Polyamines and DNA methylation in childhood leukaemia

2007 ◽  
Vol 35 (2) ◽  
pp. 331-335 ◽  
Author(s):  
R.G. Schipper ◽  
L.P. van den Heuvel ◽  
A.A.J. Verhofstad ◽  
R.A. De Abreu
Keyword(s):  
Dna Methylation ◽  
Anticancer Agents ◽  
Enzyme Inhibitors ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Inhibitory Effect ◽  
Polyamine Metabolism ◽  
Childhood Leukaemia ◽  
Clinical Value ◽  
Leukaemic Cells

Both polyamine metabolism and DNA methylation play an important role in normal and malignant growth. Specific enzyme inhibitors or drugs that interfere with these metabolic pathways have proven to be potential anticancer agents. Since DNA methylation and polyamine metabolism depend on a common substrate, i.e. S-adenosylmethionine, interaction between both pathways can be expected. Little is known about the relationship between these pathways but studies are available indicating that polyamines and DNA methylation are directly or indirectly interconnected, metabolically as well as physiologically with respect to the regulation of cell growth, differentiation and cancer development. These considerations give rise to the possibility that, by targeting both pathways, a more profound and effective inhibitory effect on the growth of malignant cells can be achieved. In previous studies we showed that 6-MP (6-mercaptopurine) as well as MTX (methotrexate), well-known drugs in the treatment of acute lymphoblastic leukaemia, inhibit DNA methylation and induce apoptosis in malignant blood cells. Our recent results show that combined treatment with 6-MP, MTX and drugs interfering with polyamine metabolism has additive/synergistic effects on the growth, cell viability and/or apoptotic death of leukaemic cells. Such a combination therapy could have great clinical value for patients in which therapy using inhibitors of thiopurines/purine metabolism has failed.

scholarly journals Synergistic anti-biofilm effects of Brassicaceae plant extracts in combination with proteinase K against Escherichia coli O157:H7

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wen Si Hu ◽  
Da Min Nam ◽  
Joo-Sung Kim ◽  
Ok Kyung Koo
Keyword(s):  
Stainless Steel ◽  
Inhibitory Concentration ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Antimicrobial Activities ◽  
Inhibitory Effect ◽  
Proteinase K ◽  
E Coli ◽  
Log Reduction ◽  
Food Contact Surfaces

AbstractBacteria can form biofilms, complex microbial communities protected from environmental stress, on food contact surfaces. Brassicaceae plant has been shown to contain bioactive compounds with antimicrobial activities. The objective of this study was to evaluate the synergistic effects of Brassicaceae species and proteinase K against E. coli O157:H7 biofilm. We determined the minimum biofilm inhibitory concentration, the fractional inhibitory concentration indexes, and the synergistic inhibitory effect of Raphanus sativus var. longipinnatus, R. sativus, and Brassica oleracea var. acephala extracts with proteinase K on E. coli O157:H7. The biofilm showed a 49% reduction with 2 mg/mL R. sativus. The combination of proteinase K 25 µg/mL significantly increased the effect of 2 mg/mL R. sativus var. longipinnatus and the combined treatment yielded up to 2.68 log reduction on stainless steel coupons. The results showed that the combination of R. sativus var. longipinnatus extract and proteinase K could serve as an anti-biofilm agent with synergistic effects for inhibiting E. coli O157:H7 biofilm on stainless steel surfaces.

scholarly journals PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness

2020 ◽  
Vol 21 (24) ◽  
pp. 9715
Author(s):  
Patrycja Gralewska ◽  
Arkadiusz Gajek ◽  
Agnieszka Marczak ◽  
Michał Mikuła ◽  
Jerzy Ostrowski ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Anticancer Agents ◽  
Synthetic Lethality ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Parp Inhibition ◽  
Ovarian Cancer Cells ◽  
Cancer Resistance ◽  
Strand Breaks ◽  
Alternative Treatment Strategy

