• The Korean Journal of Physiology and Pharmacology
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• v.13 no.4
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• pp.281-285
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• 2009

Rotenone, a mitochondrial complex I inhibitor, can induce the pathological features of Parkinson's disease (PD). In the present study, naringin, a grapefruit flavonoid, inhibited rotenone-induced cell death in human neuroblastoma SH-SY5Y cells. We assessed cell death and apoptosis by measuring mitogen-activated protein kinase (MAPKs) and caspase (CASPs) activities and by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 4,6-diamidino-2-phenylindole (DAPI) staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Naringin also blocked rotenone-induced phosphorylation of Jun NH2-terminal protein kinase (JNK) and P38, and prevented changes in B-cell CLL/lymphoma 2 (BCL2) and BCL2-associated X protein (BAX) expression levels. In addition, naringin reduced the enzyme activity of caspase 3 and cleavages of caspase 9, poly (ADP-ribose) polymerase (PARP), and caspase 3. These results suggest that naringin has a neuroprotective effect on rotenone-induced cell death in human neuroblastoma SH-SY5Y cells.

• Journal of Microbiology and Biotechnology
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• v.13 no.3
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• pp.394-399
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• 2003

The in vitro cytotoxic effects of newly synthesized copper (II) glycinate complex were investigated in two gastric cancer cell lines of SNU484 and SNU638 cells. The complex inhibited the growth and decreased the viability of both gastric cancer cells in a dose-dependent manner. Gastric cancer tells treated with the complex exhibited the features of apoptosis, as demonstrated by fragmentation of chromosomal DNA, activation of caspase-3-like enzyme, and cleavage of poly［ADP-ribose］ polymerase (PARP). With the treatment of copper (II) glycinate complex, the active form of caspase-3 was observed in SNU484 cells, but not in SNU638 cells, indicating that an alternative pathway of apoptosis might have been triggered in SNU638 cells. In conclusion, copper (II) glycinate complex induces apoptosis of SNU484 and SNU638 gastric cancer cells, and it is suggested that novel copper (II) glycinate complex is highly active against human gastric cancer cells.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.6
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• pp.365-369
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• 2010

In this study, we examined whether melatonin promotes apoptotic cell death via p53 in prostate LNCaP cells. Melatonin treatment significantly curtailed the growth of LNCaP cells in a dose- and time-dependent manner. Melatonin treatment (0 to 3 mM) induced the fragmentation of poly(ADP-ribose) polymerase (PARP) and activation of caspase-3, caspase-8, and caspase-9. Moreover, melatonin markedly activated Bax expression and decreased Bcl-2 expression in dose increments. To investigate p53 and p21 expression, LNCaP cells were treated with 0 to 3 mM melatonin. Melatonin increased the expressions of p53, p21, and p27. Treatment with mitogen-activated protein kinase (MAPK) inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor), confirmed that the melatonin-induced apoptosis was p21-dependent, but ERK-independent. With the co-treatment of PD98059 and melatonin, the expression of p-p53, p21, and MDM2 did not decrease. These effects were opposite to the expression of p-p53, p21, and MDM2 observed with SP600125 and SB202190 treatments. Together, these results suggest that p53-dependent induction of JNK/p38 MAPK directly participates in apoptosis induced by melatonin.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10483-10487
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• 2015

Heptaphylline derivatives are carbazoles in Clausena harmandiana, a medicinal plant that is utilized for headache, stomach ache, and other treatments of illness. The present study examined the effects of heptaphylline and 7-methoxyheptaphylline on apoptosis of human colon adenocarcinoma cells (HT-29 cell line). Quantification of cell viability was performed using cell proliferation assay (MTT assay) and of protein expression through immunoblotting. The results showed that only heptaphylline, but not 7-methoxyheptaphylline, significantly significantly activated cleaved of caspase-3 and poly (ADP-ribose) polymerase (PARP-1) which resulted in HT-29 cell death. We found that heptaphylline activated BH3 interacting-domain death agonist (Bid) and Bak, proapoptotic proteins. In contrast, it suppressed X-linked inhibitor-of-apoptosis protein (XIAP), Bcl-xL and survivin, inhibitors of apoptosis. In addition, heptaphylline inhibited activation of NF-${\kappa}B$/p65 (rel), a regulator of apoptotic regulating proteins by suppressing the activation of Akt and $IKK{\alpha}$, upstream regulators of p65. The findings suggested that heptaphylline induces apoptosis in human colon adenocarcinoma cells.

