International Journal of Molecular Sciences

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20 pages, 5950 KiB

Open AccessArticle

The Synergistic Combination of Curcumin and Polydatin Improves Temozolomide Efficacy on Glioblastoma Cells

by Annalucia Serafino, Ewa Krystyna Krasnowska, Sabrina Romanò, Alex De Gregorio, Marisa Colone, Maria Luisa Dupuis, Massimo Bonucci, Giampietro Ravagnan, Annarita Stringaro and Maria Pia Fuggetta

Int. J. Mol. Sci. 2024, 25(19), 10572; https://doi.org/10.3390/ijms251910572 - 30 Sep 2024

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Abstract

Glioblastoma (GBL) is one of the more malignant primary brain tumors; it is currently treated by a multimodality strategy including surgery, and radio- and chemotherapy, mainly consisting of temozolomide (TMZ)-based chemotherapy. Tumor relapse often occurs due to the establishment of TMZ resistance, with [...] Read more.

Glioblastoma (GBL) is one of the more malignant primary brain tumors; it is currently treated by a multimodality strategy including surgery, and radio- and chemotherapy, mainly consisting of temozolomide (TMZ)-based chemotherapy. Tumor relapse often occurs due to the establishment of TMZ resistance, with a patient median survival time of <2 years. The identification of natural molecules with strong anti-tumor activity led to the combination of these compounds with conventional chemotherapeutic agents, developing protocols for integrated anticancer therapies. Curcumin (CUR), resveratrol (RES), and its glucoside polydatin (PLD) are widely employed in the pharmaceutical and nutraceutical fields, and several studies have demonstrated that the combination of these natural products was more cytotoxic than the individual compounds alone against different cancers. Some of us recently demonstrated the synergistic efficacy of the sublingual administration of a new nutraceutical formulation of CUR+PLD in reducing tumor size and improving GBL patient survival. To provide some experimental evidence to reinforce these clinical results, we investigated if pretreatment with a combination of CUR+PLD can improve TMZ cytotoxicity on GBL cells by analyzing the effects on cell cycle, viability, morphology, expression of proteins related to cell proliferation, differentiation, apoptosis or autophagy, and the actin network. Cell viability was assessed using the MTT assay or a CytoSmart cell counter. CalcuSyn software was used to study the CUR+PLD synergism. The morphology was evaluated by optical and scanning electron microscopy, and protein expression was analyzed by Western blot. Flow cytometry was used for the cell cycle, autophagic flux, and apoptosis analyses. The results provide evidence that CUR and PLD, acting in synergy with each other, strongly improve the efficacy of alkylating anti-tumor agents such as TMZ on drug-resistant GBL cells through their ability to affect survival, differentiation, and tumor invasiveness. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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20 pages, 14556 KiB

Open AccessArticle

The Antidepressant Drug Amitriptyline Affects Human SH-SY5Y Neuroblastoma Cell Proliferation and Modulates Autophagy

by Annagrazia Adornetto, Maria Luisa Laganà, Andrea Satriano, Ester Licastro, Maria Tiziana Corasaniti, Giacinto Bagetta and Rossella Russo

Int. J. Mol. Sci. 2024, 25(19), 10415; https://doi.org/10.3390/ijms251910415 - 27 Sep 2024

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Abstract

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and is prescribed off-label for several neurological conditions like neuropathic pain, migraines and anxiety. Besides their action on the reuptake of monoaminergic neurotransmitters, tricyclic antidepressants interact with several additional targets that may contribute [...] Read more.

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and is prescribed off-label for several neurological conditions like neuropathic pain, migraines and anxiety. Besides their action on the reuptake of monoaminergic neurotransmitters, tricyclic antidepressants interact with several additional targets that may contribute to either therapeutic or adverse effects. Here, we investigated the effects of amitriptyline on proliferation and autophagy (i.e., an evolutionarily conserved catabolic pathway responsible for the degradation and recycling of cytoplasmic material) in human SH-SY5Y neuroblastoma cell cultures. The dose and time-dependent upregulation of the autophagy marker LC3II and the autophagy receptor p62, with the accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to the amitriptyline. These effects were accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5^−/− MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine, suggesting that they were independent from autophagy modulation. Our findings demonstrate that amitriptyline acts on pathways crucial for cell and tissue homeostasis (i.e., autophagy and proliferation) and pose the basis for further studies on the potential therapeutic application of amitriptyline, as well as the consequences of its use for long-term treatments. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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15 pages, 9264 KiB

