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1.
Methods Cell Biol ; 181: 197-212, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38302240

RESUMO

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (i.e., palbociclib, abemaciclib, and ribociclib) are well known for their capacity to mediate cytostatic effects by promoting cell cycle arrest in the G1 phase, thus inhibiting cancer cell proliferation. Cytostatic effects induced by CDK4/6 inhibitors can be transient or lead to a permanent state of cell cycle arrest, commonly defined as cellular senescence. Induction of senescence is often associated to metabolic modifications and to the acquisition of a senescence-associated secretory phenotype (SASP) by cancer cells, which in turn can promote or limit antitumor immunity (and thus the efficacy of CDK4/6 inhibitors) depending on SASP components. Thus, although accumulating evidence suggests that anti-cancer effects of CDK4/6 inhibitors also depend on the promotion of antitumor immune responses, assessing cell cycle arrest and progression in cells treated with palbociclib remains a key approach for investigating the efficacy of CDK4/6 inhibitors. Here, we describe a method to assess cell cycle distribution simultaneously with active DNA replication by flow cytometry in cultured hormone receptor-positive breast cancer MCF7 cells.


Assuntos
Neoplasias da Mama , Citostáticos , Humanos , Feminino , Citostáticos/farmacologia , Citometria de Fluxo , Inibidores de Proteínas Quinases/farmacologia , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/farmacologia , Pontos de Checagem do Ciclo Celular , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ciclo Celular
2.
Front Immunol ; 15: 1310443, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38327525

RESUMO

Cancer is still considered a lethal disease worldwide and the patients' quality of life is affected by major side effects of the treatments including post-surgery complications, chemo-, and radiation therapy. Recently, new therapeutic approaches were considered globally for increasing conventional cancer therapy efficacy and decreasing the adverse effects. Bioactive peptides obtained from plant and animal sources have drawn increased attention because of their potential as complementary therapy. This review presents a contemporary examination of bioactive peptides derived from natural origins with demonstrated anticancer, ant invasion, and immunomodulation properties. For example, peptides derived from common beans, chickpeas, wheat germ, and mung beans exhibited antiproliferative and toxic effects on cancer cells, favoring cell cycle arrest and apoptosis. On the other hand, peptides from marine sources showed the potential for inhibiting tumor growth and metastasis. In this review we will discuss these data highlighting the potential befits of these approaches and the need of further investigations to fully characterize their potential in clinics.


Assuntos
Neoplasias , Qualidade de Vida , Humanos , Animais , Neoplasias/tratamento farmacológico , Peptídeos/química , Apoptose , Pontos de Checagem do Ciclo Celular
3.
Bioorg Chem ; 144: 107142, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38280358

RESUMO

The abnormal activation of Cullin RING E3 Ligases (CRLs) is closely associated with the occurrence and development of various cancers. Targeting the neddylation pathway represents an effective approach for cancer treatment. In this work, we reported that WS-299, structurally featuring a coumarin moiety attached to the triazolopyrimidine, exhibited excellent anti-proliferative activity in MGC-803 and HGC-27 cells. WS-299 exerted potent anticancer effects by inhibiting clone formation, EdU incorporation and inducing cell cycle arrest. WS-299 inhibited CUL3/5 neddylation and caused an obvious accumulation of Nrf2 and NOXA, substrates of CRL3 and CRL5, respectively. Biochemical studies showed that WS-299 inhibited CUL3 neddylation by inhibiting RBX1-UBE2M interaction. The anti-proliferative effect of WS-299 was mainly induced by NOXA-mediated apoptosis. Of note, Nrf2 attenuated WS-299-induced reactive oxygen species (ROS) levels. Furthermore, Nrf2 accumulation also had an antagonistic effect on NOXA-induced apoptosis. Therefore, WS-299 and siNrf2 synergistically increased ROS levels, apoptotic cells and suppressed tumor growth in vivo. Taken together, our research clarified the anti-cancer mechanisms of WS-299 through targeting the RBX1-UBE2M protein-protein interaction and inhibiting the neddylation modification of CUL3 and CUL5. More importantly, our studies also demonstrated that combination of WS-299 with shNrf2 could be an effective strategy for treating gastric cancers.


