ABSTRACT
Ferroptosis, characterized by ironmediated nonapoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantioobtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has antihyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit8, EdU staining and migration assays were employed to assess the antiliver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoylCoA desaturase 1 (SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo. Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory elementbinding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2related factor 2/heme oxygenase1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.
Subject(s)
Ferroptosis , Lipogenesis , Liver Neoplasms , Stearoyl-CoA Desaturase , Xenograft Model Antitumor Assays , Ferroptosis/drug effects , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Stearoyl-CoA Desaturase/metabolism , Stearoyl-CoA Desaturase/genetics , Animals , Lipogenesis/drug effects , Mice , Cell Proliferation/drug effects , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Male , Drug Synergism , Hep G2 Cells , CarbolinesABSTRACT
In our ongoing work to create potential antifungal agents, we synthesized and tested a group of C1-substituted acylhydrazone ß-carboline analogues 9a-o and 10a-o for their effectiveness against Valsa mali, Fusarium solani, Fusarium oxysporum, and Fusarium graminearum. Their compositions were analyzed using different spectral techniques, such as 1H/13C NMR and HRMS, with the structure of 9l being additionally confirmed through X-ray diffraction. The antifungal evaluation showed that, among all the target ß-carboline analogues, compounds 9n and 9o exhibited more promising and broad-spectrum antifungal activity than the commercial pesticide hymexazol. Several intriguing findings regarding structure-activity relationships (SARs) were examined. In addition, the cytotoxicity test showed that these acylhydrazone ß-carboline analogues with C1 substitutions exhibit a preference for fungi, with minimal harm to healthy cells (LO2). The reported findings provide insights into the development of ß-carboline analogues as new potential antifungal agents.
Subject(s)
Antifungal Agents , Carbolines , Fusarium , Hydrazones , Microbial Sensitivity Tests , Carbolines/chemistry , Carbolines/pharmacology , Carbolines/chemical synthesis , Antifungal Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Structure-Activity Relationship , Fusarium/drug effects , Hydrazones/pharmacology , Hydrazones/chemistry , Hydrazones/chemical synthesis , Molecular Structure , HumansABSTRACT
Diffuse large B-cell lymphoma (DLBCL), an invasive lymphoma with substantial heterogeneity, can be mainly categorised into germinal centre B-cell-like (GCB) and non-GCB subtypes. DLBCL cells are highly susceptible to ferroptosis, which offers an effective avenue for treating recurrent and refractory DLBCL. Moreover, various heat shock proteins are involved in regulating the sensitivity of tumour cells to ferroptosis. Among these proteins, tailless complex polypeptide 1 (TCP1), a subunit of chaperonin-containing T-complex protein-1 (CCT), plays a role in tumour proliferation and survival. Therefore, we explored the role of TCP1 in different DLBCL subtypes, the sensitivity of GCB and non-GCB subtypes to the ferroptosis inducer RAS-selective lethal small molecule 3 (RSL3), and the underlying molecular mechanism. In GCB cells, TCP1 promoted RSL3-induced ferroptosis. Notably, TCP1 could bind with acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme regulating lipid composition and facilitating ferroptosis, to reduce its ubiquitination and degradation. This interaction activated the ACSL4/LPCAT3 signalling pathway and promoted ferroptosis in the GCB subtype. However, in the non-GCB subtype, TCP1 did not act as a positive regulator but served as a predictor of an unfavourable prognosis in patients with non-GCB. In conclusion, our results suggest that in DLBCL, high TCP1 expression enhances the sensitivity of GCB tumour cells to ferroptosis and serves as a marker of poor prognosis in patients with non-GCB DLBCL.
