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21 pages, 9506 KiB

Open AccessArticle

The Mechanisms of GPR55 Receptor Functional Selectivity during Apoptosis and Proliferation Regulation in Cancer Cells

by Mikhail G. Akimov, Natalia M. Gretskaya, Polina V. Dudina, Galina D. Sherstyanykh, Galina N. Zinchenko, Oksana V. Serova, Ksenia O. Degtyaryova, Igor E. Deyev and Vladimir V. Bezuglov

Int. J. Mol. Sci. 2023, 24(6), 5524; https://doi.org/10.3390/ijms24065524 - 14 Mar 2023

Cited by 7 | Viewed by 2013

Abstract

GPR55 is a non-canonical cannabinoid receptor, important for cancer proliferation. Depending on the ligand, it induces either cell proliferation or death. The objective of the study was to establish the mechanisms of this multidirectional signaling. Using the CRISPR-Cas9 system, the GPR55, CB1, CB2, [...] Read more.

GPR55 is a non-canonical cannabinoid receptor, important for cancer proliferation. Depending on the ligand, it induces either cell proliferation or death. The objective of the study was to establish the mechanisms of this multidirectional signaling. Using the CRISPR-Cas9 system, the GPR55, CB1, CB2, and GPR18 receptor knockouts of the MDA-MB-231 line were obtained. After the CB2 receptor knockout, the pro-apoptotic activity of the pro-apoptotic ligand docosahexaenoyl dopamine (DHA-DA) slightly increased, while the pro-proliferative activity of the most active synthetic ligand of the GPR55 receptor (ML-184) completely disappeared. On the original cell line, the stimulatory effect of ML-184 was removed by the CB2 receptor blocker and by GPR55 receptor knockout. Thus, it can be confidently assumed that when proliferation is stimulated with the participation of the GPR55 receptor, a signal is transmitted from the CB2 receptor to the GPR55 receptor due to the formation of a heterodimer. GPR18 was additionally involved in the implementation of the pro-apoptotic effect of DHA-DA, while the CB1 receptor is not involved. In the implementation of the pro-apoptotic action of DHA-DA, the elimination of Gα₁₃ led to a decrease in cytotoxicity. The obtained data provide novel details to the mechanism of the pro-proliferative action of GPR55. Full article

(This article belongs to the Special Issue Cell Apoptosis 2.0)

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15 pages, 8437 KiB

Open AccessArticle

Cyclophilin A Inhibitors Suppress Proliferation and Induce Apoptosis of MKN45 Gastric Cancer Stem-like Cells by Regulating CypA/CD147-Mediated Signaling Pathway

by Hee Jeong Cho and Hye Jin Jung

Int. J. Mol. Sci. 2023, 24(5), 4734; https://doi.org/10.3390/ijms24054734 - 1 Mar 2023

Cited by 11 | Viewed by 2513

Abstract

Gastric cancer stem cells (GCSCs) are a subgroup of gastric cancer (GC) cells with high self-renewal and multi-lineage differentiation abilities that lead to tumor initiation, metastasis, drug resistance, and tumor relapse. Therefore, the eradication of GCSCs can contribute to the effective treatment of [...] Read more.

Gastric cancer stem cells (GCSCs) are a subgroup of gastric cancer (GC) cells with high self-renewal and multi-lineage differentiation abilities that lead to tumor initiation, metastasis, drug resistance, and tumor relapse. Therefore, the eradication of GCSCs can contribute to the effective treatment of advanced or metastatic GC. In our previous study, compound 9 (C9), a novel derivative of nargenicin A1, was identified as a potential natural anticancer agent that specifically targeted cyclophilin A (CypA). However, its therapeutic effect and molecular mechanisms of action on GCSC growth have not been assessed. In this study, we investigated the effects of natural CypA inhibitors, including C9 and cyclosporin A (CsA), on the growth of MKN45-derived GCSCs. Compound 9 and CsA effectively suppressed cell proliferation by inducing cell cycle arrest at the G0/G1 phase and promoted apoptosis by activating the caspase cascade in MKN45 GCSCs. In addition, C9 and CsA potently inhibited tumor growth in the MKN45 GCSC-grafted chick embryo chorioallantoic membrane (CAM) model. Furthermore, the two compounds significantly decreased the protein expression of key GCSC markers including CD133, CD44, integrin α6, Sox2, Oct4, and Nanog. Notably, the anticancer activities of C9 and CsA in MKN45 GCSCs were associated with the regulation of CypA/CD147-mediated AKT and mitogen-activated protein kinase (MAPK) signaling pathways. Collectively, our findings suggest that the natural CypA inhibitors C9 and CsA could be novel anticancer agents used to combat GCSCs by targeting the CypA/CD147 axis. Full article

(This article belongs to the Special Issue Cell Apoptosis 2.0)