Poly (ADP-ribose) polymerase inhibitor (PARPi, olaparib) impairs the repair of DNA single-strand breaks (SSBs), resulting in double-strand breaks (DSBs) that cannot be repaired efficiently in homologous recombination repair (HRR)-deficient cancers such as BRCA1/2-mutant cancers, leading to synthetic lethality. Despite the efficacy of olaparib in the treatment of BRCA1/2 deficient tumors, PARPi resistance is common. We hypothesized that the combination of olaparib with anticancer agents that disrupt HRR by targeting ataxia telangiectasia and Rad3-related protein (ATR) or checkpoint kinase 1 (CHK1) may be an effective strategy to reverse ovarian cancer resistance to olaparib. Here, we evaluated the effect of olaparib, the ATR inhibitor AZD6738, and the CHK1 inhibitor MK8776 alone and in combination on cell survival, colony formation, replication stress response (RSR) protein expression, DNA damage, and apoptotic changes in BRCA2 mutated (PEO-1) and HRR-proficient BRCA wild-type (SKOV-3 and OV-90) cells. Combined treatment caused the accumulation of DNA DSBs. PARP expression was associated with sensitivity to olaparib or inhibitors of RSR. Synergistic effects were weaker when olaparib was combined with CHK1i and occurred regardless of the BRCA2 status of tumor cells. Because PARPi increases the reliance on ATR/CHK1 for genome stability, the combination of PARPi with ATR inhibition suppressed ovarian cancer cell growth independently of the efficacy of HRR. The present results were obtained at sub-lethal doses, suggesting the potential of these inhibitors as monotherapy as well as in combination with olaparib.

Synergistic Antitumor Effect of 5-Fluorouracil Combined with Constituents from Pleurospermum lindleyanum in Hepatocellular carcinoma SMMC-7721 Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Xiao-Feng Zhu ◽  
Xiao-Jin Li ◽  
Zhong-Lian Cao ◽  
Xiu-Jie Liu ◽  
Ping Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Effectiveness ◽  
Synergistic Effects ◽  
Folk Medicine ◽  
Inhibitory Effect ◽  
Caspase 9 ◽  
Whole Plant ◽  
Anti Cancer ◽  
Induced Apoptosis

Background: A Chinese folk medicine plant Pleurospermum lindleyanum possesses pharmacological activities of heat-clearing, detoxifying and preventing from hepatopathy, coronary heart disease, hypertension, and high altitude sickness. We isolated and characterized its constituents to investigate its synergistic effects against human hepatoma SMMC-7721 cells. Objective: The aim of this study was to explore the synergistic anti-cancer activities of isolates from P. lindleyanum with 5-FU on hepatoma SMMC-7721 cells in vitro and their primary mechanisms. Methods: Sequential chromatographic techniques were conducted for the isolation studies. The isolates structures were established by spectroscopic analysis as well as X-ray crystallographic diffraction. Growth inhibition was detected by MTT assay. The isobologram method was used to assess the effect of drug combinations. Flow cytometry and western blot were used to examine apoptosis and protein expression. Results: A new coumarin (16), along with sixteen known compounds, were isolated from the whole plant of P. lindleyanum and their structures were elucidated by spectroscopic methods. Four coumarins (2, 3, 5, and 16), two flavonoids (8 and 9) and three phytosterols and triterpenes (12-14) were found to synergistically enhance the inhibitory effect of 5-FU against SMMC-7721 cells. Among them, compounds 3 and 16 exhibited the best synergistic effects with IC50 of 5-FU reduced by 16-fold and 22-fold possessing the minimum Combination Index (CI) 0.34 and 0.27. The mechanism of action of combinations might be through synergistic arresting for the cell cycle at G1 phases and the induction of apoptosis. Moreover, western blotting and molecular docking revealed that compounds 3 or 5 might promote 5-FU-induced apoptosis by regulating the expression of Caspase 9 and PARP. Conclusion: Constituents from P. lindleyanum may improve the treatment effectiveness of 5-FU against hepatocellular carcinoma cells.