Subject(s)
Chaperonin Containing TCP-1 , Coenzyme A Ligases , Ferroptosis , Lymphoma, Large B-Cell, Diffuse , Ferroptosis/genetics , Humans , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/genetics , Coenzyme A Ligases/metabolism , Coenzyme A Ligases/genetics , Prognosis , Cell Line, Tumor , Chaperonin Containing TCP-1/metabolism , Chaperonin Containing TCP-1/genetics , Animals , Mice , Female , Gene Expression Regulation, Neoplastic , Male , CarbolinesABSTRACT
3-Tetrazolyl-ß-carbolines were prepared by the Pictet-Spengler approach using a tryptophan analogue as building block, in which the carboxylic acid was replaced by the bioisosteric tetrazole group. Knowing that ß-carbolines are often associated with psychopharmacological effects, the study of the 3-tetrazolyl-ß-carbolines as potential neuroprotective agents against Parkinson's disease was investigated. The evaluation of neuroprotective effects against 1-methyl-4-phenylpyridin-1-ium (MPP+)-induced cytotoxicity allowed to identify compounds with relevant neuroprotective activity. One derivative, 3-(1-benzyl-1H-tetrazol-5-yl)-1-(p-dimethylaminophenyl)-ß-carboline, stood out for its low cytotoxicity and excellent performance, preventing cell death induced by this neurotoxin. The most promising compounds were also evaluated for their neuroprotective properties against iron (III)-induced cytotoxicity. However, only one 3-tetrazolyl-ß-carboline derivative slightly reduced iron-induced cytotoxicity. Overall, the neuroprotective properties of 3-tetrazolyl-ß-carbolines have been demonstrated and this finding may contribute to the development of new therapies for Parkinson's disease.
Subject(s)
Carbolines , Neuroprotective Agents , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/chemical synthesis , Carbolines/chemistry , Carbolines/pharmacology , Carbolines/chemical synthesis , Structure-Activity Relationship , Humans , Molecular Structure , Cell Survival/drug effects , Tetrazoles/chemistry , Tetrazoles/pharmacology , Tetrazoles/chemical synthesis , Dose-Response Relationship, Drug , AnimalsABSTRACT
Background: Tau accumulation in Alzheimer's disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-ß deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge. Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline. We also tested the predictive performance of thresholds in the proposed new NIA-AA biological staging for Alzheimer's disease where multiple levels of tau positivity are used to stage participants. Methods: 18F-flortaucipir scans from 301 non-demented participants were processed and sampled. Four cognitive measures were assessed longitudinally. Regional standardized uptake value ratios were split into infra- and suprathreshold groups at baseline using previously derived thresholds. Survival analysis, log rank testing, and Generalized Estimation Equations assessed the relationship between the application of regional sensitivity/specificity thresholds and change in cognitive measures as well as tau threshold performance in predicting cognitive decline within the new NIA-AA biological staging. Results: The meta temporal region was best for predicting risk of short-term cognitive decline in suprathreshold, as compared to infrathreshold participants. When applying multiple levels of tau positivity, each subsequent level of tau identified cognitive decline at earlier timepoints. Conclusions: When using 18F-flortaucipir, meta temporal suprathreshold classification was associated with increased risk of cognitive decline, suggesting that abnormal tau deposition in the cortex predicts decline. Likewise, the application of multiple levels of tau clearly predicts the distinctive cognitive trajectories in the new NIA-AA biological staging framework.
Subject(s)
Cognitive Dysfunction , Positron-Emission Tomography , tau Proteins , Humans , tau Proteins/metabolism , Female , Male , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/diagnostic imaging , Aged , Middle Aged , Carbolines , Disease Progression , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Longitudinal Studies , Neuropsychological Tests , Brain/metabolism , Brain/diagnostic imaging , Brain/pathology , Aged, 80 and over , Sensitivity and SpecificityABSTRACT
BACKGROUND/AIMS: Anti-programmed cell death protein 1 (PD-1) treatment has exhibited clinical benefits in colorectal cancer (CRC). However, the low response rate of CRC to immunotherapy is an urgent problem that needs to be solved. MATERIALS AND METHODS: MC-38 tumor cells was challenged subcutaneously in the flank of 7-week-old male C57BL/6 mice. The mice were randomly divided into 3 groups, and 200µg/mouse anti-PD-1 antibody and 100 mg/kg RAS-Seletive Lethal 3 (RSL) or phosphate buffer saline (PBS) were intraperitoneally injected every 2 days. The expression of oxidative stress and ferroptosis-related genes was measured by Western blotting, real-time reverse transcription-polymerase chain reaction, Prussian blue staining, and enzyme-linked immunosorbent assay. RESULTS: Anti-PD-1 treatment-unresponsive tumors showed stronger immunosuppression than responsive tumors. Notably, the responsive tumors showed higher levels of H2O2 and reactive oxygen species, both of which could impair the antitumor effect of cytotoxic CD8+ T cells. The anti-PD-1 treatment-responsive tumors showed a higher expression of pro-ferroptosis genes and Fe2+ accumulation than those of anti-PD-1 nonresponsive tumors, indicating the potential role of ferroptosis in the efficacy of anti-PD-1 treatment. In MC-38 syngeneic tumor model, (1S, 3R)-RSL3 (RSL), a glutathione peroxidase 4 inhibitor, effectively promoted the antitumor effect of anti-PD-1 treatment in vivo. However, anti-PD-1 treatment did not affect the levels of ferroptosis-related genes in tumor model. Mechanistically, RSL treatment significantly upregulated the frequency of proliferating (ki67+) and cytotoxic (GZMB+) CD8+ T cells. Furthermore, the frequency of tumor neoantigen-specific interferon (IFN)-γ CD8+ T cells showed a significant increase after RSL plus anti-PD-1 treatment. CONCLUSION: RSL may be a promising drug for potentiating the antitumor efficiency of anti-PD-1 treatment in CRC.
