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1.
Anticancer Res ; 40(10): 5517-5527, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988875

RESUMO

BACKGROUND/AIM: Drug resistance is a significant cause of high mortality in ovarian cancer (OC) patients. The reverse transcriptase inhibitor azidothymidine (AZT) has been utilized as a treatment for tumors, but its role in OC treatment has not been revealed. The aim of the present in vitro study was to examine the influence of AZT on the growth of human OC cells and the involved proteins. MATERIALS AND METHODS: The proliferation, cell cycle distribution, extent of apoptosis, mitotic index, and terminal restriction fragment length were examined in three OC cell lines, CaOV3, TOV112D, and TOV21G, treated with AZT. RESULTS: AZT inhibited growth of the TOV21G and CaOV3 cell lines by regulating cell cycle distribution. Specifically, AZT caused G2/M phase arrest on TOV21G cells and S phase arrest on CaOV3 cells. In addition, AZT treatment induced up-regulation of p21 and p16 in the TOV21G and CaOV3 cell line, respectively. CONCLUSION: AZT inhibited cell proliferation in serous and clear cell OC via the regulation of cell cycle distribution.


Assuntos
Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Zidovudina/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
2.
Anticancer Res ; 40(9): 4979-4987, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878786

RESUMO

BACKGROUND/AIM: Multiple myeloma is a highly heterogeneous disease of clonal plasma cells. Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their precise mechanisms of actions are not well understood. MATERIALS AND METHODS: Cell-cycle regulation and pro-apoptotic effects of two histone deacetylase inhibitors, suberohydroxamic acid (SAHA) and suberoylanilide hydroxamic acid (SBHA), were analyzed in multiple myeloma cell lines RPMI8226 and U266 with differing TP53 status using gene-expression analysis. RESULTS: Enhanced expression of cyclin-dependent kinase inhibitor 1A (CDKN1A/p21WAF/CIP1) detected in the TP53-deleted U266 cell line after SAHA treatment indicates the P53-independent mode of transcriptional activation of CDKN1A gene. In contrast, CDKN1A gene expression was significantly increased by both SBHA and SAHA treatment of TP53-mutated RPMI8226 cells. CONCLUSION: SAHA appears to be a potentially effective pro-apoptotic and anticancer drug with universal application in the treatment of heterogeneous populations of multiple myeloma cells.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Mieloma Múltiplo/patologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteína Supressora de Tumor p53/genética
3.
Anticancer Res ; 40(9): 5191-5200, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878807

RESUMO

BACKGROUND/AIM: Colorectal cancer is one of the most common malignancies worldwide. Small molecule-based chemotherapy is an attractive approach for the chemoprevention and treatment of colorectal cancer. Methylsulfonylmethane (MSM) is a natural organosulfur compound with anticancer properties, as revealed by studies on in vitro models of gingival, prostate, lung, hepatic, and breast cancer. However, the molecular mechanisms underlying the effects of MSM in colon cancer cells remain unclear. MATERIALS AND METHODS: Here, we investigated the effects of MSM, especially on the cell cycle arrest and apoptosis, in HT-29 cells. RESULTS: MSM suppressed the viability of HT-29 cells by inducing apoptosis and cell cycle arrest at the G0/G1 phase. MSM suppressed the sphere-forming ability and expression of stemness markers in HT-29 cells. CONCLUSION: MSM has anti-cancer effects on HT-29 cells, and induces cell cycle arrest and apoptosis, while suppressing the stemness potential.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Sulfonas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HT29 , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Esferoides Celulares , Células Tumorais Cultivadas
4.
Tumour Biol ; 42(9): 1010428320954735, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32873193