Open AccessArticle

Gene Expression Reprogramming by Citrate Supplementation Reduces HepG2 Cell Migration and Invasion

by Rocchina Miglionico, Ilenia Matera, Giovanna Maria Ventola, Giovanna Marchese, Vittorio Abruzzese, Magnus Monné, Angela Ostuni and Faustino Bisaccia

Int. J. Mol. Sci. 2024, 25(12), 6509; https://doi.org/10.3390/ijms25126509 - 13 Jun 2024

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Abstract

Citrate, which is obtained from oxaloacetate and acetyl-CoA by citrate synthase in mitochondria, plays a key role in both normal and cancer cell metabolism. In this work, we investigated the effect of 10 mM extracellular citrate supplementation on HepG2 cells. Gene expression reprogramming [...] Read more.

Citrate, which is obtained from oxaloacetate and acetyl-CoA by citrate synthase in mitochondria, plays a key role in both normal and cancer cell metabolism. In this work, we investigated the effect of 10 mM extracellular citrate supplementation on HepG2 cells. Gene expression reprogramming was evaluated by whole transcriptome analysis using gene set enrichment analysis (GSEA). The transcriptomic data were validated through analyzing changes in the mRNA levels of selected genes by qRT-PCR. Citrate-treated cells exhibited the statistically significant dysregulation of 3551 genes; 851 genes were upregulated and 822 genes were downregulated. GSEA identified 40 pathways affected by differentially expressed mRNAs. The most affected biological processes were related to lipid and RNA metabolism. Several genes of the cytochrome P450 family were upregulated in treated cells compared to controls, including the CYP3A5 gene, a tumor suppressor in hepatocellular carcinoma (HCC) that plays an important protective role in HCC metastasis. The citrate-induced dysregulation of cytochromes could both improve the effectiveness of chemotherapeutics used in combination and reduce the aggressiveness of tumors by diminishing cell migration and invasion. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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14 pages, 4700 KiB

Open AccessArticle

Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia

by Fabienne R. S. Adriaanse, Pauline Schneider, Susan T. C. J. M. Arentsen-Peters, Ana M. Neves da Fonseca, Janine Stutterheim, Rob Pieters, C. Michel Zwaan and Ronald W. Stam

Int. J. Mol. Sci. 2024, 25(11), 6020; https://doi.org/10.3390/ijms25116020 - 30 May 2024

Cited by 2 | Viewed by 1314

Abstract

Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying KMT2A gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have [...] Read more.

Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying KMT2A gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have garnered attention for their potential therapeutic efficacy in treating KMT2A-rearranged acute leukemias. However, resistance to menin inhibition poses challenges, and identifying which patients would benefit from revumenib treatment is crucial. Here, we investigated the in vitro response to revumenib in KMT2A-rearranged ALL and AML. While ALL samples show rapid, dose-dependent induction of leukemic cell death, AML responses are much slower and promote myeloid differentiation. Furthermore, we reveal that acquired resistance to revumenib in KMT2A-rearranged ALL cells can occur either through the acquisition of MEN1 mutations or independently of mutations in MEN1. Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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19 pages, 5953 KiB

Open AccessArticle

(2,6-Dimethylphenyl)arsonic Acid Induces Apoptosis through the Mitochondrial Pathway, Downregulates XIAP, and Overcomes Multidrug Resistance to Cytostatic Drugs in Leukemia and Lymphoma Cells In Vitro

by Nathalie Wilke, Corazon Frias, Albrecht Berkessel and Aram Prokop

Int. J. Mol. Sci. 2024, 25(9), 4713; https://doi.org/10.3390/ijms25094713 - 26 Apr 2024

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Abstract

Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation [...] Read more.

Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of Bcl-2 (B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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21 pages, 4869 KiB

Open AccessArticle

Zeolitic Imidazole Framework/Silica Nanocomposite for Targeted Cancer Therapeutics: Comparative Study of Chemo-Drug Cisplatin (CPt) and Green Platinum (GPt) Efficacy

by Hend Ghnaim Alotaibi, Eman Al-Abbad, Dana Almohazey, Vijaya Ravinayagam, Sultan Akhtar, Hatim Dafalla and B. Rabindran Jermy

Int. J. Mol. Sci. 2024, 25(6), 3157; https://doi.org/10.3390/ijms25063157 - 9 Mar 2024

Cited by 3 | Viewed by 1754

Abstract

A chemo-drug such as cisplatin is effective for cancer treatment but remains non-specific, is susceptible to drug resistance, and induces several side effects on organ systems. Zeolitic imidazolate framework-8, a type of MOF, has gained attention, including as a drug delivery method for [...] Read more.

A chemo-drug such as cisplatin is effective for cancer treatment but remains non-specific, is susceptible to drug resistance, and induces several side effects on organ systems. Zeolitic imidazolate framework-8, a type of MOF, has gained attention, including as a drug delivery method for targeted cancer therapeutics. In this study, ZIF-8/Silica nanocomposite was synthesized using a one-pot hydrothermal technique using the Stober technique. We studied the effect of phyto-synthesized GPt and chemo-drug cisplatin CPt on ZIF-8/Silica for targeted efficacy of cancer therapy. The texture, morphology, and chemical environment of Pt on ZIF-8/Silica were analyzed using different characterization techniques such as XRD, FT-IR, BET, diffuse reflectance spectroscopy, SEM-EDX, TEM, zeta potential, and TGA analysis. The isothermal behavior of CPt and GPt adsorption was investigated using isotherm models like Langmuir, Freundlich, and Temkin isotherm. The adsorption kinetics indicating the adsorption efficiency of GPt and CPt are influenced by the concentration of Pt complex and the adsorption sites of ZIF-8/Silica. A high entrapment efficiency and loading capacity of GPt (86% and 4.3%) and CPt (91% and 4.5%) were evident on ZIF-8/Silica. The nanocomposite showed a pH-sensitive Pt release using a dialysis membrane technique. For instance, a high release of GPt (93%) was observed under pH = 6.6 in 72 h, while the release reduced to 50% at pH 7.4 in 72 h. The anti-cancer activity of nanoformulations was studied in vitro using MCF7 (breast cancer cells) and HFF-1 (human foreskin fibroblast) cells. The findings demonstrated that GPt is as effective as CPt; the EC50 value for MCF7 cells treated with ZIF-8/Silica/Cp/PEG was 94.86 µg/mL, whereas for ZIF-8/Silica/GPt/PEG it was 60.19 µg/mL. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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20 pages, 2741 KiB

Open AccessArticle

Enhancement of the Antitumor and Antimetastatic Effect of Topotecan and Normalization of Blood Counts in Mice with Lewis Carcinoma by Tdp1 Inhibitors—New Usnic Acid Derivatives

by Tatyana E. Kornienko, Arina A. Chepanova, Alexandra L. Zakharenko, Aleksandr S. Filimonov, Olga A. Luzina, Nadezhda S. Dyrkheeva, Valeriy P. Nikolin, Nelly A. Popova, Nariman F. Salakhutdinov and Olga I. Lavrik

Int. J. Mol. Sci. 2024, 25(2), 1210; https://doi.org/10.3390/ijms25021210 - 19 Jan 2024

Cited by 2 | Viewed by 1268

Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we [...] Read more.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we synthesized usnic acid derivatives, which are hybrids of its known derivatives: tumor sensitizers to topotecan. New compounds inhibit Tdp1 in the micromolar and submicromolar concentration range; some of them enhance the effect of topotecan on the metabolic activity of cells of various lines according to the MTT test. One of the new compounds (compound 7) not only sensitizes Krebs-2 and Lewis carcinomas of mice to the action of topotecan, but also normalizes the state of the peripheral blood of mice, which is disturbed in the presence of a tumor. Thus, the synthesized substances may be the prototype of a new class of additional therapy for cancer. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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17 pages, 1961 KiB