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19 pages, 3025 KiB

Open AccessArticle

Neurotoxic/Neuroprotective Effects of Clozapine and the Positive Allosteric Modulator of mGluR2 JNJ-46356479 in Human Neuroblastoma Cell Cultures

by Patricia Gassó, Albert Martínez-Pinteño, Natalia Rodríguez, Santiago Madero, Marta Gómez, Alex G. Segura, Clemente García-Rizo, Constanza Morén, Sergi Mas and Eduard Parellada

Int. J. Mol. Sci. 2023, 24(3), 2054; https://doi.org/10.3390/ijms24032054 - 20 Jan 2023

Cited by 1 | Viewed by 2001

Abstract

Current antipsychotics (APs) effectively control positive psychotic symptoms, mainly by blocking dopamine (DA) D2 receptors, but have little effect on negative and cognitive symptoms. Increased glutamate (GLU) release would trigger neurotoxicity, leading to apoptosis and synaptic pruning, which is involved in the pathophysiology [...] Read more.

Current antipsychotics (APs) effectively control positive psychotic symptoms, mainly by blocking dopamine (DA) D2 receptors, but have little effect on negative and cognitive symptoms. Increased glutamate (GLU) release would trigger neurotoxicity, leading to apoptosis and synaptic pruning, which is involved in the pathophysiology of schizophrenia. New pharmacological strategies are being developed such as positive allosteric modulators (PAMs) of the metabotropic GLU receptor 2 (mGluR2) that inhibit the presynaptic release of GLU. We previously reported that treatment of adult mice with JNJ-46356479 (JNJ), a recently developed mGluR2 PAM, partially improved neuropathological deficits and schizophrenia-like behavior in a postnatal ketamine mouse model. In the present study, we evaluated, for the first time, the putative neuroprotective and antiapoptotic activity of JNJ in a human neuroblastoma cell line and compared it with the effect of clozapine (CLZ) as a clinical AP with the highest efficacy and with apparent utility in managing negative symptoms. Specifically, we measured changes in cell viability, caspase 3 activity and apoptosis, as well as in the expression of key genes involved in survival and cell death, produced by CLZ and JNJ alone and in combination with a high DA or GLU concentration as apoptosis inducers. Our results suggest that JNJ is not neurotoxic and attenuates apoptosis, particularly by decreasing the caspase 3 activation induced by DA and GLU, as well as increasing and decreasing the number of viable and apoptotic cells, respectively, only when cultures were exposed to GLU. Its effects seem to be less neurotoxic and more neuroprotective than those observed with CLZ. Moreover, JNJ partially normalized altered expression levels of glycolytic genes, which could act as a protective factor and be related to its putative neuroprotective effect. More studies are needed to define the mechanisms of action of this GLU modulator and its potential to become a novel therapeutic agent for schizophrenia. Full article

(This article belongs to the Special Issue Cell Apoptosis 2.0)

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14 pages, 5397 KiB

Open AccessArticle

The Effect of Silica Nanoparticles (SiNPs) on Cytotoxicity, Induction of Oxidative Stress and Apoptosis in Breast Cancer Cell Lines

by Rafał Krętowski, Agata Jabłońska-Trypuć and Marzanna Cechowska-Pasko

Int. J. Mol. Sci. 2023, 24(3), 2037; https://doi.org/10.3390/ijms24032037 - 20 Jan 2023

Cited by 6 | Viewed by 2803

Abstract

Breast cancer is one of the most common cancers in women. Silica nanoparticles (SiNPs) belong to the group of often-used nanoparticles in biomedical applications. The mechanisms of the cytotoxicity, apoptosis, and oxidative stress induced by the 5–15 nm SiNPs still remain unclear. The [...] Read more.

Breast cancer is one of the most common cancers in women. Silica nanoparticles (SiNPs) belong to the group of often-used nanoparticles in biomedical applications. The mechanisms of the cytotoxicity, apoptosis, and oxidative stress induced by the 5–15 nm SiNPs still remain unclear. The aim of the study was to evaluate the anti-cancer effect and mechanism of action of SiNPs in breast cancer cell lines. The breast cancer MDA-MB-231 and ZR-75-1 cell lines were analyzed using MTT assay, flow cytometry, and spectrophotometric methods. In this paper, we presented findings about the cytotoxicity, apoptosis, and oxidative stress in both breast cancer cell lines. We indicated that 5–15 nm SiNPs induced dose-dependent cytotoxicity in MDA-MB-231 and ZR-75-1 cells. Moreover, we demonstrated that the process of apoptosis in the studied cell lines was associated with a decrease in the mitochondrial membrane potential (ΔΨ_m) and an increase in the activity of caspase-9 and caspase-3. Based on the obtained results, 5–15 nm SiNPs are able to induce the mitochondrial apoptosis pathway. Analyzed nanoparticles have also been found to cause an increase in selected oxidative stress parameters in both breast cancer cell lines. The presented study provides an explanation of the possible mechanisms of 5–15 nm SiNPs action in breast cancer cells. Full article