Assuntos
Fator 2 Relacionado a NF-E2 , Neoplasias Gástricas , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem do Ciclo Celular , Estresse Oxidativo , Proteínas de Transporte/metabolismo , Proteínas Culina/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo
4.
BMC Vet Res ; 20(1): 3, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172758

RESUMO

BACKGROUND: Canine mammary gland cancer (CMGC) is a common neoplasm in intact bitches. However, the benefit of adjuvant chemotherapy is unclear. The aim of this study was to investigate the anti-proliferative effects of paclitaxel on CMGC in in-vitro and in-vivo settings. RESULTS: Paclitaxel dose-dependently inhibited viability and induced G2/M phase cell cycle arrest and apoptosis in both primary and metastatic CMGC cell lines (CIPp and CIPm). In animal experiments, the average tumour volume decreased significantly in proportion to the administered oral paclitaxel dose. By examining tumour tissue using a TUNEL assay and immunohistochemical staining with anti-CD31 as a marker of endothelial differentiation, respectively, it was confirmed that oral paclitaxel induced apoptosis and exerted an anti-angiogenetic effect in tumour tissues. Further, downregulation of cyclin D1 in tumour tissues suggested that oral paclitaxel induced cell cycle arrest in tumour tissues in-vivo. CONCLUSIONS: Our results suggest that paclitaxel may have anti-cancer effects on CMGC through cell cycle arrest, induction of apoptosis, and anti-angiogenesis. This study could provide a novel approach to treat CMGC.


Assuntos
Neoplasias da Mama , Doenças do Cão , Animais , Cães , Camundongos , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Doenças do Cão/tratamento farmacológico , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias da Mama/veterinária
5.
Int J Biol Macromol ; 259(Pt 1): 129177, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38176488

RESUMO

We reported the anti-cervical cancer effect of proprietary saponin content from seeds of Impatiens balsamina L., Hosenkoside A. Our study found that Hosenkoside A significantly promotes cell apoptosis and cell cycle arrest after administration, exhibiting anti-tumor effects. Then the transcriptome sequencing results after administration showed that Hosenkoside A had a significant inhibitory effect on Histone deacetylase 3 (HDAC3). After sufficient administration time, the inhibition of HDAC3 expression level leads to a significant decrease in lysine acetylation at histone 3 sites 4 and 9, blocking the activation of Signal transducer and activator of transcription 3 (STAT3) and achieving anti-tumor effects. In addition, we encapsulated Hosenkoside A into polypeptide metal complexes (PMC) to form slow-release spheres. This material breaks down in the tumor environment, not only does it solve the problem of low drug solubility, but it also achieves targeted sustained-release drug delivery. Under the same concentration of stimulation, the PMC complex group showed better anti-tumor effects in both in vitro and in vivo experiments.


Assuntos
Complexos de Coordenação , Neoplasias do Colo do Útero , Feminino , Humanos , Complexos de Coordenação/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Histonas/metabolismo , Pontos de Checagem do Ciclo Celular , Peptídeos/farmacologia , Peptídeos/metabolismo , Acetilação , Apoptose , Linhagem Celular Tumoral
6.
Chem Biol Drug Des ; 103(1): e14429, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38230769

RESUMO

Considering the therapeutic efficacy of Stachydrine on breast cancer (BC), this study aims to decipher the relevant mechanism. The effects of Stachydrine on BC cell viability, proliferation and apoptosis were firstly investigated. Then, Bioinformatics was applied to sort out the candidate interacting with Stachydrine as well as its expression and downstream target in BC. Relative expressions of genes of interest as well as proliferation- and apoptosis-related factors in BC cells were quantified through quantitative reverse-transcription PCR and western blot as appropriate. As a result, Stachydrine inhibited the proliferation, down-regulated the expressions of proliferating cell nuclear antigen and CyclinD1, enhanced cell cycle arrest and apoptosis, and up-regulated the levels of Cleaved caspase-3 and Cleaved caspase-9 in BC cells. Phospholipase A2 Group IIA (PLA2G2A) was predicted as the candidate interacting with Stachydrine and to be lowly expressed in BC. PLA2G2A silencing reversed while PLA2G2A overexpression reinforced the effects of Stachydrine. Decorin (DCN) was the downstream target of PLA2G2A and also lowly expressed in BC. PLA2G2A silencing counteracted yet overexpressed PLA2G2A strengthened the promoting effects of Stachydrine on DCN level. Collectively, Stachydrine inhibits the growth of BC cells to promote cell cycle arrest and apoptosis via PLA2G2A/DCN axis.


