EGFR will induce an angiogenic factor (VEGF) release for binding with VEGFR2. However, the existence of VEGF up-regulation independent of EGFR leads to cancer cell resistance to anti-EGFR. Therefore, a therapeutic approach targeting EGFR and VEGFR2 simultaneously may improve the outcome of cancer treatment. The present study was designed to identify potential compounds as a dual inhibitor of EGFR and VEGFR2 by the computational method. Firstly, the ligand-based pharmacophore model for each target was setup to screen of ZINC database of purchasable compounds. The hit compounds obtained by pharmacophore screening were then further screened by molecular docking studies. Taking erlotinib (EGFR inhibitor) and axitinib (VEGFR2 inhibitor) as reference drugs, six potential compounds (ZINC08398597, ZINC12047553, ZINC16525481, ZINC17418102, ZINC21942954, and ZINC38484632) were selected based on their docking scores and binding interaction. However, molecular dynamics simulations demonstrated that only ZINC16525481 and ZINC38484632 which have good binding free energy and stable hydrogen bonding interactions with EGFR and VEGFR2. The result represents a promising starting point for developing potent dual tyrosine kinases inhibitor of EGFR and VEGFR2. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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14 pages, 3220 KiB  
Article
Hydroxy-Propil-β-Cyclodextrin Inclusion Complexes of two Biphenylnicotinamide Derivatives: Formulation and Anti-Proliferative Activity Evaluation in Pancreatic Cancer Cell Models
by Rosa Maria Iacobazzi, Annalisa Cutrignelli, Angela Stefanachi, Letizia Porcelli, Angela Assunta Lopedota, Roberta Di Fonte, Antonio Lopalco, Simona Serratì, Valentino Laquintana, Nicola Silvestris, Massimo Franco, Saverio Cellamare, Francesco Leonetti, Amalia Azzariti and Nunzio Denora
Int. J. Mol. Sci. 2020, 21(18), 6545; https://doi.org/10.3390/ijms21186545 - 7 Sep 2020
Cited by 4 | Viewed by 2828
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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15 pages, 5452 KiB  
Article
A Novel Synthetic Compound (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile Inhibits TNFα-Induced MMP9 Expression via EGR-1 Downregulation in MDA-MB-231 Human Breast Cancer Cells
by Munki Jeong, Euitaek Jung, Young Han Lee, Jeong Kon Seo, Seunghyun Ahn, Dongsoo Koh, Yoongho Lim and Soon Young Shin
Int. J. Mol. Sci. 2020, 21(14), 5080; https://doi.org/10.3390/ijms21145080 - 18 Jul 2020
Cited by 5 | Viewed by 2236
Abstract
Breast cancer is a common malignancy among women worldwide. Gelatinases such as matrix metallopeptidase 2 (MMP2) and MMP9 play crucial roles in cancer cell migration, invasion, and metastasis. To develop a novel platform compound, we synthesized a flavonoid derivative, (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile (named DK4023) and [...] Read more.
Breast cancer is a common malignancy among women worldwide. Gelatinases such as matrix metallopeptidase 2 (MMP2) and MMP9 play crucial roles in cancer cell migration, invasion, and metastasis. To develop a novel platform compound, we synthesized a flavonoid derivative, (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile (named DK4023) and characterized its inhibitory effects on the motility and MMP2 and MMP9 expression of highly metastatic MDA-MB-231 breast cancer cells. We found that DK4023 inhibited tumor necrosis factor alpha (TNFα)-induced motility and F-actin formation of MDA-MB-231 cells. DK4023 also suppressed the TNFα-induced mRNA expression of MMP9 through the downregulation of the TNFα-extracellular signal-regulated kinase (ERK)/early growth response 1 (EGR-1) signaling axis. These results suggest that DK4023 could serve as a potential platform compound for the development of novel chemopreventive/chemotherapeutic agents against invasive breast cancer. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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Review

Jump to: Research

13 pages, 708 KiB  
Review
Delivering Therapeutics to Glioblastoma: Overcoming Biological Constraints
by Elza N. Mathew, Bethany C. Berry, Hong Wei Yang, Rona S. Carroll and Mark D. Johnson
Int. J. Mol. Sci. 2022, 23(3), 1711; https://doi.org/10.3390/ijms23031711 - 2 Feb 2022
Cited by 32 | Viewed by 4088
Abstract
Glioblastoma multiforme is the most lethal intrinsic brain tumor. Even with the existing treatment regimen of surgery, radiation, and chemotherapy, the median survival time is only 15–23 months. The invasive nature of this tumor makes its complete removal very difficult, leading to a [...] Read more.
