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1.
ACS Omega ; 8(44): 41204-41213, 2023 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-37970041

RESUMO

Combinational treatment is a promising strategy for better cancer treatment outcomes. Chrysin and luteolin have demonstrated effective anticancer activity. Cisplatin and topotecan are commonly used for the treatment of human cancers. However, various side effects including drug resistance are an imperative restriction to use them as pharmacological therapy. Therefore, the aim was to use these agents in combination with flavones for better efficacy. In the present study, it was found that the combination of chrysin and cisplatin and luteolin and cisplatin significantly improved the anticancer effect as both the combinations showed synergistic interactions [combinational index (CI < 1)]. Remarkably, the combination of chrysin and luteolin with topotecan depicted the antagonistic interaction (CI > 1). Further, increased expression of the pro-apoptotic proteins Bax and caspase 8 and the inhibition of the antiapoptotic protein Bcl-2 were instituted in the synergistic doses (chrysin + cisplatin and luteolin + cisplatin), hence promoting apoptosis. Also, it was found that the synergistic combination inhibited the migration of HeLa cells by downregulation of metalloproteases and upregulation of TIMPs. However, there are no significant changes depicted in the antagonistic combinations which support their role in their antagonistic effects. Based on these results, it can be inferred that the two or more drug combinations need to be explored well for their interaction to enhance the therapeutic outcomes.

2.
Int J Mol Sci ; 23(7)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35409426

RESUMO

Cancer progression is linked to abnormal epigenetic alterations such as DNA methylation and histone modifications. Since epigenetic alterations, unlike genetic changes, are heritable and reversible, they have been considered as interesting targets for cancer prevention and therapy by dietary compounds such as luteolin. In this study, epigenetic modulatory behaviour of luteolin was analysed on HeLa cells. Various assays including colony forming and migration assays, followed by biochemical assays of epigenetic enzymes including DNA methyltransferase, histone methyl transferase, histone acetyl transferase, and histone deacetylases assays were performed. Furthermore, global DNA methylation and methylation-specific PCR for examining the methylation status of CpG promoters of various tumour suppressor genes (TSGs) and the expression of these TSGs at transcript and protein level were performed. It was observed that luteolin inhibited migration and colony formation in HeLa cells. It also modulated DNA methylation at promoters of TSGs and the enzymatic activity of DNMT, HDAC, HMT, and HAT and reduced the global DNA methylation. Decrease in methylation resulted in the reactivation of silenced tumour suppressor genes including FHIT, DAPK1, PTEN, CDH1, SOCS1, TIMPS, VHL, TP53, TP73, etc. Hence, luteolin-targeted epigenetic alterations provide a promising approach for cancer prevention and intervention.


Assuntos
Luteolina , Neoplasias , Metilação de DNA , Metilases de Modificação do DNA/genética , Desmetilação , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Células HeLa , Código das Histonas , Histona Desacetilases/metabolismo , Humanos , Luteolina/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética
3.
Semin Cancer Biol ; 86(Pt 3): 666-681, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-34216789

RESUMO

An overwhelming number of research articles have reported a strong relationship of the microbiome with cancer. Microbes have been observed more commonly in the body fluids like urine, stool, mucus of people with cancer compared to the healthy controls. The microbiota is responsible for both progression and suppression activities of various diseases. Thus, to maintain healthy human physiology, host and microbiota relationship should be in a balanced state. Any disturbance in this equilibrium, referred as microbiome dysbiosis becomes a prime cause for the human body to become more prone to immunodeficiency and cancer. It is well established that some of these microbes are the causative agents, whereas others may encourage the formation of tumours, but very little is known about how these microbial communications causing change at gene and epigenome level and trigger as well as encourage the tumour growth. Various studies have reported that microbes in the gut influence DNA methylation, DNA repair and DNA damage. The genes and pathways that are altered by gut microbes are also associated with cancer advancement, predominantly those implicated in cell growth and cell signalling pathways. This study exhaustively reviews the current research advancements in understanding of dysbiosis linked with colon, lung, ovarian, breast cancers and insights into the potential molecular targets of the microbiome promoting carcinogenesis, the epigenetic alterations of various potential targets by altered microbiota, as well as the role of various chemopreventive agents for timely prevention and customized treatment against various types of cancers.