Assuntos
Neoplasias da Mama , MicroRNAs , Prolina/análogos & derivados , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Apoptose , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Linhagem Celular Tumoral , Fosfolipases A2 do Grupo II , Decorina/farmacologia
7.
Nanomedicine (Lond) ; 19(1): 43-58, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38197371

RESUMO

Aim: To fabricate and characterize metformin-loaded PLGA nanoparticles and investigate their inhibitory effect on HepG2 cells. Materials & methods: The nanoparticles were prepared using a double emulsification method, then characterized and subjected to a series of in vitro assays on HepG2 cells. Results: The nanoparticles were ~277.9 nm in size, and the entrapment efficiency and drug loading of metformin were 31.3 and 14.4%, respectively. In vitro studies suggested that the nanoparticles showed a higher inhibitory effect on HepG2 cells compared with metformin alone, mainly attributed to its blockage of autophagy, and ultimately result in cell cycle inhibition. Conclusion: The metformin-loaded PLGA nanoparticles could inhibit mTOR activity, increase p53 levels and decrease HIF1A levels, which ultimately caused HepG2 cell cycle arrest.


Metformin, a well-known drug for the treatment of diabetes, has potential anticancer effects. Our experiment is fabricating metformin into nanoformulations (tiny particles) to enhance its anticancer effect. Cancer cells respond to nutrient-deficient environments by autophagy, this involves breaking down internal structures to scavenge for nutrients, which is one of the reasons why cancer cells are so resilient. If we can interfere with this autophagy of cancer cells, we can reduce the viability of cancer cells. Speaking of autophagy, we have to mention lysosomes, which are acidic organelles within the cell that are the end point of autophagy. Lysosomes need to maintain an acidic environment to ensure the activity of various enzymes within them. These enzymes break down a variety of biological components into 'building blocks' which can be used to make other structures. Our study found that the nanoformulation disrupts the lysosomal acidic environment and thus causes autophagy blockage. As a result, cancer cells are unable to cope with nutrient deficiencies through autophagy and suffer the negative effects of autophagy blockage, such as the inability to degrade damaged organelles and proteins within the cancer cell. This causes the growth and proliferation of cancer cells to slow down and results in the death of the cancer cells.


Assuntos
Metformina , Nanopartículas , Humanos , Metformina/farmacologia , Células Hep G2 , Linhagem Celular Tumoral , Pontos de Checagem do Ciclo Celular , Autofagia , Apoptose
8.
J Gene Med ; 26(1): e3661, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38282144

RESUMO

BACKGROUND: Upregulation of SMC1A (Structural maintenance of chromosomes 1A) is linked with many types of cancer and its oncogenic function, which has been associated with crucial cellular mechanisms (cell division, cell cycle checkpoints regulation and DNA repair). Recent studies have shown that SMC1A was involved in breast cancer, although the exact mechanisms of SMC1A remain to be determined. METHODS: Using The Cancer Genome Atlas (TCGA) database, we examined SMC1A expression and its relation to other genes, including FOXM1 and STMN1. Short hairpin RNA was used to subsequently examine the biological roles of SMC1A in MDA-MB-231 and MDA-MB-468 cell lines. Bioinformatics were performed to identify the SMC1A-related gene FOXM1. RESULTS: Here, we used the TCGA database to show that SMC1A is overexpressed in breast cancer. Later investigations showed SMC1A's role in breast cancer cell survival, apoptosis and invasion. Using bioinformatics and western blot assays, we confirmed that FOXM1 acted as the downstream of SMC1A, and SMC1A knockdown significantly downregulated the FOXM1 expression via the AKT signal pathway. Interestingly, the inhibition effects induced by SMC1A downregulation could be reversed by FOXM1 overexpression. In the clinic, SMC1A expression is favorably linked with FOXM1 expression in breast cancer tumor tissues. CONCLUSIONS: Collectively, our results not only enhance our knowledge of SMC1A's molecular pathways in breast cancer, but also suggest a potential new therapeutic target.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Transdução de Sinais , Pontos de Checagem do Ciclo Celular , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Estatmina/genética
9.
Int J Mol Sci ; 25(2)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38279263