RESUMO

Acute myeloid leukemia is the most common form of acute leukemia in adults, constituting about 80% of cases. Although remarkable progress has been made in the therapeutic scenario for patients with acute myeloid leukemia, research and development of new and effective anticancer agents to improve patient outcome and minimize toxicity is needed. In this study, the antitumor activity of axolotl (AXO) Ambystoma mexicanum crude extract was assessed in vitro on the human acute myeloid leukemia HL-60 cell line. The anticancer activity was evaluated in terms of ability to influence proliferative activity, cell viability, cell cycle arrest, and differentiation. Moreover, gene expression analysis was performed to evaluate the genes involved in the regulation of these processes. The AXO crude extract exhibited antiproliferative but not cytotoxic activities on HL-60 cells, with cell cycle arrest in the G0/G1 phase. Furthermore, the AXO-treated HL-60 cells showed an increase in both the percentage of nitroblue tetrazolium positive cells and the expression of CD11b, whereas the proportion of CD14-positive cells did not change, suggesting that extract is able to induce differentiation toward the granulocytic lineage. Finally, the treatment with AXO extract caused upregulation of CEBPA, CEBPB, CEBPE, SPI1, CDKN1A, and CDKN2C, and downregulation of c-MYC. Our data clearly show the potential anticancer activity of Ambystoma mexicanum on HL-60 cells and suggest that it could help develop promising therapeutic agents for the treatment of acute myeloid leukemia.


Assuntos
Ambystoma mexicanum , Proliferação de Células/efeitos dos fármacos , Misturas Complexas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-myc/genética
5.
Chem Biol Interact ; 330: 109229, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32835667

RESUMO

Cell cycle dysregulation is the mainstay of aberrant cell proliferation, which leads to tumor progression. Mutations in tumor cells initiate various dysregulated pathways and spontaneous over-proliferation with genomic/chromosomal instability. Despite advances in cancer therapy, it has remained a medicinal challenge to treat. Besides, the complexity of pathophysiological pathways behind cancer raises the need for novel multi-target agents, possessing fewer side effects. Alkaloid-based therapies have been explored so far to target cell division in cancer, including vinca alkaloids. As a class of hopeful ß-carboline derivatives, growing evidence has indicated their auspicious roles in combating cancer by inhibiting topoisomerase (TOPO), kinesin Eg5, telomerase, cyclin-dependent kinase (CDK), IκB kinase (IKK), and polo-like kinase-1 (PLK1) in the transition phases of cell cycle. In this review, in vitro potential of ß-carboline has been revealed through targeting cell division cycle at different phases. In conclusion, ß-carboline alkaloids could be introduced as novel candidates in cancer therapy.


Assuntos
Carbolinas/farmacologia , Ciclo Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Carbolinas/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Humanos
6.
Yonsei Med J ; 61(7): 587-596, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32608202

RESUMO

PURPOSE: The current study aimed to investigate the synergistic antitumor effect of combined treatment with 17-DMAG (HSP90 inhibitor) and NVP-BEZ235 (PI3K/mTOR dual inhibitor) on cisplatin-resistant human bladder cancer cells. MATERIALS AND METHODS: Human bladder cancer cells exhibiting cisplatin resistance (T24R2) were exposed to escalating doses of 17-DMAG (2.5-20 nM) with or without NVP-BEZ236 (0.5-4 µM) in combination with cisplatin. Antitumor effects were assessed by CCK-8 analysis. Based on the dose-response study, synergistic interactions between the two regimens were evaluated using clonogenic assay and combination index values. Flow cytometry and Western blot were conducted to analyze mechanisms of synergism. RESULTS: Dose- and time-dependent antitumor effects for 17-DMAG were observed in both cisplatin-sensitive (T24) and cisplatin-resistant cells (T24R2). The antitumor effect of NVP-BEZ235, however, was found to be self-limiting. The combination of 17-DMAG and NVP-BEZ235 in a 1:200 fixed ratio showed a significant antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range, and clonogenic assay showed compatible results with synergy tests. Three-dimensional analysis revealed strong synergy between the two drugs with a synergy volume of 201.84 µM/mL²%. The combination therapy resulted in G1-phase cell cycle arrest and caspase-dependent apoptosis confirmed by the Western blot. CONCLUSION: HSP90 inhibitor monotherapy and in combination with the PI3K/mTOR survival pathway inhibitor NVP-BEZ235 shows a synergistic antitumor effect in cisplatin-resistant bladder cancers, eliciting cell cycle arrest at the G1 phase and induction of caspase-dependent apoptotic pathway.