• Journal of Microbiology and Biotechnology
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• v.25 no.3
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• pp.418-422
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• 2015

In the course of screening for novel cell cycle inhibitors and apoptotic inducers, CR389, elucidated as 5-(1H-benzoimidazol-2-yl)-1H-pyridin-2-one, was generated as a new hit compound. Flow cytometric analysis and western blots of PA-1 cells treated with $60{\mu}M$ CR389 revealed an appreciable cell cycle arrest at the G2/M phase through direct inhibition of the CDK1 complex. In addition, activation of p53 via phosphorylation at Ser15 and subsequent up-regulation of p21^CIP1 showed that CR389 also induces p53-dependent-p21^CIP1-mediated cell cycle arrest. Furthermore, apoptotic induction in $60{\mu}M$ CR389-treated PA-1 cells is associated with the release of cytochrome c from mitochondria through up-regulation of the proapoptotic Bax protein, which results in the activation of procaspase-9 and -3, and the cleavage of poly(ADP-ribose) polymerase (PARP). Accordingly, CR389 seems to have multiple mechanisms of antiproliferative activity through p53-mediated pathways against human ovarian cancer cells. Therefore, we conclude that CR389 is a candidate therapeutic agent for the treatment of human ovarian cancer via the activation of p53.

• Fisheries and Aquatic Sciences
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• v.18 no.1
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• pp.35-44
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• 2015

We previously identified Streptomyces griseus as an anti-cancer agent (Kim et al., 2014). In this study, we isolated compounds from S. griseus and evaluated their anticancer effect and toxicity in vitro and in vivo. Preparative centrifugal partition chromatography (CPC) was used to obtain three compounds, cyclo($_{\small{L}}$-[4-hydroxyprolinyl]-$_{\small{L}}$-leucine], cyclo($_{\small{L}}$-Phe-trans-4-hydroxy-$_{\small{L}}$-Pro) and phenethyl acetate (PA). We chose PA, which had the highest anticancer activity, as a target compound for further experiments. PA induced the formation of apoptotic bodies, DNA fragmentation, DNA accumulation in $G_0/G_1$ phase, and reactive oxygen species (ROS) formation. Furthermore, PA treatment increased Bax/Bcl-xL expression, activated caspase-3, and cleaved poly-ADP-ribose polymerase (PARP) in HL-60 cells. Simultaneous evaluation in vitro and in vivo, revealed that PA exhibited no toxicity in Vero cells and zebrafish embryos. We revealed, for the first time, that PA generates ROS, and that this ROS accumulation induced the Bcl signaling pathway.

• Journal of Physiology & Pathology in Korean Medicine
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• v.21 no.6
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• pp.1513-1519
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• 2007

Yukwool-tang (YWT) is a traditional Chinese medicine, which has been used for patients suffering from a uterine disease in Oriental medicine. In the present study, it was examined the biochemical mechanisms of apoptosis by YWT in human cervical carcinoma HeLa cells. It was found that YWT could inhibit the cell growth of HeLa cells in a dose-dependent manner, which was associated with apoptotic cell death such as formation of apoptotic bodies and DNA fragmentation. Flow cytometry analysis confirmed that YWT treatment increased populations of apoptotic-sub-G1 phase of the cell cycle. We observed the p53-independent induction of p21 proteins, down-regulation of anti apoptotic Bcl-2 expression and proteolytic activation of caspase-3 in YWT-treated HeLa cells. YWT treatment also concomitant degradation and/or inhibition of poly (ADP-ribose) polymerase (PARP), phospholipase C-1 ($PLC{\gamma}1$), ${\beta}-catenin$ and DNA fragmentation factor 45/inhibitor of caspase-activated DNase (DFF45/ICAD). Taken together, these findings partially provide novel insights into the possible molecular mechanism of the anti-cancer activity of YWT.