RESUMO

Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision of replication for fast proliferation and increased genomic instability. To overcome the consequences of improper replication control, malignant cells frequently inactivate parts of their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other pathways which help to maintain replication fork stability (ATR-CHK1). This creates a dependency on the remaining DDR pathways, vulnerability to further destabilization of replication and synthetic lethality of DDR inhibitors with common oncogenic alterations such as mutations of TP53, RB1, ATM, amplifications of MYC, CCNE1 and others. The response to RS is normally limited by coordination of cell cycle, transcription and replication. Inhibition of WEE1 and PKMYT1 kinases, which prevent unscheduled mitosis entry, leads to fragility of under-replicated sites. Recent evidence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets-ATR, CHK1, PARP and their inhibitors.


Assuntos
Dano ao DNA , Neoplasias , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Replicação do DNA , Neoplasias/tratamento farmacológico , Neoplasias/genética
10.
J Toxicol Environ Health A ; 87(7): 294-309, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38279841

RESUMO

Piperlongumine (PLN) is a biologically active alkaloid/amide derived from Piper longum, with known promising anticancer activity. The aim of this study was to compare the antiproliferative activity of PLN in human breast MCF-7 adenocarcinoma cell line with effects in HB4a normal mammary epithelial non-tumor cell line. The parameters examined were cell growth, viability, reactive oxygen species (ROS) levels and DNA damage, as well as the effects on the modulating targets responsible through regulation of these pathways. PLN increased ROS levels and expression of the SOD1 antioxidant enzyme. PLN inhibited the expression of the antioxidant enzymes catalase, TRx1, and PRx2. The ability of PLN to inhibit antioxidant enzyme expression was associated with the oxidative stress response. PLN induced genotoxicity in both cell lines and upregulated the levels of GADD45A mRNA and p21 protein. The DNA damage response ATR protein was downregulated in both cell lines and contributed to an enhanced PLN genotoxicity. In HB4a cells, Chk1 protein, and mRNA levels were also decreased. In response to elevated ROS levels and DNA damage induction, the cells were arrested at the G2/M phase, probably in an attempt to promote cell survival. Although cell viability was reduced in both cell lines, only HB4a cells underwent apoptotic cell death, whereas other types of cellular death may be involved in MCF-7 cells. Taken together, these data provide insight into the anticancer mechanisms attributed to PLN effects, which acts as an inhibitor of DNA damage response (DDR) proteins and antioxidant enzymes.


Assuntos
Antioxidantes , Benzodioxóis , Dano ao DNA , Humanos , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/farmacologia , Células MCF-7 , Apoptose , Ciclo Celular , Pontos de Checagem do Ciclo Celular , RNA Mensageiro , Linhagem Celular Tumoral
11.
Cell Death Dis ; 15(1): 74, 2024 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-38242874

RESUMO

Copy number variations (CNVs) play a vital role in regulating genes expression and tumorigenesis. We explored the copy number alterations in early-stage lung adenocarcinoma using high-throughput sequencing and nucleic acid flight mass spectrometry technology, and found that 8q22.1-22.2 is frequently amplified in lung adenocarcinoma tissues. COX6C localizes on the region and its expression is notably enhanced that driven by amplification in lung adenocarcinoma. Knockdown of COX6C significantly inhibits the cell proliferation, and induces S-G2/M cell cycle arrest, mitosis deficiency and apoptosis. Moreover, COX6C depletion causes a deficiency in mitochondrial fusion, and impairment of oxidative phosphorylation. Mechanistically, COX6C-induced mitochondrial deficiency stimulates ROS accumulation and activates AMPK pathway, then leading to abnormality in spindle formation and chromosome segregation, activating spindle assemble checkpoint, causing mitotic arrest, and ultimately inducing cell apoptosis. Collectively, we suggested that copy amplification-mediated COX6C upregulation might serves as a prospective biomarker for prognosis and targeting therapy in patients with lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Proliferação de Células , Complexo IV da Cadeia de Transporte de Elétrons , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Variações do Número de Cópias de DNA/genética , Pontos de Checagem da Fase G2 do Ciclo Celular , Neoplasias Pulmonares/patologia , Mitose/genética , Espécies Reativas de Oxigênio/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo
12.
Biomed Pharmacother ; 171: 116179, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38278023