Assuntos
Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Lactamas Macrocíclicas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Dano ao DNA/efeitos dos fármacos , Humanos , Imidazóis , Lactamas Macrocíclicas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Quinolinas , Serina-Treonina Quinases TOR/metabolismo
7.
Nucleic Acids Res ; 48(14): 7844-7855, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32652013

RESUMO

The catalytic activity of human AURORA-A kinase (AURKA) regulates mitotic progression, and its frequent overexpression in major forms of epithelial cancer is associated with aneuploidy and carcinogenesis. Here, we report an unexpected, kinase-independent function for AURKA in DNA replication initiation whose inhibition through a class of allosteric inhibitors opens avenues for cancer therapy. We show that genetic depletion of AURKA, or its inhibition by allosteric but not catalytic inhibitors, blocks the G1-S cell cycle transition. A catalytically inactive AURKA mutant suffices to overcome this block. We identify a multiprotein complex between AURKA and the replisome components MCM7, WDHD1 and POLD1 formed during G1, and demonstrate that allosteric but not catalytic inhibitors prevent the chromatin assembly of functional replisomes. Indeed, allosteric but not catalytic AURKA inhibitors sensitize cancer cells to inhibition of the CDC7 kinase subunit of the replication-initiating factor DDK. Thus, our findings define a mechanism essential for replisome assembly during DNA replication initiation that is vulnerable to inhibition as combination therapy in cancer.


Assuntos
Aurora Quinase A/fisiologia , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Complexos Multienzimáticos/metabolismo , Regulação Alostérica , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular , Pontos de Checagem da Fase G1 do Ciclo Celular , Células HeLa , Humanos , Interfase/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Origem de Replicação
8.
Chem Biol Interact ; 328: 109200, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32702347

RESUMO

Activation of Notch signaling is associated with tumor aggressiveness, poor clinical outcome and drug resistance in breast cancer patients. Targeting Notch signaling with small molecule inhibitors may be a better strategy for anticancer drug development. We identified 3-O-(E)-p-Coumaroylbetulinic acid (CB) as a lead compound and potent inhibitor of Notch signaling pathway. Treatment of human breast cancer MBA-MD-231 and T47D cells with CB resulted in a dose- and time-dependent inhibition of cell viability and G0/G1-phase cell cycle arrest. This effect was associated with a marked decrease in the expression of cyclin D1 and its activating partner, cyclin-dependent kinase 2 with concomitant increase in cyclin kinase inhibitor p21, operative in G1-phase of the cell cycle. CB treatment induced early apoptosis in breast cancer cells as evident by increase in cleaved caspase-3, decrease in Bcl2 and survivin, surge in reactive oxygen species and disruption of mitochondrial membrane potential. CB treatment altered Notch target genes viz. Hes1, Hey1 and E-cadherin at mRNA and protein level in time-dependent manner along with decrease in Notch promoter activity at IC50 concentration. Furthermore, CB treatment decreased mammosphere formation in MCF-7 cells through down-modulation of the Notch signaling pathway and suppression of self-renewal markers such as c-Myc, SOX-2 and CD44. Our findings demonstrate that CB possess anticancer activity in breast cancer cells and suppresses self-renewal ability in the mammosphere as a result of modulation in cell-cycle machinery, disruption of mitochondrial function, induction of apoptosis, and Notch inhibition.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
9.
Anticancer Res ; 40(8): 4695-4700, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727794