POSSIBLE ROLE OF 5α-ANDROSTANE-3α,17β-DIOL IN THE CONTROL OF FOLLICLE-STIMULATING HORMONE SECRETION IN THE IMMATURE FEMALE RAT

1982 ◽  
Vol 92 (1) ◽  
pp. 37-42 ◽  
Author(s):  
H. M. A. MEIJS-ROELOFS ◽  
P. KRAMER ◽  
L. GRIBLING-HEGGE
Keyword(s):  
Inhibitory Action ◽  
Combined Treatment ◽  
Hormone Secretion ◽  
Inhibitory Effect ◽  
Ovariectomized Rats ◽  
Female Rat ◽  
Immature Rat ◽  
Rat Strain ◽  
Intact Rats

A possible role of 5α-androstane-3α,17β-diol (3α-androstanediol) in the control of FSH secretion was studied at various ages in ovariectomized rats. In the rat strain used, vaginal opening, coincident with first ovulation, generally occurs between 37 and 42 days of age. If 3α-androstanediol alone was given as an ovarian substitute, an inhibitory effect on FSH release was evident with all three doses tested (50, 100, 300 μg/100 g body wt) between 13 and 30 days of age; at 33–35 days of age only the 300 μg dose caused some inhibition of FSH release. Results were more complex if 3α-androstanediol was given in combined treatment with oestradiol and progesterone. Given with progesterone, 3α-androstanediol showed a synergistic inhibitory action on FSH release between 20 and 30 days of age. However, when 3α-androstanediol was combined with oestradiol a clear decrease in effect, as compared to the effect of oestradiol alone, was found between 20 and 30 days of age. Also the effect of combined oestradiol and progesterone treatment was greater than the effect of combined treatment with oestradiol, progesterone and 3α-androstanediol. At all ages after day 20 none of the steroid combinations tested was capable of maintaining FSH levels in ovariectomized rats similar to those in intact rats. It is concluded that 3α-androstanediol might play a role in the control of FSH secretion in the immature rat, but after day 20 the potentially inhibitory action of 3α-androstanediol on FSH secretion is limited in the presence of oestradiol.

Progressive alteration of DNA methylation of Alu, MGMT, MINT2, and TFPI2 genes in colonic mucosa during colorectal cancer development

2021 ◽  
pp. 1-6
Author(s):  
Ben Kang ◽  
Hyun Seok Lee ◽  
Seong Woo Jeon ◽  
Soo Yeun Park ◽  
Gyu Seog Choi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Healthy Subjects ◽  
Large Scale ◽  
Methylation Status ◽  
Clinical Information ◽  
Field Cancerization ◽  
Aberrant Methylation ◽  
Clinical Value ◽  
Mortality And Morbidity

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is characterized by different pathways of carcinogenesis and is a heterogeneous disease with diverse molecular landscapes that reflect histopathological and clinical information. Changes in the DNA methylation status of colon epithelial cells have been identified as critical components in CRC development and appear to be emerging biomarkers for the early detection and prognosis of CRC. OBJECTIVE: To explore the underlying disease mechanisms and identify more effective biomarkers of CRC. METHODS: We compared the levels and frequencies of DNA methylation in 11 genes (Alu, APC, DAPK, MGMT, MLH1, MINT1, MINT2, MINT3, p16, RGS6, and TFPI2) in colorectal cancer and its precursor adenomatous polyp with normal tissue of healthy subjects using pyrosequencing and then evaluated the clinical value of these genes. RESULTS: Aberrant methylation of Alu, MGMT, MINT2, and TFPI2 genes was progressively accumulated during the normal-adenoma-carcinoma progression. Additionally, CGI methylation occurred either as an adenoma-associated event for APC, MLH1, MINT1, MINT31, p16, and RGS6 or a tumor-associated event for DAPK. Moreover, relatively high levels and frequencies of DAPK, MGMT, and TFPI2 methylation were detected in the peritumoral nonmalignant mucosa of cancer patients in a field-cancerization manner, as compared to normal mucosa from healthy subjects. CONCLUSION: This study identified several biomarkers associated with the initiation and progression of CRC. As novel findings, they may have important clinical implications for CRC diagnostic and prognostic applications. Further large-scale studies are needed to confirm these findings.

scholarly journals Combination of Modified Atmosphere and Irradiation for the Phytosanitary Disinfestation of Trogoderma granarium Everts (Coleoptera: Dermestidae)