RESUMO

BACKGROUND: Acute erythroleukemia (AEL) is acute myeloid leukemia characterized by malignant erythroid proliferation. AEL has a low survival rate, which has seriously threatened the health of older adults. Calothrixin B is a carbazole alkaloid isolated from the cyanobacteria Calothrix and exhibits anti-cancer activity. To discover more potential anti-erythroleukemia compounds, we used calothrixin B as the structural skeleton to synthesize a series of new compounds. METHODS: In the cell culture model, we evaluated apoptosis and cell cycle arrest using MTT assay, flow cytometry analysis, JC-1 staining, Hoechst 33258 staining, and Western blot. Additionally, assessing the curative effect in the animal model included observation of the spleen, HE staining, flow cytometry analysis, and detection of serum biochemical indexes. RESULTS: Among the Calothrixin B derivatives, H-107 had the best activity against leukemic cell lines. H-107 significantly inhibited the proliferation of HEL cells with an IC50 value of 3.63 ± 0.33 µM. H-107 induced apoptosis of HEL cells by damaging mitochondria and activating the caspase cascade and arrested HEL cells in the G0/G1 phase. Furthermore, H-107 downregulated the protein levels Ras, p-Raf, p-MEK, p-ERK and c-Myc. Pretreatment with ERK inhibitor (U0126) increased H-107-induced apoptosis. Thus, H-107 inhibited the proliferation of HEL cells by the ERK /Ras/Raf/MEK signal pathways. Interestingly, H-107 promoted erythroid differentiation into the maturation of erythrocytes and effectively activated the immune cells in erythroleukemia mice. CONCLUSION: Overall, our findings suggest that H-107 can potentially be a novel chemotherapy for erythroleukemia.


Assuntos
Alcaloides Indólicos , Leucemia Eritroblástica Aguda , Animais , Camundongos , Sistema de Sinalização das MAP Quinases , Pontos de Checagem do Ciclo Celular , Apoptose , Quinases de Proteína Quinase Ativadas por Mitógeno , Proliferação de Células , Ciclo Celular , Linhagem Celular Tumoral
13.
Int J Mol Sci ; 25(2)2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38256052

RESUMO

Breast cancer stands out as the most widespread form of cancer globally. In this study, the anticancer activities of Clerodendrum chinense (C. chinense) stem ethanolic extract were investigated. High-performance liquid chromatography (HPLC) analysis identified verbascoside and isoverbascoside as the major bioactive compounds in the C. chinense stem extract. Successfully developed nanoparticles exhibited favorable hydrodynamic diameter, polydispersity index, and surface charge, thus ensuring stability after four months of storage. The total phenolic content and total flavonoid contents in the nanoparticles were reported as 88.62% and 95.26%, respectively. The C. chinense stem extract demonstrated a dose-dependent inhibitory effect on MCF-7, HeLa, A549, and SKOV-3 cancer cell lines, with IC50 values of 109.2, 155.6, 206.9, and 423 µg/mL, respectively. C. chinense extract and NPs exhibited dose-dependent cytotoxicity and the highest selectivity index values against MCF-7 cells. A dose-dependent reduction in the colony formation of MCF-7 cells was observed following treatment with the extract and nanoparticles. The extract induced cytotoxicity in MCF-7 cells through apoptosis and necrosis. C. chinense stem extract and nanoparticles decreased mitochondrial membrane potential (MMP) and induced G0/G1 phase arrest in MCF-7 cells. In conclusion, use of C. chinense stem extract and nanoparticles may serve as a potential therapeutic approach for breast cancer, thus warranting further exploration.