(This article belongs to the Special Issue Cell Apoptosis 2.0)

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19 pages, 6396 KiB

Open AccessArticle

Impact of Enniatin B and Beauvericin on Lysosomal Cathepsin B Secretion and Apoptosis Induction

by Mohammed Aufy, Ramadan F. Abdelaziz, Ahmed M. Hussein, Nermina Topcagic, Hadil Shamroukh, Mostafa A. Abdel-Maksoud, Tamer Z. Salem and Christian R. Studenik

Int. J. Mol. Sci. 2023, 24(3), 2030; https://doi.org/10.3390/ijms24032030 - 19 Jan 2023

Cited by 11 | Viewed by 6326

Abstract

Enniatin B (ENN B) and Beauvericin (BEA) are cyclohexadepsipeptides that can be isolated from Fusarium and Beauveria bassiana, respectively. Both compounds are cytotoxic and ionophoric. In the present study, the mechanism of cell death induced by these compounds was investigated. Epidermal carcinoma-derived [...] Read more.

Enniatin B (ENN B) and Beauvericin (BEA) are cyclohexadepsipeptides that can be isolated from Fusarium and Beauveria bassiana, respectively. Both compounds are cytotoxic and ionophoric. In the present study, the mechanism of cell death induced by these compounds was investigated. Epidermal carcinoma-derived cell line KB-3-1 cells were treated with different concentrations of these compounds. The extracellular secretion of cathepsin B increased in a concentration-dependent manner, and the lysosomal staining by lysotracker red was reduced upon the treatment with any of the compounds. However, the extracellular secretion of cathepsin L and cathepsin D were not affected. Inhibition of cathepsin B with specific inhibitor CA074 significantly reduced the cytotoxic effect of both compounds, while inhibition of cathepsin D or cathepsin L did not influence the cytotoxic activities of both compounds. In vitro labelling of lysosomal cysteine cathepsins with Ethyl (2S, 3S)-epoxysuccinate-Leu-Tyr-Acp-Lys (Biotin)-NH2 (DCG04) was not affected in case of cathepsin L upon the treatment with both compounds, while it was significantly reduced in case of cathepsin B. In conclusion, ENN B and BEA increase lysosomal Ph, which inhibits delivery of cathepsin B from Golgi to lysosomes, thereby inducing cathepsin B release in cytosol, which activates caspases and hence the apoptotic pathway. Full article

(This article belongs to the Special Issue Cell Apoptosis 2.0)

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22 pages, 6536 KiB

Open AccessArticle

Protective Effects of Hexarelin and JMV2894 in a Human Neuroblastoma Cell Line Expressing the SOD1-G93A Mutated Protein

by Ramona Meanti, Martina Licata, Laura Rizzi, Elena Bresciani, Laura Molteni, Silvia Coco, Vittorio Locatelli, Robert J. Omeljaniuk and Antonio Torsello

Int. J. Mol. Sci. 2023, 24(2), 993; https://doi.org/10.3390/ijms24020993 - 4 Jan 2023

Cited by 1 | Viewed by 2212

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease whose etiology remains unresolved; nonetheless, mutations of superoxide dismutase 1 (SOD1) have been associated with several variants of ALS. Currently available pharmacologic interventions are only symptomatic and palliative in effect; therefore, there is [...] Read more.

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease whose etiology remains unresolved; nonetheless, mutations of superoxide dismutase 1 (SOD1) have been associated with several variants of ALS. Currently available pharmacologic interventions are only symptomatic and palliative in effect; therefore, there is a pressing demand for more effective drugs. This study examined potential therapeutic effects of growth hormone secretagogues (GHSs), a large family of synthetic compounds, as possible candidates for the treatment of ALS. Human neuroblastoma cells expressing the SOD1-G93A mutated protein (SH-SY5Y SOD1^G93A cells) were incubated for 24 h with H₂O₂ (150 µM) in the absence, or presence, of GHS (1 µM), in order to study the protective effect of GHS against increased oxidative stress. The two GHSs examined in this study, hexarelin and JMV2894, protected cells from H₂O₂-induced cytotoxicity by activating molecules that regulate apoptosis and promote cell survival processes. These findings suggest the possibility of developing new GHS-based anti-oxidant and neuroprotective drugs with improved therapeutic potential. Further investigations are required for the following: (i) to clarify GHS molecular mechanisms of action, and (ii) to envisage the development of new GHSs that may be useful in ALS therapy. Full article

(This article belongs to the Special Issue Cell Apoptosis 2.0)