Insects ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 442
Author(s):  
Qing-Ying Zhao ◽  
Tian-Xiu Li ◽  
Zi-Jiao Song ◽  
Tao Sun ◽  
Bo Liu ◽  
...  
Keyword(s):  
Late Stage ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Modified Atmosphere ◽  
Trogoderma Granarium ◽  
Combination Treatments ◽  
Phytosanitary Measure ◽  
Ma Packaging ◽  
Confirmatory Tests ◽  
Lethal Time

The khapra beetle, Trogoderma granarium Everts, is defined as one of the most important quarantine pests globally, and fumigation with methyl bromide, an ozone-depleting substance, is a common phytosanitary measure currently used. The modified atmosphere (MA), irradiation, and their combination treatments of T. granarium larvae and adults were performed at room temperature (24–26 ℃) to develop an ecofriendly phytosanitary disinfestation measure and to shorten the exposure time and overcome treatment disadvantages of irradiation. Late-stage larvae are determined as the most tolerant stage resulted in large LT99.9968 values of 32.6 (29.2–37.5) and 38.0 (35.1–41.7) days treated under 1% and 2% O2 (with N2 balance) atmosphere, respectively. Ionizing radiation was used to enhance the effect of MA and the mortality was highly significantly affected by all the interaction effects, indicating that the synergistic effects present in all the combined treatments. The synergistic ratios, which is defined as the estimated lethal time for MA treatment (LD90, LD99, and LD99.9968), divided by that of combined treatment, were between 1.47 and 2.47. In the confirmatory tests, no individuals recovered from a sum of 111,366 late-stage larvae treated under 1% O2 atmosphere for 14- or 15-d after 200 Gy irradiation, which resulted in validating the probit estimations and achieving an efficacy of 99.9973% mortality at 95% confidence level. Therefore, these treatment schedules are recommended to disinfest T. granarium infecting commodities for phytosanitary purposes under the warehouse, MA packaging, or in combination with international transportation by train or sea container.

Investigation of antiproliferative effects of gossypin on lung cancer cell line

2021 ◽  
pp. 37-40
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Anticancer Agents ◽  
A549 Cells ◽  
Supportive Therapy ◽  
Cancer Cell Line ◽  
Inhibitory Effect ◽  
Lung Cancer Cell Line ◽  
Cancer Treatments ◽  
Mtt Method

Purpose: The rapid growth, morbidity and mortality of lung cancer and the lack of effective treatment have attracted great interest from researchers to find new cancer treatments aimed at the effect of gossypine on cell proliferation and apoptosis of A549 cells. The most used of these products are flavonoids. Gossypin is a potential chemo preventive and therapeutic agent for lung cancer. Material and Method: We investigated the effect of Gossypin anticancer activity on A549 cell proliferation with MTT method, depending on dose and time. In addition, mRNA expression levels of the apoptotic markers caspase-3 (CAS-3) and caspase-9 (CAS-9) were investigated by real-time PCR. In our study, six groups were used as control, gossypin (10, 20, 40 μM), cisplatin 5 μg/mL and cisplatin 5 μg/mL+gossypin 40 μM combine concentrations. The proliferative and antiapoptotic effects of gossypin at 24, 48 and 72 hours were investigated. Results were analyzed and presented as cell viability (%). Results: In our results, it was determined that gossypin especially at a dose of 40 μM and at 72 hours showed almost as much effect on A549 cells, but the highest inhibitory effect was seen in the 40 combined group of cisplatin 5 μg / mL + gossypin. In addition, gossypin caused a significant increase in apoptosis genes (CASP-3, CASP-9) compared to control. Conclusion: Our study showed that gossypin significantly increases the chemosensitivity of cisplatin. Based on this, it is predicted that gossypin can be used as a supportive therapy that increases the effectiveness of anticancer agents. However, more detailed research should be done for this.