Subject(s)
Colorectal Neoplasms , Ferroptosis , Programmed Cell Death 1 Receptor , Animals , Male , Mice , Carbolines , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Models, Animal , Ferroptosis/drug effects , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Mice, Inbred C57BL , Oxidative Stress/drug effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. METHODS: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. RESULTS: Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction. INTERPRETATION: Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Azacitidine , Leukemia, Myeloid, Acute , Maximum Tolerated Dose , Myelodysplastic Syndromes , Proto-Oncogene Proteins c-mdm2 , Humans , Male , Azacitidine/administration & dosage , Azacitidine/adverse effects , Azacitidine/therapeutic use , Female , Aged , Middle Aged , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Aged, 80 and over , Myelodysplastic Syndromes/drug therapy , Adult , Treatment Outcome , Carbolines , Heterocyclic Compounds, 4 or More RingsABSTRACT
BACKGROUND: Declining ability to independently perform instrumental activities of daily living (IADL) is a hallmark of early-stage Alzheimer's disease (AD). Financial capacity, an aspect of IADL, includes financial skills such as balancing a checkbook and making change and is potentially sensitive to early decline in cognitive abilities, raising the question of how financial capacity is affected by buildup of cerebral tau and amyloid-hallmarks of AD pathology. OBJECTIVES: This study aimed to examine the relationship between cerebral tau, amyloid, and their interaction with change in financial capacity over time. DESIGN: Participants were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to have at least one yearly follow-up Financial Capacity Instrument-Short Form (FCI-SF) exam and a flortaucipir (tau) PET scan within 6 months of baseline (and in a subset, a florbetapir (amyloid) PET scan within a year of baseline). SETTING: Multi-center international cohort study. PARTICIPANTS: Sample size was 507-322 cognitively normal (CN) and 185 with amnestic mild cognitive impairment (MCI). Sixty-two percent (N=316) had amyloid data. MEASUREMENTS: Linear mixed-effects models predicted FCI-SF total score from baseline tau, age, gender, premorbid intelligence, executive function, memory, and the interaction of each with time. Regions of interest included inferior temporal, entorhinal cortex, precuneus, posterior cingulate, supramarginal, and dorsolateral prefrontal (DLPF). Additional models examined amyloid and its interaction with tau. Results were adjusted for multiple comparisons. RESULTS: Among the whole sample and in CN participants alone, higher baseline tau in all regions, most prominently in the inferior temporal, entorhinal cortex, and supramarginal regions, was significantly associated with worse performance on the FCI-SF over time. Among MCI participants alone, this relationship was significant in the entorhinal cortex (unstandardized b = 0.27, t = 3.71, adjusted p = 0.001), inferior temporal (b = 0.27, t = 3.96, p < 0.001), precuneus (b = 0.27, t = 3.04, p = 0.01), and supramarginal (b = 0.27, t = 2.74, p = 0.02) regions. Amyloid alone was significantly associated with worse FCI-SF performance in only the whole sample (b = 0.15, t = 2.37, p = 0.04), and a three-way interaction between tau, amyloid, and time was only present for entorhinal cortex tau in CN individuals (b = -1.61, t = -2.61, p = 0.03). CONCLUSIONS: Early tau accumulation is linked to worsening financial capacity over time in CN older adults and MCI. Declining financial capacity may signal pathological buildup and serve as an early warning sign for AD, and future research should continue to investigate the longitudinal relationship between tau, financial capacity, and other IADL.