Open AccessArticle

TR-57 Treatment of SUM159 Cells Induces Mitochondrial Dysfunction without Affecting Membrane Potential

by Artem Mishukov, Ekaterina Mndlyan, Alexey V. Berezhnov, Margarita Kobyakova, Yana Lomovskaya, Ekhson Holmuhamedov and Irina Odinokova

Int. J. Mol. Sci. 2024, 25(2), 1193; https://doi.org/10.3390/ijms25021193 - 18 Jan 2024

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Abstract

Recent works identified ClpXP, mitochondrial caseinolytic protease, as the only target of imipridones, a new class of antitumor agents. Our study of the mechanism of imipridone derivative TR-57 action in SUM159 human breast cancer cells demonstrated mitochondrial fragmentation, degradation of mitochondrial mtDNA and [...] Read more.

Recent works identified ClpXP, mitochondrial caseinolytic protease, as the only target of imipridones, a new class of antitumor agents. Our study of the mechanism of imipridone derivative TR-57 action in SUM159 human breast cancer cells demonstrated mitochondrial fragmentation, degradation of mitochondrial mtDNA and mitochondrial dysfunction due to inhibition of Complex I and Complex II activity. Complete inhibition of oxidative phosphorylation accompanied 90, 94, 88 and 87% decreases in the content of Complex I, II, III and IV proteins, respectively. The content of the F_OF₁-ATPase subunits decreased sharply by approximately 35% after 24 h and remained unchanged up to 72 h of incubation with TR-57. At the same time, a disappearance of the ATPIF1, the natural inhibitor of mitochondrial F_OF₁-ATPase, was observed after 24 h exposure to TR-57. ATPase inhibitor oligomycin did not affect the mitochondrial membrane potential in intact SUM159, whereas it caused a 65% decrease in TR-57-treated cells. SUM159 cells incubated with TR57 up to 72 h retained the level of proteins facilitating the ATP transfer across the mitochondrial membranes: VDAC1 expression was not affected, while expression of ANT-1/2 and APC2 increased by 20% and 40%, respectively. Thus, our results suggest that although TR-57 treatment leads to complete inhibition of respiratory chain activity of SUM159 cells, hydrolysis of cytoplasmic ATP by reversal activity of F_OF₁-ATPase supports mitochondrial polarization. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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27 pages, 7013 KiB

Open AccessArticle

2-Aminothiazole-Flavonoid Hybrid Derivatives Binding to Tau Protein and Responsible for Antitumor Activity in Glioblastoma

by Rayane Hedna, Attilio DiMaio, Maxime Robin, Diane Allegro, Mario Tatoni, Vincent Peyrot, Pascale Barbier, Hervé Kovacic and Gilles Breuzard

Int. J. Mol. Sci. 2023, 24(20), 15050; https://doi.org/10.3390/ijms242015050 - 10 Oct 2023

Cited by 2 | Viewed by 1659

Abstract

Tau protein has been described for several decades as a promoter of tubulin assembly into microtubules. Dysregulation or alterations in Tau expression have been related to various brain cancers, including the highly aggressive and lethal brain tumor glioblastoma multiform (GBM). In this respect, [...] Read more.

Tau protein has been described for several decades as a promoter of tubulin assembly into microtubules. Dysregulation or alterations in Tau expression have been related to various brain cancers, including the highly aggressive and lethal brain tumor glioblastoma multiform (GBM). In this respect, Tau holds significant promise as a target for the development of novel therapies. Here, we examined the structure–activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau binding, Tau fibrillation, and cellular effects on Tau-expressing cancer cells. By spectrofluorometric approach, we found that two compounds, 2 and 9, demonstrated high affinity for Tau and exhibited a strong propensity to inhibit Tau fibrillation. Then, the biological activity of these compounds was evaluated on several Tau-expressing cells derived from glioblastoma. The two lead compounds displayed a high anti-metabolic activity on cells related to an increased fission of the mitochondria network. Moreover, we showed that both compounds induced microtubule bundling within newly formed neurite-like protrusions, as well as with defection of cell migration. Taken together, our results provide a strong experimental basis to develop new potent molecules targeting Tau-expressing cancer cells, such as GBM. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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17 pages, 6972 KiB

