A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells

Patra, Nabanita; De, Umasankar; Kang, Jin-Ah; Kim, Ji Mim; Ahn, Mee Young; Lee, Joo Young; Jung, Jee H.; Chung, Hae Young; Moon, Hyung Ryong; Kim, Hyung Sik

doi:10.1016/j.ejphar.2011.02.015

Cited by 46 publications

(28 citation statements)

References 34 publications

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“…Commercially available topoisomerase II drug screening kit (TopoGEN, Inc., Columbus, OH) was used and assay was performed as previously described by Patra et al (39). Briefly, substrate supercoiled pHot1 DNA (0.25 mg) was incubated with 4 units (2 ml) of human DNA topoisomerase II, 50 mg/ml AF4 (2 ml) and assay buffer (4 ml) in 37 C for 30 min.…”

Section: Measurement Of Dna Topoisomerase II Activitymentioning

confidence: 99%

Flavonoid-Enriched Apple Fraction AF4 Induces Cell Cycle Arrest, DNA Topoisomerase II Inhibition, and Apoptosis in Human Liver Cancer HepG2 Cells

Sudan

Rupasinghe

2014

Nutrition and Cancer

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Apples are a major source of dietary phytochemicals such as flavonoids in the Western diet. Here we report anticancer properties and possible mechanism of action of apple flavonoid-enriched fraction (AF4) isolated from the peels of Northern Spy apples in human hepatocellular carcinoma cells, HepG2. Treatment with AF4 induced cell growth inhibition in HepG2 cells in time- and dose-dependent manner. Concentration of 50 μg/ml (50 μg total monomeric polyphenols/ml) AF4 was sufficient to induce a significant reduction in cell viability within 6 h of treatment (92%, P < 0.05) but had very low toxicity (minimum 4% to maximum 16%) on primary liver and lung cells, which was significantly lower than currently prescribed chemotherapy drug Sorafenib (minimum 29% to maximum 49%, P < 0.05). AF4 induced apoptosis in HepG2 cells within 6 h of treatment via activation of caspase-3. Cell cycle analysis via flow-cytometer showed that AF4 induced G2/M phase arrest. Further, results showed that AF4 acts as a strong DNA topoisomerase II catalytic inhibitor, which may be a plausible reason to drive the cells to apoptosis. Overall, our data suggests that AF4 possesses a significantly stronger antiproliferative and specific action than Sorafenib in vitro and is a potential natural chemotherapy agent for treatment of liver cancer.

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Section: Measurement Of Dna Topoisomerase II Activitymentioning

confidence: 99%

Flavonoid-Enriched Apple Fraction AF4 Induces Cell Cycle Arrest, DNA Topoisomerase II Inhibition, and Apoptosis in Human Liver Cancer HepG2 Cells

Sudan

Rupasinghe

2014

Nutrition and Cancer

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“…Commercially available topoisomerase II drug screening kit (TopoGEN, Inc., Columbus, OH, USA) was utilized and assay was performed as explained by Patra et al 21 Briefly, substrate supercoiled pHot1 DNA (0.25 mg) was incubated with four units (2 mL) of human DNA topoisomerase II, test compounds (2 mL) and assay buffer (4 mL) in 37 C for 30 min. The reaction was terminated by the addition of 10% sodium dodecyl sulphate (2 mL) followed by digestion with proteinase K (50 mg/mL) at 37 C for 15 min.…”

Section: Topoisomerase II Assaymentioning

confidence: 99%

Antiproliferative activity of long chain acylated esters of quercetin-3-O-glucoside in hepatocellular carcinoma HepG2 cells

Sudan

Rupasinghe

2015

Exp Biol Med (Maywood)

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Despite their strong role in human health, poor bioavailability of flavonoids limits their biological effects in vivo. Enzymatically catalyzed acylation of fatty acids to flavonoids is one of the approaches of increasing cellular permeability and hence, biological activities. In this study, six long chain fatty acid esters of quercetin-3-O-glucoside (Q3G) acylated enzymatically and were used for determining their antiproliferative action in hepatocellular carcinoma cells (HepG2) in comparison to precursor compounds and two chemotherapy drugs (Sorafenib and Cisplatin). Fatty acid esters of Q3G showed significant inhibition of HepG2 cell proliferation by 85 to 90% after 6 h and 24 h of treatment, respectively. The cell death due to these novel compounds was associated with cell-cycle arrest in S-phase and apoptosis observed by DNA fragmentation, fluorescent microscopy and elevated caspase-3 activity and strong DNA topoisomerase II inhibition. Interestingly, Q3G esters showed significantly low toxicity to normal liver cells than Sorafenib (P < 0.05), a chemotherapy drug for hepatocellular carcinoma. Among all, oleic acid ester of Q3G displayed the greatest antiproliferation action and a high potential as an anti-cancer therapeutic. Overall, the results of the study suggest strong antiproliferative action of these novel food-derived compounds in treatment of cancer.

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“…It has also been shown that blocking some groups (e.g., C3 hydroxyl and C7 hydroxyl groups) in quercetin by the introduction of the lipophilic moiety pivaloxymethyl (POM) enhances its solubility, decreases its metabolism, enhances stability (half-life increased from 10 h for quercetin to >72 h for its quercetin-POM conjugates at pH 7.4), and increases its effectiveness by preventing chemical and metabolic hydrolysis [207]. An epoxypropoxy flavonoid derivative (MHY336), by inhibiting the enzyme topoisomerase II enzyme, exhibited significant potency against the prostate cancer cell lines LNCaP, PC-3, and DU145 [208]. …”

Section: Approaches To Surmount Flavonoid Pk/pd and Other Barriersmentioning

confidence: 99%

Cancer chemoprevention through dietary flavonoids: what’s limiting?

2017

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Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their effective use, including (1) the isolation and purification of flavonoids from their natural resources; (2) demonstration of the effects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and (3) numerous pharmacokinetic challenges (e.g., bioavailability, drug–drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and efforts that are being made to surmount these challenges.

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A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells

Cited by 46 publications

References 34 publications

Flavonoid-Enriched Apple Fraction AF4 Induces Cell Cycle Arrest, DNA Topoisomerase II Inhibition, and Apoptosis in Human Liver Cancer HepG2 Cells

Flavonoid-Enriched Apple Fraction AF4 Induces Cell Cycle Arrest, DNA Topoisomerase II Inhibition, and Apoptosis in Human Liver Cancer HepG2 Cells

Antiproliferative activity of long chain acylated esters of quercetin-3-O-glucoside in hepatocellular carcinoma HepG2 cells

Cancer chemoprevention through dietary flavonoids: what’s limiting?

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