RESUMO

BACKGROUND/AIM: We investigated the anti-proliferative effect of quercetin on liver cancer cell lines. MATERIALS AND METHODS: Thirteen liver cancer cell lines were cultured followed by treatment with varying concentrations of quercetin (0-100 µM) or quercetin and 5-FU, and the cell viability was analysed by the MTT assay. Flow cytometry was also used to examine cell cycle progression after treatment with quercetin. RESULTS: The addition of quercetin resulted in a dose- and time-dependent suppression of cell proliferation. In some cell lines, treatment with quercetin and 5-FU caused an additional or synergistic effect. Most cell lines displayed cell cycle arrest at different phases of the cell cycle. CONCLUSION: Quercetin inhibits the proliferation of liver cancer cells via induction of apoptosis and cell cycle arrest.


Assuntos
Neoplasias Hepáticas/tratamento farmacológico , Quercetina/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia
10.
PLoS One ; 15(7): e0234103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645016

RESUMO

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).


Assuntos
Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Animais , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/efeitos dos fármacos , Quinase 9 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Humanos , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/farmacologia
11.
Toxicol Lett ; 332: 74-81, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32645459

RESUMO

Long-term exposure to benzene is associated with adverse health effects such as leukemia. Abnormal cell cycle progression has been reported participating in tumorigenesis. Our previous study found that lncRNA-OBFC2A was involved in benzene toxicity through regulating cell proliferation. However, the function of lncRNA-OBFC2A in the regulation of cell cycle remains obscure and the precise mechanisms need to be explored. In vitro study, results showed that benzene metabolic, 1,4-Benzoquinone (1,4-BQ), induced cell cycle arrest at the G1 phase accompanied with decreased expression of Cyclin D1 in a dose-dependently manner. Interestingly, lncRNA-OBFC2A overexpression was found in AHH-1 cells treated with 1,4-BQ and while interference with lncRNA-OBFC2A, the expression of Cyclin D1 were reversed. Further, we found that lncRNA-OBFC2A can interact with Smad3 to control cell cycle via modulating Cyclin D1 expression. In benzene exposed workers, the expression of lncRNA-OBFC2A and Smad3 increased while cyclin D1 decreased which was consistent with the in vitro experiment, meanwhile, the significant associations among them were also found. Thus, these findings indicate that lncRNA-OBFC2A targeted to Smad3 regulated cyclin D1 influences cell cycle arrest induced by 1,4-BQ. LncRNA-OBFC2A, Smad3 and Cyclin D1 as a set of biomarkers play important roles in benzene haematotoxicity.


Assuntos
Benzoquinonas/toxicidade , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ciclina D1/efeitos dos fármacos , RNA Longo não Codificante/efeitos dos fármacos , Proteína Smad3/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Fase G1/efeitos dos fármacos , Doenças Hematológicas/induzido quimicamente , Neoplasias Hematológicas/induzido quimicamente , Humanos , Proteômica
12.
PLoS One ; 15(6): e0232068, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559187

RESUMO

Cyclin Dependent Kinase 9 (CDK9) associates with Bromodomain and Extra-Terminal Domain (BET) proteins to promote transcriptional elongation by phosphorylation of serine 2 of RNAP II C-terminal domain. We examined the therapeutic potential of selective CDK9 inhibitors (AZD 4573 and MC180295) against human multiple myeloma cells in vitro. Short-hairpin RNA silencing of CDK9 in Multiple Myeloma (MM) cell lines reduced cell viability compared to control cells showing the dependency of MM cells on CDK9. In order to explore synergy with the CDK9 inhibitor, proteolysis targeting chimeric molecule (PROTAC) ARV 825 was added. This latter drug causes ubiquitination of BET proteins resulting in their rapid and efficient degradation. Combination treatment of MM cells with ARV 825 and AZD 4573 markedly reduced their protein expression of BRD 2, BRD 4, MYC and phosphorylated RNA pol II as compared to each single agent alone. Combination treatment synergistically inhibited multiple myeloma cells both in vitro and in vivo with insignificant weight loss. The combination also resulted in marked increase of apoptotic cells at low dose compared to single agent alone. Taken together, our studies show for the first time that the combination of a BET PROTAC (ARV 825) plus AZD 4573 (CDK9 inhibitor) is effective against MM cells.