Open AccessArticle

Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins

by Varvara Maksimova, Valeriia Popova, Anzhelika Prus, Evgeniya Lylova, Olga Usalka, Guzel Sagitova, Ekaterina Zhidkova, Julia Makus, Ekaterina Trapeznikova, Gennady Belitsky, Marianna Yakubovskaya and Kirill Kirsanov

Int. J. Mol. Sci. 2023, 24(16), 12874; https://doi.org/10.3390/ijms241612874 - 17 Aug 2023

Cited by 1 | Viewed by 1902

Abstract

The development of malignant tumors is caused by a complex combination of genetic mutations and epigenetic alterations, the latter of which are induced by either external environmental factors or signaling disruption following genetic mutations. Some types of cancer demonstrate a significant increase in [...] Read more.

The development of malignant tumors is caused by a complex combination of genetic mutations and epigenetic alterations, the latter of which are induced by either external environmental factors or signaling disruption following genetic mutations. Some types of cancer demonstrate a significant increase in epigenetic enzymes, and targeting these epigenetic alterations represents a compelling strategy to reverse cell transcriptome to the normal state, improving chemotherapy response. Curaxin CBL0137 is a new potent anticancer drug that has been shown to activate epigenetically silenced genes. However, its detailed effects on the enzymes of the epigenetic system of transcription regulation have not been studied. Here, we report that CBL0137 inhibits the expression of DNA methyltransferase DNMT3a in HeLa TI cells, both at the level of mRNA and protein, and it decreases the level of integral DNA methylation in Ca Ski cells. For the first time, it is shown that CBL0137 decreases the level of BET family proteins, BRD2, BRD3, and BRD4, the key participants in transcription elongation, followed by the corresponding gene expression enhancement. Furthermore, we demonstrate that CBL0137 does not affect the mechanisms of histone acetylation and methylation. The ability of CBL0137 to suppress DNMT3A and BET family proteins should be taken into consideration when combined chemotherapy is applied. Our data demonstrate the potential of CBL0137 to be used in the therapy of tumors with corresponding aberrant epigenetic profiles. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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13 pages, 1310 KiB

Open AccessArticle

Benzenesulfonamide Analogs: Synthesis, Anti-GBM Activity and Pharmacoprofiling

by Akshaya Murugesan, Saravanan Konda Mani, Ramesh Thiyagarajan, Suresh Palanivel, Atash V. Gurbanov, Fedor I. Zubkov and Meenakshisundaram Kandhavelu

Int. J. Mol. Sci. 2023, 24(15), 12276; https://doi.org/10.3390/ijms241512276 - 31 Jul 2023

Cited by 3 | Viewed by 1560

Abstract

The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives [...] Read more.

The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives were synthesized, and their inhibitory activities in TrkA overexpressing cells, U87 and MEF cells were investigated. The cytotoxic effect of benzenesulfonamide derivatives and cisplatin was determined using trypan blue exclusion assays. The mode of interaction of benzenesulfonamides with TrkA was predicted by docking and structural analysis. ADMET profiling was also performed for all compounds to calculate the drug likeness property. Appropriate QSAR models were developed for studying structure–activity relationships. Compound 4-[2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfon-amide (AL106) and 4-[2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (AL107) showed acceptable binding energies with the active sites for human nerve growth factor receptor, TrkA. Here, AL106 was identified as a potential anti-GBM compound, with an IC₅₀ value of 58.6 µM with a less toxic effect in non-cancerous cells than the known chemotherapeutic agent, cisplatin. In silico analysis indicated that AL106 formed prominent stabilizing hydrophobic interactions with Tyr359, Ser371, Ile374 and charged interactions with Gln369 of TrkA. Furthermore, in silico analysis of all benzenesulfonamide derivatives revealed that AL106 has good pharmacokinetics properties, drug likeness and toxicity profiles, suggesting the compound may be suitable for clinical trial. Thus, benzenesulfonamide analog, AL106 could potentially induce GBM cell death through its interaction with TrkA and might be an attractive strategy for developing a drug targeted therapy to treat glioblastoma. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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19 pages, 1823 KiB