• Preventive Nutrition and Food Science
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• v.7 no.2
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• pp.128-132
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• 2002

The present study was performed to observe the role of protein kinase C (PKC) inhibitors (H-7, staurosporine) and daunorubicin in the cell death process of MCF7 cells; and examined whether or not the type of induced cell death was apoptosis. The usefulness of the combined therapy of PKC inhibitors and daunorubicin to improve the adverse effect of daunorubicin was also investigated. Cell death was induced by treatment with PKC inhibitors or daunorubicin. Characteristic morphologic features of cell shrinkage, chromatic condensation, and cytoplasmic vacuolization were observed. These treatments also stimulated the cleavage of poly-(ADP-ribose) polymerase (PARP), an early event in apoptosis. With slight differences in the percentage of apoptosis-induced cells, staurosporine, H-7 and daunorubicin effectively induced apoptosis in MCF7 cells. Furthermore, combined treatment of PKC inhibitors and daunorubicin significantly drove the cells into an apoptotic state. Hence, our results revealed the possible therapeutic value of combined therapy for the prevention of drug resistance and adverse side effects.

• The Journal of Internal Korean Medicine
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• v.29 no.1
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• pp.42-66
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• 2008

Aconiti Tuber is a traditional medicinal plant generally used in Oriental medicine therapy. In this study, we investigated the biochemical mechanisms of anti-proliferative effects by the methanol extract of Aconiti tuber (MEBJ) in Caki-1 human renal cell carcinoma cells. It was found that MEBJ could inhibit, in a dose-dependent manner, cell growth which was associated with apoptotic cell death such as formation of apoptotic bodies, DNA fragmentation and increased populations of apoptotic-sub G1 phase. Apoptosis of Caki-1 cells by MEBJ was associated with an up-regulation of pro-apoptotic Bax expression, and a down-regulation of anti-apoptotic Bcl-2 in a dose-dependent manner; however, the levels of IAP family were not affected. MEBJ treatment also induced the proteolytic activation of caspase-3 and -8, and a inhibition of poly(ADP-ribose) polymerase (PARP) and $PLC{\gamma}1$ protein. Furthermore, MEBJ treatment caused a dose-dependent inhibition of iNOS and cyclooxygenase-2 (Cox-2). Though further studies will be needed to identify the active compounds that confer the anti-cancer activity of MEBJ, the present findings provide important new insights into the possible molecular mechanisms of the apoptotic activity of MEBJ in cancer cells.

• Natural Product Sciences
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• v.23 no.1
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• pp.21-28
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• 2017

In our program to search for new AMP-activated protein kinase (AMPK) activators from plants that exert potential anticancer property, we found that an EtOAc extract of Myristica fragrans (nutmeg) activated AMPK enzyme in human breast cancer MCF-7 cells. Two major diarylbutane-type lignans, macelignan and meso-dihydroguaiaretic acid (MDGA), were isolated as active principles from this extract. Treatment of breast cancer cells with two compounds induced cellular apoptosis, evidenced by cleavage of poly-(ADP-ribose) polymerase (PARP) and Ser 15 phosphorylation of p53. Moreover, macelignan and MDGA significantly inhibited the colony formation of MCF-7 breast cancer cells on soft agar. Intraperitoneal injection of macelignan and MDGA (20 mg/kg) suppressed the tumor growth of 4T1 mammary cancer cells. These results indicate that the chemopreventive effects of two major diarylbutane-type lignans from Myristica fragrans (nutmeg) may be associated with induction of apoptosis presumably through AMPK activation.