Subject(s)
Activities of Daily Living , Cognitive Dysfunction , Positron-Emission Tomography , tau Proteins , Humans , Cognitive Dysfunction/metabolism , Female , Aged , Male , tau Proteins/metabolism , Longitudinal Studies , Cognition/physiology , Aged, 80 and over , Brain/metabolism , Brain/diagnostic imaging , Aniline Compounds , Carbolines , Amyloid beta-Peptides/metabolism , Ethylene Glycols , Alzheimer Disease/metabolism , Alzheimer Disease/diagnostic imagingABSTRACT
[18F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer's disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-ß. It is also unclear whether flortaucipir can detect tau in definite primary age-related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [18F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-ß PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-ß phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-ß phase. Flortaucipir uptake linearly increased with the amyloid-ß phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer's disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-ß phase, and were useful for distinguishing different ADNC scores and PART.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Carbolines , Positron-Emission Tomography , Tauopathies , tau Proteins , Humans , Positron-Emission Tomography/methods , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , tau Proteins/metabolism , Carbolines/metabolism , Amyloid beta-Peptides/metabolism , Tauopathies/diagnostic imaging , Tauopathies/metabolism , Tauopathies/pathology , Aged , Female , Male , Aged, 80 and over , Middle Aged , Brain/metabolism , Brain/diagnostic imaging , Brain/pathologyABSTRACT
Light and pH dual-responsive ion transporters offer better applicability for cancer due to higher tunability and low cytotoxicity. Herein, we demonstrate the development of pH-responsive ß-carboline-based ionophores and photocleavable-linker appended ß-carboline-based proionophores to facilitate the controlled transport of Cl- across membranes, leading to apoptotic and autophagic cancer cell death.
Subject(s)
Carbolines , Light , Carbolines/chemistry , Carbolines/pharmacology , Humans , Hydrogen-Ion Concentration , Apoptosis/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Ion Transport/drug effects , Cell Line, Tumor , Molecular Structure , Ionophores/chemistry , Ionophores/pharmacology , Drug Screening Assays, AntitumorABSTRACT
Ir(III) and Ru(II) polypyridyl complexes are promising photosensitizers (PSs) for photodynamic therapy (PDT) due to their outstanding photophysical properties. Herein, one series of cyclometallated Ir(III) complexes and two series of Ru(II) polypyridyl derivatives bearing three different thiazolyl-ß-carboline N^N' ligands have been synthesized, aiming to evaluate the impact of the different metal fragments ([Ir(C^N)2]+ or [Ru(N^N)2]2+) and N^N' ligands on the photophysical and biological properties. All the compounds exhibit remarkable photostability under blue-light irradiation and are emissive (605 < λem < 720 nm), with the Ru(II) derivatives displaying higher photoluminescence quantum yields and longer excited state lifetimes. The Ir PSs display pKa values between 5.9 and 7.9, whereas their Ru counterparts are less acidic (pKa > 9.3). The presence of the deprotonated form in the Ir-PSs favours the generation of reactive oxygen species (ROS) since, according to theoretical calculations, it features a low-lying ligand-centered triplet excited state (T1 = 3LC) with a long lifetime. All compounds have demonstrated anticancer activity. Ir(III) complexes 1-3 exhibit the highest cytotoxicity in dark conditions, comparable to cisplatin. Their activity is notably enhanced by blue-light irradiation, resulting in nanomolar IC50 values and phototoxicity indexes (PIs) between 70 and 201 in different cancer cell lines. The Ir(III) PSs are also activated by green (with PI between 16 and 19.2) and red light in the case of complex 3 (PI = 8.5). Their antitumor efficacy is confirmed by clonogenic assays and using spheroid models. The Ir(III) complexes rapidly enter cells, accumulating in mitochondria and lysosomes. Upon photoactivation, they generate ROS, leading to mitochondrial dysfunction and lysosomal damage and ultimately cell apoptosis. Additionally, they inhibit cancer cell migration, a crucial step in metastasis. In contrast, Ru(II) complex 6 exhibits moderate mitochondrial activity. Overall, Ir(III) complexes 1-3 show potential for selective light-controlled cancer treatment, providing an alternative mechanism to chemotherapy and the ability to inhibit lethal cancer cell dissemination.