Assuntos
Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas/metabolismo , Proteólise/efeitos dos fármacos , Animais , Azepinas/farmacologia , Azepinas/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 9 Dependente de Ciclina/genética , Quinase 9 Dependente de Ciclina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Camundongos , Camundongos SCID , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , RNA Polimerase II/metabolismo , RNA Interferente Pequeno/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Talidomida/uso terapêutico , Transplante Heterólogo
13.
Prostate ; 80(12): 993-1005, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32559345

RESUMO

BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay of treatment for castration-resistant prostate cancer (CRPC). Unfortunately, although ADT initially prolongs survival, most patients relapse and develop resistance. Clinical failure of these treatments in CRPC highlights the urgent need to develop novel strategies to more effectively block androgen receptor (AR) signaling and target other oncogenic factors responsible for ADT resistance. METHODS: We developed a small-molecule compound LG1836 and investigated the in vitro and in vivo activity of LG1836 against CRPC in cellular and animal models. RESULTS: LG1836 exhibits potent in vitro cytotoxicity in CRPC cells. Mechanistic studies demonstrated that LG1836 inhibits the expression of AR and AR variant 7, partially mediated via proteasome-dependent protein degradation. LG1836 also suppresses survivin expression and effectively induces apoptosis in CRPC cells. Significantly, as a single agent, LG1836 is therapeutically efficacious in suppressing the in vivo growth of CRPC in the subcutaneous and intraosseous models and extends the survival of tumor-bearing mice. CONCLUSIONS: These preclinical studies indicate that LG1836 is a promising lead compound for the treatment of CRPC.


Assuntos
Piperidinas/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Neoplasias de Próstata Resistentes à Castração/patologia , Distribuição Aleatória , Receptores Androgênicos/biossíntese , Receptores Androgênicos/metabolismo , Survivina/antagonistas & inibidores , Survivina/biossíntese , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Mol Cell Biol ; 40(17)2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32541066

RESUMO

Rad3 is the orthologue of ATR and the sensor kinase of the DNA replication checkpoint in Schizosaccharomyces pombe Under replication stress, it initiates checkpoint signaling at the forks necessary for maintaining genome stability and cell survival. To better understand the checkpoint initiation process, we have carried out a genetic screen in fission yeast by random mutation of the genome, looking for mutants defective in response to the replication stress induced by hydroxyurea. In addition to the previously reported mutant with a C-to-Y change at position 307 encoded by tel2 (tel2-C307Y mutant) (Y.-J. Xu, S. Khan, A. C. Didier, M. Wozniak, et al., Mol Cell Biol 39:e00175-19, 2019, https://doi.org/10.1128/MCB.00175-19), this screen has identified six mutations in rqh1 encoding a RecQ DNA helicase. Surprisingly, these rqh1 mutations, except for a start codon mutation, are all in the helicase domain, indicating that the helicase activity of Rqh1 plays an important role in the replication checkpoint. In support of this notion, integration of two helicase-inactive mutations or deletion of rqh1 generated a similar Rad3 signaling defect, and heterologous expression of human RECQ1, BLM, and RECQ4 restored the Rad3 signaling and partially rescued a rqh1 helicase mutant. Therefore, the replication checkpoint function of Rqh1 is highly conserved, and mutations in the helicase domain of these human enzymes may cause the checkpoint defect and contribute to the cancer predisposition syndromes.