Assuntos
Adenocarcinoma , Neoplasias da Mama , Clerodendrum , Humanos , Feminino , Potencial da Membrana Mitocondrial , Neoplasias da Mama/tratamento farmacológico , Apoptose , Pontos de Checagem do Ciclo Celular , Células HeLa , Proliferação de Células , Extratos Vegetais/farmacologia
14.
Bioorg Med Chem Lett ; 99: 129598, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38169246

RESUMO

The synthesis of compounds based on fragments derived from natural products (NPs) serves as a source of inspiration for the design of pseudo-natural products (PNPs), to identify bioactive molecules that exhibit similar characteristics to NPs. These novel molecular scaffolds exhibit previously unexplored biological activities as well. This study reports the development and synthesis of a novel pentacyclic ring system, the indole-pyrimidine-quinoline (IPQ) scaffold. The design of this scaffold was based on the structural characteristics of four natural products, namely tryptanthrin, luotonin A, rutaecarpine, and camptothecin. Several successive steps accomplished the effective synthesis of the IPQ scaffold. The constituent components of the pentacycle, containing the indole, quinazolinone, pyrimidone, and quinoline units, possess significant biological significance. Compound 1a demonstrated noteworthy anti-tumor activity efficacy against A549 cell lines among the tested compounds. The compound 1a was observed to elicit cell cycle arrest in both the G2/M and S phases, as well as trigger apoptosis in A549 cells. These effects were attributed to its ability to modulate the activation of mitochondrial-related mitogen-activated protein kinase (MAPK) signaling pathways.


Assuntos
Antineoplásicos , Produtos Biológicos , Quinolinas , Antineoplásicos/química , Apoptose , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Quinolinas/farmacologia , Indóis/química , Indóis/farmacologia , Pirimidinas
15.
ACS Chem Biol ; 19(1): 173-184, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38193430

RESUMO

Small molecules that induce protein degradation hold the potential to overcome several limitations of the currently available inhibitors. Monovalent or molecular glue degraders, in particular, enable the benefits of protein degradation without the disadvantages of high molecular weight and the resulting challenge in drug development that are associated with bivalent molecules like Proteolysis Targeting Chimeras. One key challenge in designing monovalent degraders is how to build in the degrader activity─how can we convert an inhibitor into a degrader? If degradation activity requires very specific molecular features, it will be difficult to find new degraders and challenging to optimize those degraders toward drugs. Herein, we demonstrate that an unexpectedly wide range of modifications to the degradation-inducing group of the cyclin K degrader CR8 are tolerated, including both aromatic and nonaromatic groups. We used these findings to convert the pan-CDK inhibitors dinaciclib and AT-7519 to Cyclin K degraders, leading to a novel dinaciclib-based compound with improved degradation activity compared to CR8 and confirm the mechanism of degradation. These results suggest that general design principles can be generated for the development and optimization of monovalent degraders.


Assuntos
Ciclinas , Proteólise , Pontos de Checagem do Ciclo Celular , Ciclinas/metabolismo
16.
Nat Commun ; 15(1): 79, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167301

RESUMO

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.


Assuntos
Ferroptose , Neoplasias , Humanos , Gotículas Lipídicas/metabolismo , Ácidos Graxos Insaturados/metabolismo , Peroxidação de Lipídeos , Triglicerídeos/metabolismo , Pontos de Checagem do Ciclo Celular , Neoplasias/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico
17.
Future Med Chem ; 16(4): 369-388, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38288571

RESUMO

Cyclin-dependent kinases (CDKs) play an important role in the regulation of cell proliferation, and many CDK inhibitors were developed. However, pan-CDK inhibitors failed to be approved due to intolerant toxicity or low efficacy and the use of selective CDK4/6 inhibitors is limited by resistance. Protein degraders have the potential to increase selectivity, efficacy and overcome resistance, which provides a novel strategy for regulating CDKs. In this review, we summarized the function of CDKs in regulating the cell cycle and transcription, and introduced the representative CDK inhibitors. Then we made a detailed introduction about four types of CDKs degraders, including their action mechanisms, research status and application prospects, which could help the development of novel CDKs degraders.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Quinases Ciclina-Dependentes , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pontos de Checagem do Ciclo Celular , Ciclo Celular , Neoplasias/tratamento farmacológico , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Quinase 2 Dependente de Ciclina
18.
Biochim Biophys Acta Gen Subj ; 1868(2): 130535, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38103757