Abstract 341: Synergistic Effects of Renal Dopamine and Gastrin Receptors in Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Yue Chen ◽  
Shuo Zhen ◽  
Laureano Asico ◽  
Pedro Jose ◽  
Chunyu Zeng
Keyword(s):  
Atpase Activity ◽  
Sodium Excretion ◽  
Synergistic Effects ◽  
Inhibitory Effect ◽  
Receptor Interaction ◽  
Gastrin Receptor ◽  
Wky Rats ◽  
Link Type ◽  
Renal Dopamine ◽  
Stimulation Of

Oral NaCl produces stronger natriuresis and diuresis as compared with venous infusion of same amount of NaCl, indicating the existence of renal-gastric axis. Although numerous hormones are secreted in gastrointestinal tract, gastrin is evident one due to its natriuretic effects and taken-up by the renal proximal tubule (RPT) cells. We hypothesize that there is an interaction between gastrin and dopamine receptor in kidney, which synergistically increases sodium excretion, the impaired interaction would be involved in the pathogenesis of hypertension. In WKY rats, infusion of gastrin, via renal artery, induced natriuresis and diuresis, which was blocked in the presence of CI988, a gastrin receptor blocker. Similarly, the natriuretic and diuretic effect of fenoldopam, a D1-like receptor agonist, was blocked by the D1-like receptor antagonist, SCH23390 , indicating that gastrin and fenoldopam, via individual receptor, play natriuretic and diuretic effects. Our further study found that lower dosages of gastrin or fenoldopam could not induce natriuresis and diuresis alone, while putting together induced natriuretic and diuretic effects. The above-mentioned effects were lost in SHRs. We also found, in the presence of SCH23390 , gastrin-mediated natriuresis and diuresis was partially blocked. Similarly, in the presence of CI988, the natriuretic and diuretic effects of fenoldopam were partially blocked, indicating the interaction between gastrin and D1-like receptor. The gastrin/D1-like receptor interaction was also confirmed in the RPT cells. Stimulation of one receptor increased the expression of the other. Stimulation of either D1-like receptor or gastrin receptor inhibited the Na + -K + -ATPase activity in RPT cells, while in the presence of SCH23390 , the inhibitory effect of gastrin on Na + -K + -ATPase activity was partially blocked. In the presence of CI988, D1-like receptor-mediated inhibitory effect of Na + -K + -ATPase activity in RPT cells was partially inhibited. It indicated the synergistic effect between gastrin and D1-like receptor would increase the sodium excretion in WKY rats; the impaired interaction might be involved in the pathogenesis of hypertension.

scholarly journals Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

2018 ◽  
Vol 19 (10) ◽  
pp. 3106 ◽  
Author(s):  
Kuniyasu Soda
Keyword(s):  
Dna Methylation ◽  
Carbon Metabolism ◽  
Methylation Status ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Dna Methyltransferases ◽  
Polyamine Metabolism ◽  
Methyl Group ◽  
Wide Range ◽  
One Carbon Metabolism

Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.

scholarly journals Antiproliferative Activity of Combined Biochanin A and Ginsenoside Rh2 on MDA-MB-231 and MCF-7 Human Breast Cancer Cells

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2908 ◽  
Author(s):  
Guixing Ren ◽  
Zhenxing Shi ◽  
Cong Teng ◽  
Yang Yao
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Human Breast Cancer ◽  
Synergistic Effects ◽  
Inhibitory Effect ◽  
Biochanin A ◽  
Migration And Invasion ◽  
Ginsenoside Rh2 ◽  
Human Breast ◽  
Mcf 7

Breast cancer is the most frequently diagnosed cancer in women worldwide. The antiproliferative activities of biochanin A (BA) and ginsenoside Rh2 were determined by evaluating their inhibitory effect on MDA-MB-231 human breast cancer cell proliferation. The combination of BA with Rh2 was also assessed. In MDA cells, combination treatment led to a decrease in the EC50 values of BA and Rh2 to 25.20 μM and 22.75 μM, respectively. In MCF-7 cells, the EC50 values of combined BA and Rh2 decreased to 27.68 μM and 25.41 μM, respectively. BA combined with Rh2 also improved the inhibition of MDA-MB-231 and MCF-7 cell migration and invasion compared to the individual compounds. Western blot analysis demonstrated upregulation in p-p53, p-p38, and p-ASK1 proteins while levels of TRAF2 were downregulated. These results suggest that BA combined with Rh2 exhibits synergistic effects against MDA-MB-231 and MCF-7 cell proliferation.

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