Assuntos
Microbiota , Neoplasias , Humanos , Disbiose/complicações , Disbiose/genética , Epigenômica , Epigênese Genética , Neoplasias/genética
4.
Oncol Lett ; 21(3): 192, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33574931

RESUMO

Flavonoids, a subclass of polyphenols, have been shown to be effective against several types of cancer, by decreasing proliferation and inducing apoptosis. Therefore, the aim of the present study was to assess the anti-carcinogenic potential of luteolin on HeLa human cervical cancer cells, through the use of a cell viability assay, DNA fragmentation assay, mitochondrial membrane potential assay, cell cycle analysis using Annexin/PI staining and flow cytometry, gene expression analysis and a protein profiling array. Luteolin treatment exhibited cytotoxicity towards HeLa cells in a dose- and time-dependent manner, and its anti-proliferative properties were confirmed by accumulation of luteolin-treated cells in sub-G1 phases. Cytotoxicity induced by luteolin treatment resulted in apoptosis, which was mediated through depolarization of the mitochondrial membrane potential and DNA fragmentation. Furthermore, luteolin treatment increased the expression of various proapoptotic genes, including APAF1, BAX, BAD, BID, BOK, BAK1, TRADD, FADD, FAS, and Caspases 3 and 9, whereas the expression of anti-apoptotic genes, including NAIP, MCL-1 and BCL-2, was decreased. Cell cycle regulatory genes, including CCND1, 2 and 3, CCNE2, CDKN1A, CDKN2B, CDK4 and CDK2, were decreased following treatment. Expression of TRAILR2/DR5, TRAILR1/DR4, Fas/TNFRSF6/CD95 and TNFR1/TNFRSF1A, as well as pro-apoptotic proteins, including BAD, BAX and Cytochrome C were consistently increased, and the expression of antiapoptotic proteins, HIF1α, BCL-X, MCL1 and BCL2, were found to be decreased following treatment. Expression of AKT1 and 2, ELK1, PIK3C2A, PIK3C2B, MAPK14, MAP3K5, MAPK3 and MAPK1 was significantly decreased at the transcriptional level. Expression of GSK3b (p-ser9), PRAS 40 (p-Ther246), BAD (p-ser112), PTEN (p-ser380), AKT (p-ser473), ERK2 (p-Y185/Y187), RISK2 (p-ser386), P70S6k (p-Thr421/ser424), PDK1(p-ser241), ERK1 (p-T202/Y204) and MTOR (p-ser2448) was downregulated and expression of P53 (p-ser241) and P27(p-Thr198) was upregulated by luteolin in a dose-dependent manner, indicating its anti-proliferative and apoptosis enabling properties, and this may have been mediated via inhibition of the AKT and the MAPK pathways.

5.
Front Genet ; 12: 768130, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35096000

RESUMO

Purpose: Plant-derived phytochemicals have shown epigenetic modulatory effect in different types of cancer by reversing the pattern of DNA methylation and chromatin modulation, thereby restoring the function of silenced tumor-suppressor genes. In the present study, attempts have been made to explore chrysin-mediated epigenetic alterations in HeLa cells. Methods: Colony formation and migration assays followed by methylation-specific PCR for examining the methylation status of CpG promoters of various tumor-suppressor genes (TSGs) and the expression of these TSGs at the transcript and protein levels were performed. Furthermore, global DNA methylation; biochemical activities of DNA methyltransferases (DNMTs), histone methyl transferases (HMTs), histone deacetylases (HDACs), and histone acetyl transferases (HATs) along with the expression analysis of chromatin-modifying enzymes; and H3 and H4 histone modification marks analyses were performed after chrysin treatment. Results: The experimental analyses revealed that chrysin treatment encourages cytostatic behavior as well as inhibits the migration capacity of HeLa cells in a time- and dose-dependent manner. Chrysin reduces the methylation of various tumor-suppressor genes, leading to their reactivation at mRNA and protein levels. The expression levels of various chromatin-modifying enzymes viz DNMTs, HMTs, HDACs, and HATS were found to be decreased, and H3 and H4 histone modification marks were modulated too. Also, reduced global DNA methylation was observed following the treatment of chrysin. Conclusion: This study concludes that chrysin can be used as a potential epigenetic modifier for cancer treatment and warrants for further experimental validation.