Assuntos
Quinase do Ponto de Checagem 2/metabolismo , DNA Helicases/metabolismo , Replicação do DNA , DNA Fúngico/biossíntese , Proteínas de Schizosaccharomyces pombe/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/genética , DNA Helicases/genética , DNA Fúngico/genética , DNA Fúngico/metabolismo , Instabilidade Genômica , Hidroxiureia/farmacologia , Proteínas Quinases/metabolismo , RecQ Helicases/genética , RecQ Helicases/metabolismo , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Transdução de Sinais/efeitos dos fármacos
15.
Nat Chem Biol ; 16(7): 716-724, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32572259

RESUMO

Largely non-overlapping sets of cyclin-dependent kinases (CDKs) regulate cell division and RNA polymerase II (Pol II)-dependent transcription. Here we review the molecular mechanisms by which specific CDKs are thought to act at discrete steps in the transcription cycle and describe the recent emergence of transcriptional CDKs as promising drug targets in cancer. We emphasize recent advances in understanding the transcriptional CDK network that were facilitated by development and deployment of small-molecule inhibitors with increased selectivity for individual CDKs. Unexpectedly, several of these compounds have also shown selectivity in killing cancer cells, despite the seemingly universal involvement of their target CDKs during transcription in all cells. Finally, we describe remaining and emerging challenges in defining functions of individual CDKs in transcription and co-transcriptional processes and in leveraging CDK inhibition for therapeutic purposes.


Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , RNA Polimerase II/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Humanos , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteínas Quinases/química , Proteólise , RNA Polimerase II/antagonistas & inibidores , RNA Polimerase II/metabolismo , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/química , Transcrição Genética
16.
Crit Rev Oncol Hematol ; 151: 102979, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32480349

RESUMO

Treatment of oncologic patients has progressed greatly the last few years with the development of immune checkpoint inhibitors (ICPIs). These drugs are associated with the immune system and, thus, may cause side effects of immune origin, the so called immune related adverse events (irAEs). Immune related AEs may actually affect all organs and systems and frequently resemble clinical entities commonly encountered in clinical practice. As ICPIs have improved both quality of life and life expectancy, clinicians of various specialties may need to deal with irAEs in their everyday practice. Therefore, they should be able to recognize them timely and treat them accordingly. Herein, we review the pathophysiology, clinical manifestations and treatment of irAEs.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Imunoterapia/efeitos adversos , Doenças Metabólicas/induzido quimicamente , Neoplasias/tratamento farmacológico , Humanos , Qualidade de Vida
17.
Anticancer Res ; 40(6): 3209-3220, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487615

RESUMO

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is one among the most common cancers worldwide. Recently, dietary phytochemicals have been reported as an attractive approach to improve the symptoms of NSCLC patients. Tannic acid is a natural polyphenol, which is known to have anticancer effects on in vitro models of breast, gingival and colon cancer. However, the molecular mechanisms associated with the actions of tannic acid on A549 human lung cancer cells have not been elucidated. MATERIALS AND METHODS: In this study, we analyzed the effect of tannic acid on A549 cells and their underlying mechanisms using western blotting, flow cytometry, invasion assay and tumorsphere formation assay. RESULTS: Tannic acid treatment suppressed the viability of A549 cells through cell cycle arrest and induction of the intrinsic pathways of apoptosis. In addition, the various malignant phenotypes of A549 cells including invasion, migration, and stemness were inhibited by tannic acid treatment. CONCLUSION: Tannic acid could be used as an effective inhibitor of lung cancer progression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Taninos/uso terapêutico , Células A549 , Apoptose , Linhagem Celular Tumoral , Humanos , Transdução de Sinais , Taninos/farmacologia
18.
Life Sci ; 256: 117971, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553925