Open AccessReview

Breast Cancer Treatment Strategies Targeting the Tumor Microenvironment: How to Convert “Cold” Tumors to “Hot” Tumors

by Liucui Yang, Qingyi Hu and Tao Huang

Int. J. Mol. Sci. 2024, 25(13), 7208; https://doi.org/10.3390/ijms25137208 - 29 Jun 2024

Cited by 1 | Viewed by 1826

Abstract

Breast cancer characterized as “cold tumors” exhibit low levels of immune cell infiltration, which limits the efficacy of conventional immunotherapy. Recent studies have focused on strategies using nanotechnology combined with tumor microenvironment modulation to transform “cold tumors” into “hot tumors”. This approach involves [...] Read more.

Breast cancer characterized as “cold tumors” exhibit low levels of immune cell infiltration, which limits the efficacy of conventional immunotherapy. Recent studies have focused on strategies using nanotechnology combined with tumor microenvironment modulation to transform “cold tumors” into “hot tumors”. This approach involves the use of functionalized nanoparticles that target and modify the tumor microenvironment to promote the infiltration and activation of antitumor immune cells. By delivering immune activators or blocking immunosuppressive signals, these nanoparticles activate otherwise dormant immune responses, enhancing tumor immunogenicity and the therapeutic response. These strategies not only promise to increase the response rate of breast cancer patients to existing immunotherapies but also may pave new therapeutic avenues, providing a new direction for the immunotherapy of breast cancer. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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29 pages, 1835 KiB

Open AccessReview

Exploring the Complexity and Promise of Tumor Immunotherapy in Drug Development

by Yiyuan Feng, Caiying He, Chang Liu, Bingjie Shao, Dong Wang and Peijie Wu

Int. J. Mol. Sci. 2024, 25(12), 6444; https://doi.org/10.3390/ijms25126444 - 11 Jun 2024

Viewed by 1157

Abstract

Cancer represents a significant threat to human health, and traditional chemotherapy or cytotoxic therapy is no longer the sole or preferred approach for managing malignant tumors. With advanced research into the immunogenicity of tumor cells and the growing elderly population, tumor immunotherapy has [...] Read more.

Cancer represents a significant threat to human health, and traditional chemotherapy or cytotoxic therapy is no longer the sole or preferred approach for managing malignant tumors. With advanced research into the immunogenicity of tumor cells and the growing elderly population, tumor immunotherapy has emerged as a prominent therapeutic option. Its significance in treating elderly cancer patients is increasingly recognized. In this study, we review the conceptual classifications and benefits of immunotherapy, and discuss recent developments in new drugs and clinical progress in cancer treatment through various immunotherapeutic modalities with different mechanisms. Additionally, we explore the impact of immunosenescence on the effectiveness of cancer immunotherapy and propose innovative and effective strategies to rejuvenate senescent T cells. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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26 pages, 1779 KiB

Open AccessReview

Combination of Oncolytic Virotherapy with Different Antitumor Approaches against Glioblastoma

by Alisa Ageenko, Natalia Vasileva, Vladimir Richter and Elena Kuligina

Int. J. Mol. Sci. 2024, 25(4), 2042; https://doi.org/10.3390/ijms25042042 - 7 Feb 2024

Cited by 2 | Viewed by 2886

Abstract

Glioblastoma is one of the most malignant and aggressive tumors of the central nervous system. Despite the standard therapy consisting of maximal surgical resection and chemo- and radiotherapy, the median survival of patients with this diagnosis is about 15 months. Oncolytic virus therapy [...] Read more.

Glioblastoma is one of the most malignant and aggressive tumors of the central nervous system. Despite the standard therapy consisting of maximal surgical resection and chemo- and radiotherapy, the median survival of patients with this diagnosis is about 15 months. Oncolytic virus therapy is one of the promising areas for the treatment of malignant neoplasms. In this review, we have focused on emphasizing recent achievements in virotherapy, both as a monotherapy and in combination with other therapeutic schemes to improve survival rate and quality of life among patients with glioblastoma. Full article

(This article belongs to the Special Issue New Agents and Novel Drugs Use for the Oncological Diseases Treatment)

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