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17 pages, 5449 KiB

Open AccessArticle

Involvement of AMPKα and MAPK-ERK/-JNK Signals in Docetaxel-Induced Human Tongue Squamous Cell Carcinoma Cell Apoptosis

by Chin-Chuan Su, Jhe-Wei Lin, Kai-Yao Chang, Cheng-Tien Wu, Shing-Hwa Liu, Kai-Chih Chang, Jui-Ming Liu, Kuan-I Lee, Kai-Min Fang and Ya-Wen Chen

Int. J. Mol. Sci. 2022, 23(22), 13857; https://doi.org/10.3390/ijms232213857 - 10 Nov 2022

Cited by 9 | Viewed by 2226

Abstract

Cancers of the oral cavity can develop in the anatomic area extending from the lip, gum, tongue, mouth, and to the palate. Histologically, about 85–90% of oral cavity cancers are of the type squamous cells carcinomas (SCCs). The incidence of oral tongue SCC [...] Read more.

Cancers of the oral cavity can develop in the anatomic area extending from the lip, gum, tongue, mouth, and to the palate. Histologically, about 85–90% of oral cavity cancers are of the type squamous cells carcinomas (SCCs). The incidence of oral tongue SCC is higher in the tongue than any other anatomic area of the oral cavity. Here, we investigated the therapeutic effects and molecular mechanisms of docetaxel, which is a paclitaxel antitumor agent, on the cell growth of a human tongue SCC-derived SAS cell line. The results showed that docetaxel (10–300 nM) induced cytotoxicity and caspase-3 activity in SAS cells. Moreover, docetaxel (100 nM) promoted the expression of apoptosis-related signaling molecules, including the cleavages of caspase-3, caspase-7, and poly (ADP-ribose) polymerase (PARP). In mitochondria, docetaxel (100 nM) decreased the mitochondrial membrane potential (MMP) and Bcl-2 mRNA and protein expression and increased cytosolic cytochrome c protein expression and Bax mRNA and protein expression. In terms of mitogen-activated protein kinase (MAPK) and adenosine monophosphate-activated protein kinase (AMPK) signaling, docetaxel increased the expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-c-Jun N-terminal kinase (JNK), and p-AMPKα protein expression but not p-p38 protein expression. Moreover, the increase in caspase-3/-7 activity and Bax protein expression and decreased Bcl-2 protein expression and MMP depolarization observed in docetaxel-treated SAS cells could be reversed by treatment with either SP600125 (a JNK inhibitor), PD98059 (an MEK1/2 (mitogen-activated protein kinase kinase 1/2) inhibitor), or compound c (an AMPK inhibitor). The docetaxel-induced increases in p-JNK, p-ERK, and p-AMPKα protein expression could also be reversed by treatment with either SP600125, PD98059, or compound c. These results indicate that docetaxel induces human tongue SCC cell apoptosis via interdependent MAPK-JNK, MAPK-ERK1/2, and AMPKα signaling pathways. Our results show that docetaxel could possibly exert a potent pharmacological effect on human oral tongue SCC cell growth. Full article

(This article belongs to the Special Issue Cell Apoptosis 2.0)

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Review

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17 pages, 1912 KiB

Open AccessReview

Monoclonal Antibodies: The Greatest Resource to Treat Multiple Myeloma

by Fabiola De Luca, Alessandro Allegra, Carla Di Chio, Santo Previti, Maria Zappalà and Roberta Ettari

Int. J. Mol. Sci. 2023, 24(4), 3136; https://doi.org/10.3390/ijms24043136 - 5 Feb 2023

Cited by 12 | Viewed by 5980

Abstract

Multiple myeloma (MM) is a currently incurable hematologic cancer. This disease is characterized by immunological alterations of myeloid cells and lymphocytes. The first-line therapy involves the use of classic chemotherapy; however, many patients have a relapsed form that could evolve into a refractory [...] Read more.

Multiple myeloma (MM) is a currently incurable hematologic cancer. This disease is characterized by immunological alterations of myeloid cells and lymphocytes. The first-line therapy involves the use of classic chemotherapy; however, many patients have a relapsed form that could evolve into a refractory MM. The new therapeutic frontiers involve the use of new monoclonal antibodies (Mab) such as daratumumab, isatuximab, and elotuzumab. In addition to monoclonal antibodies, new immunotherapies based on modern bispecific antibodies and chimeric antigen receptor (CAR) T cell therapy have been investigated. For this reason, immunotherapy represents the greatest hope for the treatment of MM. This review intends to focus the attention on the new approved antibody targets. The most important are: CD38 (daratumumab and isatuximab), SLAM7 (elotuzumab), and BCMA (belantamab mafodotin) for the treatment of MM currently used in clinical practice. Although the disease is still incurable, the future perspective is to find the best therapeutic combination among all available drugs. Full article

(This article belongs to the Special Issue Cell Apoptosis 2.0)

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