RESUMO

AIMS: Multiple myeloma (MM) was recently reported to rely on increased oxidative phosphorylation (OXPHOS) for survival, providing a potential opportunity for MM therapy. Herein, we aimed to propose a novel targeted drug for MM treatment, followed by the exploration of reason for OXPHOS enhancement in MM cells. MATERIALS AND METHODS: The expression of OXPHOS genes and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was analyzed using bioinformatics analyses, followed by verification in MM cell lines. The effects of SR18292 on OXPHOS were measured by qRT-PCR, Western blot, transmission electron microscopy, oxygen consumption rate and so on. The proliferation and apoptosis were evaluated by CCK-8, flow cytometry and Western blot. The efficiency and safety of SR18292 were assessed in a mouse model of MM. KEY FINDINGS: The OXPHOS genes were generally overexpressed in MM cells, which was associated with poorer prognosis of MM patients. PGC-1α, a transcriptional coactivator, was upregulated in MM cells, and MM patients with higher PGC-1α expression exhibited increased enrichment of the OXPHOS gene set. Treatment with SR18292 (an inhibitor of PGC-1α) significantly impaired the proliferation and survival of MM cells due to OXPHOS metabolism dysfunction, which leads to energy exhaustion and oxidative damage. Besides, SR18292 potently inhibited tumor growth at a well-tolerated dose in MM model mice. SIGNIFICANCE: The overexpression of OXPHOS gene set mediated by upregulated PGC-1α provides a structural basis for enhanced OXPHOS in MM cells, and SR18292 (a PGC-1α inhibitor) exerts potent antimyeloma effects, offering a potential tangible avenue for MM therapy.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Fosforilação Oxidativa , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Metabolismo Energético/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Mieloma Múltiplo/ultraestrutura , Fosforilação Oxidativa/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Life Sci ; 256: 117983, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32565252

RESUMO

Estrogen receptor (ER) positive accounts for a large proportion of breast cancer. Although there are many targeted therapeutic drugs, the emergence of drug resistance urgently requires the development of new drugs. Arctigenin (Arc), a lignan found in certain plants of the Asteraceae, has the effect on inhibiting breast cancer, but its molecular mechanism has not been clear. AIMS: To this end, the current study focuses on understanding the mechanism of Arc on ER-positive breast cancer cells. MAIN METHODS: Colony formation experiments and sulforhodamine B methods were used to determine the growth-inhibitory effect of Arc. The cell cycle and apoptosis were analyzed by flow cytometry. Alterations of signaling proteins were measured by Western blotting. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. KEY FINDINGS: The experimental results show that Arc did not induce apoptosis in ER-positive breast cancer cell, rather caused G1 cycle arrest by decreasing cyclin D1 levels without effect on altering CDK4/6 levels. Moreover, we have demonstrated that Arc decreases cyclin D1 levels through prompting Akt/GSK3ß-mediated degradation. SIGNIFICANCE: These findings warrant the potential of Arc as a candidate treatment for ER-positive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Ciclina D1/metabolismo , Furanos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Lignanas/farmacologia , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Feminino , Furanos/uso terapêutico , Humanos , Lignanas/uso terapêutico , Células MCF-7 , Proteólise/efeitos dos fármacos
20.
Nat Commun ; 11(1): 2743, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488087

RESUMO

Concerted multidisciplinary efforts have led to the development of Cyclin-Dependent Kinase inhibitors (CDKi's) as small molecule drugs and chemical probes of intracellular CDK function. However, conflicting data has been reported on the inhibitory potency of CDKi's and a systematic characterization of affinity and selectivity against intracellular CDKs is lacking. We have developed a panel of cell-permeable energy transfer probes to quantify target occupancy for all 21 human CDKs in live cells, and present a comprehensive evaluation of intracellular isozyme potency and selectivity for a collection of 46 clinically-advanced CDKi's and tool molecules. We observed unexpected intracellular activity profiles for a number of CDKi's, offering avenues for repurposing of highly potent molecules as probes for previously unreported targets. Overall, we provide a broadly applicable method for evaluating the selectivity of CDK inhibitors in living cells, and present a refined set of tool molecules to study CDK function.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas Inibidoras de Quinase Dependente de Ciclina/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteína Quinase CDC2 , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Quinase 9 Dependente de Ciclina , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Fosforilação , Relação Estrutura-Atividade
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