RESUMO

BACKGROUND: Calcimycin (A23187) is a polyether antibiotic and divalent cation ionophore, extracted from Streptomyces chartrecensis. With wide variety of antimicrobial activities, it also exhibits cytotoxicity of tumor cells. Calcimycin exhibit therapeutic potential against tumor cell growth; however, the molecular mechanism remains to be fully elucidated. Present study explores the mechanism of calcimycin-induced apoptosis cancer cell lines. METHODS: Apoptotic induction in a dose-dependent manner were recorded with MTT assays, Phase contrast imaging, wound healing assay, fluorescence imaging by DAPI and AO/EB staining and FACS using cell line model. Mitochondrial potential was analyzed by TMRM assay as Ca2+ signaling is well known to be influenced and synchronized by mitochondria also. RESULTS: Calcimycin induces apoptosis in dose dependent manner, also accompanied by increased intracellular calcium-level and expression of purinergic receptor-P2RX4, a ligand-gated ion channel. CONCLUSION: Calcimycin tends to increase the intracellular calcium level, mRNA expression of ATP receptor P2RX4, and phosphorylation of p38. Blocking of either intracellular calcium by BAPTA-AM, P2RX4 expression by antagonist 5-BDBD, and phospho-p38 by SB203580, abrogated the apoptotic activity of calcimycin. GENERAL SIGNIFICANCE: Taken together, these results show that calcimycin induces apoptosis in P2RX4 and ATP mediated intracellular Ca2+ and p38 MAPK mediated pathway in both the cancer cell lines. This study explored a new mode of action for calcimycin in cancer that could be potentially employed in future studies for cancer therapeutic research. This study disentangles that the calcimycin-induced apoptotic cell death is P2RX4 and ATP involved, intracellular Ca2+ and p38 MAPK mediated pathway.


Assuntos
Apoptose , Calcimicina , Cálcio , Receptores Purinérgicos P2X4 , Células MCF-7 , Linhagem Celular Tumoral , Humanos , Calcimicina/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Espaço Intracelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Bioorg Chem ; 142: 106952, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37952486

RESUMO

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Neoplasias de Mama Triplo Negativas/patologia , Proteômica , Proliferação de Células , Pontos de Checagem do Ciclo Celular , Nitrogênio , Linhagem Celular Tumoral , Fosfatases cdc25 , Poli(ADP-Ribose) Polimerase-1 , Proteína Quinase CDC2
20.
Bioorg Med Chem Lett ; 97: 129550, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37952598

RESUMO

The current study aimed to test the antiproliferative activity of three azafuramidines (X, Y, and Z) against three different human cell lines; liver HepG2, breast MCF-7, and bone U2OS. And to explore the molecular mechanism(s) of the antiproliferative activity of these derivatives. The three new azafuramidines demonstrated a potent cytotoxicity at < 2 µM against the three cell lines investigated. The azafuramidines were highly selective with selectivity index âˆ¼ 47 - 61 folds indicating safety to the normal cells. In the scratch assay, azafuramidines significantly reduced the percentage of wound healing indicating ability to prevent or reduce metastasis. Derivatives X and Z arrested the HepG2 cells at S and G2/M phases detected by the flow cytometry. Derivatives X, Y, and Z elevated the apoptosis of HepG2 cells by âˆ¼ 71 %, 66 %, and 59 %, respectively. Derivatives X and Z were superior to derivative Y. The potent antiproliferative, cell cycle arrest, and pro-apoptotic efficacy of these chlorophenyl derivatives could be attributed to their ability of inducing the overexpression of p53, p21, and p27. These derivatives had the potential to act as anticancer agents and merit further investigations.


Assuntos
Antineoplásicos , Benzamidinas , Humanos , Antineoplásicos/farmacologia , Apoptose , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Benzamidinas/química , Benzamidinas/farmacologia
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