Glioblastoma multiforme is the most lethal intrinsic brain tumor. Even with the existing treatment regimen of surgery, radiation, and chemotherapy, the median survival time is only 15–23 months. The invasive nature of this tumor makes its complete removal very difficult, leading to a high recurrence rate of over 90%. Drug delivery to glioblastoma is challenging because of the molecular and cellular heterogeneity of the tumor, its infiltrative nature, and the blood–brain barrier. Understanding the critical characteristics that restrict drug delivery to the tumor is necessary to develop platforms for the enhanced delivery of effective treatments. In this review, we address the impact of tumor invasion, the molecular and cellular heterogeneity of the tumor, and the blood–brain barrier on the delivery and distribution of drugs using potential therapeutic delivery options such as convection-enhanced delivery, controlled release systems, nanomaterial systems, peptide-based systems, and focused ultrasound. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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18 pages, 2194 KiB  
Review
Strategies to Improve the Antitumor Effect of γδ T Cell Immunotherapy for Clinical Application
by Masatsugu Miyashita, Teruki Shimizu, Eishi Ashihara and Osamu Ukimura
Int. J. Mol. Sci. 2021, 22(16), 8910; https://doi.org/10.3390/ijms22168910 - 18 Aug 2021
Cited by 20 | Viewed by 4379
Abstract
Human γδ T cells show potent cytotoxicity against various types of cancer cells in a major histocompatibility complex unrestricted manner. Phosphoantigens and nitrogen-containing bisphosphonates (N-bis) stimulate γδ T cells via interaction between the γδ T cell receptor (TCR) and butyrophilin subfamily 3 member [...] Read more.
Human γδ T cells show potent cytotoxicity against various types of cancer cells in a major histocompatibility complex unrestricted manner. Phosphoantigens and nitrogen-containing bisphosphonates (N-bis) stimulate γδ T cells via interaction between the γδ T cell receptor (TCR) and butyrophilin subfamily 3 member A1 (BTN3A1) expressed on target cells. γδ T cell immunotherapy is classified as either in vivo or ex vivo according to the method of activation. Immunotherapy with activated γδ T cells is well tolerated; however, the clinical benefits are unsatisfactory. Therefore, the antitumor effects need to be increased. Administration of γδ T cells into local cavities might improve antitumor effects by increasing the effector-to-target cell ratio. Some anticancer and molecularly targeted agents increase the cytotoxicity of γδ T cells via mechanisms involving natural killer group 2 member D (NKG2D)-mediated recognition of target cells. Both the tumor microenvironment and cancer stem cells exert immunosuppressive effects via mechanisms that include inhibitory immune checkpoint molecules. Therefore, co-immunotherapy with γδ T cells plus immune checkpoint inhibitors is a strategy that may improve cytotoxicity. The use of a bispecific antibody and chimeric antigen receptor might be effective to overcome current therapeutic limitations. Such strategies should be tested in a clinical research setting. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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14 pages, 1068 KiB  
Review
Profiling Colorectal Cancer in the Landscape Personalized Testing—Advantages of Liquid Biopsy
by Donatella Verbanac, Andrea Čeri, Iva Hlapčić, Mehdi Shakibaei, Aranka Brockmueller, Božo Krušlin, Neven Ljubičić, Neven Baršić, Dijana Detel, Lara Batičić, Lada Rumora, Anita Somborac-Bačura, Mario Štefanović, Ivana Ćelap, Alma Demirović, Roberta Petlevski, József Petrik, Marija Grdić Rajković, Andrea Hulina-Tomašković, Ivana Rako, Luciano Saso and Karmela Barišićadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(9), 4327; https://doi.org/10.3390/ijms22094327 - 21 Apr 2021
Cited by 4 | Viewed by 3475
Abstract
Drug-specific therapeutic approaches for colorectal cancer (CRC) have contributed to significant improvements in patient health. Nevertheless, there is still a great need to improve the personalization of treatments based on genetic and epigenetic tumor profiles to maximize the quality and efficacy while limiting [...] Read more.
Drug-specific therapeutic approaches for colorectal cancer (CRC) have contributed to significant improvements in patient health. Nevertheless, there is still a great need to improve the personalization of treatments based on genetic and epigenetic tumor profiles to maximize the quality and efficacy while limiting cytotoxicity. Currently, CEA and CA 19-9 are the only validated blood biomarkers in clinical practice. For this reason, laboratories are trying to identify new specific prognostics and, more importantly, predictive biomarkers for CRC patient profiling. Thus, the unique landscape of personalized biomarker data should have a clinical impact on CRC treatment strategies and molecular genetic screening tests should become the standard method for diagnosing CRC. This review concentrates on recent molecular testing in CRC and discusses the potential modifications in CRC assay methodology with the upcoming clinical application of novel genomic approaches. While mechanisms for analyzing circulating tumor DNA have been proven too inaccurate, detecting and analyzing circulating tumor cells and protein analysis of exosomes represent more promising options. Blood liquid biopsy offers good prospects for the future if the results align with pathologists’ tissue analyses. Overall, early detection, accurate diagnosis and treatment monitoring for CRC with specific markers and targeted molecular testing may benefit many patients. Full article
(This article belongs to the Special Issue Strategies to Improve Antineoplastic Activity of Drugs in Cancer Progression)
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