Subject(s)
Antineoplastic Agents , Carbolines , Coordination Complexes , Drug Screening Assays, Antitumor , Iridium , Photochemotherapy , Photosensitizing Agents , Ruthenium , Humans , Iridium/chemistry , Iridium/pharmacology , Ruthenium/chemistry , Ruthenium/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Ligands , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Carbolines/chemistry , Carbolines/pharmacology , Carbolines/chemical synthesis , Molecular Structure , Structure-Activity Relationship , Cell Proliferation/drug effects , Pyridines/chemistry , Pyridines/pharmacology , Pyridines/chemical synthesis , Reactive Oxygen Species/metabolism , Dose-Response Relationship, Drug , Cell Line, Tumor , Cell Survival/drug effects , Apoptosis/drug effectsABSTRACT
In recent years, the 9H-pyrido[2,3-b]indole nuclei, also named α-carboline which is found in many organic compounds such as natural products, pharmaceuticals, and materials, have intensively stimulated the research of new synthetic pathways. After a brief report published in 2015 describing novel accesses and biological applications of α-carbolines, this update reports between 2015 and 2023 on the emergence of original syntheses to this heterocyclic nucleus. Examples representing these processes are described and the biological activities of α-carbolines are mentioned when they have been prepared for therapeutic purposes.
Subject(s)
Carbolines , Carbolines/chemistry , Carbolines/chemical synthesis , Carbolines/pharmacology , Humans , Molecular Structure , Animals , Biological Products/chemistry , Biological Products/pharmacology , Biological Products/chemical synthesisABSTRACT
Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) has provided many arguments for further clinical evaluation. By the substitution of the acidic hydrogen of 4 for different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves the hydrolytic stability of the inhibitor. Further asymmetric synthesis has shown that the (S)-configured inhibitors preferentially bind to HDAC6. This led to the highly selective and potent methyl-substituted derivative S-29b, which elicited a long-lasting tubulin hyperacetylation in MV4-11 cells. Finally, a crystal structure of the HDAC6/S-29b complex provided mechanistic explanation for the high potency and stereoselectivity of synthesized compound series.
Subject(s)
Carbolines , Histone Deacetylase 6 , Histone Deacetylase Inhibitors , Humans , Carbolines/chemistry , Carbolines/pharmacology , Carbolines/chemical synthesis , Cell Line, Tumor , Crystallography, X-Ray , Dose-Response Relationship, Drug , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/chemical synthesis , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Morpholines/chemical synthesis , Morpholines/chemistry , Morpholines/pharmacologyABSTRACT
Development of resistance to therapy-induced cell death is a major hurdle in the effective treatment of advanced solid tumors. Erastin and RSL3 were originally found to induce synthetic lethality by induction of a novel form of cell death termed ferroptosis. Emerging evidence suggests that ferroptosis inducers enhance chemosensitivity of classic therapeutic agents by triggering ferroptotic cell death. In this study we evaluated the effects of erastin and RSL3 on the resistance of docetaxel, doxorubicin, and cisplatin, and revealed a mechanism whereby these ferroptosis inducers augment docetaxel efficacy in non-small cell lung cancer by regulating redox signaling to promote ferroptosis. Transcriptome analysis revealed that combination treatment modulated not only p53 signaling pathway but also immune responses and several signaling pathways including MAPK, NF-κB and PI3K/Akt. Considering that glutathione peroxidase 4 (GPX4) serves as the main effector to protect cells from ferroptosis, this study identified three novel non-covalent GPX4 inhibitors with the aid of pharmacophore-based virtual screening. The new ferroptosis-inducing compounds synergized with docetaxel to increase the cytotoxicity by promoting ferroptotic cell death in docetaxel-resistant A549/DTX cells. Collectively, the induction of ferroptosis contributed to docetaxel-induced cytotoxic effects and overcame drug resistance in A549/DTX cells. Ferroptosis has a great potential to become a new approach to attenuate resistance to some classic therapeutic drugs in cancer patients.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Docetaxel , Drug Resistance, Neoplasm , Ferroptosis , Lung Neoplasms , Ferroptosis/drug effects , Humans , Docetaxel/pharmacology , Docetaxel/chemistry , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Drug Screening Assays, Antitumor , Molecular Structure , Piperazines/pharmacology , Piperazines/chemistry , Drug Synergism , Dose-Response Relationship, Drug , Structure-Activity Relationship , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , CarbolinesABSTRACT
BACKGROUND: ß-carboline alkaloids exert a distinguished ability to impair cell growth and induce cell death in a variety of cancers and the evaluation of such new therapeutic candidates may denote new possibilities for leukemia treatment. In this present study, we screened 12 ß-carboline derivatives containing different substituents at 1- and 3-positions of ß-carboline nucleus for their antineoplastic activities in a panel of leukemia cell lines. METHODS: The cytotoxic effects of the ß-carboline derivatives were evaluated in different leukemia cell lines as well as reactive oxygen species (ROS) generation, autophagy, and important signaling pathways. RESULTS: Treatment with the ß-carboline derivatives resulted in a potent antineoplastic activity leading to a reduced cell viability that was associated with increased cell death in a concentration-dependent manner. Interestingly, the treatment of primary mononuclear cells isolated from the peripheral blood of healthy donors with the ß-carboline derivatives showed a minor change in cell survival. The antineoplastic activity occurs by blocking ROS production causing consequent interruption of the PI3K/AKT and MAPK/ERK signaling and modulating autophagy processes. Notably, in vivo, AML burden was diminished in peripheral blood and bone marrow of a xenograft mouse model. CONCLUSIONS: Our results indicated that ß-carboline derivatives have an on-target malignant cell-killing activity and may be promising candidates for treating leukemia cells by disrupting crucial events that promote leukemia expansion and chemotherapy resistance.
Subject(s)
Antineoplastic Agents , Carbolines , Cell Survival , Leukemia, Myeloid, Acute , Reactive Oxygen Species , Xenograft Model Antitumor Assays , Carbolines/pharmacology , Humans , Animals , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Mice , Reactive Oxygen Species/metabolism , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Autophagy/drug effects , Signal Transduction/drug effects , Dose-Response Relationship, DrugABSTRACT
In the quest for potent α-glucosidase inhibitors to combat diabetes, a series of novel thiosemicarbazide-based ß-carboline derivatives (CTL1â¼36) were synthesized and evaluated. CTL1â¼36 exhibited remarkable inhibitory effects against α-glucosidase, with IC50 values ranging from 2.81 to 12.40 µM, significantly surpassing the positive control acarbose (IC50 = 564.28 µM). Notably, CTL26 demonstrated the most potent inhibition (IC50 = 2.81 µM) and was characterized as a non-competitive inhibitor. Through a combination assay with fluorescence quenching, 3D fluorescence spectra, CD spectra, and molecular docking, we elucidated that CTL26 formed a complex with α-glucosidase via hydrogen bondings and hydrophobic interactions, leading to α-glucosidase conformation changes that impaired enzymatic activity. In vivo studies revealed that oral administration of CTL26 (25 and 50 mg/kg/d) reduced fasting blood glucose levels, enhanced glucose tolerance, and ameliorated lipid abnormalities in diabetic mice. These findings positioned CTL26 as a promising candidate for the development of α-glucosidase inhibitors with anti-diabetic potential.
Subject(s)
Carbolines , Diabetes Mellitus, Experimental , Glycoside Hydrolase Inhibitors , Semicarbazides , alpha-Glucosidases , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Animals , alpha-Glucosidases/metabolism , Carbolines/pharmacology , Carbolines/chemistry , Carbolines/chemical synthesis , Semicarbazides/pharmacology , Semicarbazides/chemistry , Semicarbazides/chemical synthesis , Mice , Structure-Activity Relationship , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Molecular Structure , Molecular Docking Simulation , Dose-Response Relationship, Drug , Male , Blood Glucose/drug effects , Blood Glucose/metabolism , Blood Glucose/analysis , HumansABSTRACT
BACKGROUND: Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness. METHODS: A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample. RESULTS: Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP. CONCLUSIONS: Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Locus Coeruleus , Magnetic Resonance Imaging , Positron-Emission Tomography , tau Proteins , Humans , Locus Coeruleus/diagnostic imaging , Locus Coeruleus/pathology , Female , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Male , Aged , tau Proteins/metabolism , Aged, 80 and over , Cohort Studies , Amyloid beta-Peptides/metabolism , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Carbolines , Thiazoles , Aniline Compounds , Brain Cortical ThicknessABSTRACT
With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-ß-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.