6.
Biosci Rep ; 39(8)2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366565

RESUMO

Cancer cells have the unique ability to overcome natural defense mechanisms, undergo unchecked proliferation and evade apoptosis. While chemotherapeutic drugs address this, they are plagued by a long list of side effects and have a poor success rate. This has spurred researchers to identify safer bioactive compounds that possess chemopreventive and therapeutic properties. A wide range of experimental as well as epidemiological data encourage the use of dietary agents to impede or delay different stages of cancer. In the present study, we have examined the anti-ancer property of ubiquitous phytochemical quercetin by using cell viability assay, flow cytometry, nuclear morphology, colony formation, scratch wound assay, DNA fragmentation and comet assay. Further, qPCR analysis of various genes involved in apoptosis, cell cycle regulation, metastasis and different signal transduction pathways was performed. Proteome profiler was used to quantitate the expression of several of these proteins. We find that quercetin decreases cell viability, reduces colony formation, promotes G2-M cell cycle arrest, induces DNA damage and encourages apoptosis. Quercetin induces apoptosis via activating both apoptotic pathways with a stronger effect of the extrinsic pathway relying on the combined power of TRAIL, FASL and TNF with up-regulation of caspases and pro-apoptotic genes. Quercetin could inhibit anti-apoptotic proteins by docking studies. Further, quercetin blocks PI3K, MAPK and WNT pathways. Anticancer effect of quercetin observed in cell-based assays were corroborated by molecular biology studies and yielded valuable mechanistic information. Quercetin appears to be a promising candidate with chemopreventive and chemotherapeutic potential and warrants further research.


Assuntos
Apoptose/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quercetina/farmacologia , Neoplasias do Colo do Útero/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteínas de Neoplasias , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
7.
J Cell Biochem ; 120(10): 18357-18369, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31172592

RESUMO

The central role of epigenomic alterations in carcinogenesis has been widely acknowledged, particularly the impact of DNA methylation on gene expression across all stages of carcinogenesis is considered vital for both diagnostic and therapeutic strategies. Dietary phytochemicals hold great promise as safe anticancer agents and effective epigenetic modulators. This study was designed to investigate the potential of a phytochemical, quercetin as a modulator of the epigenetic pathways for anticancer strategies. Biochemical activity of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and global genomic DNA methylation was quantitated by an enzyme-linked immunosorbent assay based assay in quercetin-treated HeLa cells. Molecular docking studies were performed to predict the interaction of quercetin with DNMTs and HDACs. Quantitative methylation array was used to assess quercetin-mediated alterations in the promoter methylation of selected tumor suppressor genes (TSGs). Quercetin induced modulation of chromatin modifiers including DNMTs, HDACs, histone acetyltransferases (HAT) and HMTs, and TSGs were assessed by quantitative reverse transcription PCR (qRT-PCR). It was found that quercetin modulates the expression of various chromatin modifiers and decreases the activity of DNMTs, HDACs, and HMTs in a dose-dependent manner. Molecular docking results suggest that quercetin could function as a competitive inhibitor by interacting with residues in the catalytic cavity of several DNMTs and HDACs. Quercetin downregulated global DNA methylation levels in a dose- and time-dependent manner. The tested TSGs showed steep dose-dependent decline in promoter methylation with the restoration of their expression. Our study provides an understanding of the quercetin's mechanism of action and will aid in its development as a candidate for epigenetic-based anticancer therapy.


Assuntos
Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Quercetina/farmacologia , Neoplasias do Colo do Útero/genética , Antineoplásicos/farmacologia , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HeLa , Histona Acetiltransferases/química , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Histona Desacetilases/química , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Estrutura Secundária de Proteína
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