• The Korean Journal of Physiology and Pharmacology
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• v.20 no.3
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• pp.253-259
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• 2016

Previously, we found that KTH-13 isolated from the butanol fraction of Cordyceps bassiana (Cb-BF) displayed anti-cancer activity. To improve its antiproliferative activity and production yield, we employed a total synthetic approach and derivatized KTH-13 to obtain chemical analogs. In this study, one KTH-13 derivative, 4-(tert-butyl)-2,6-bis(1-phenylethyl)phenol (KTH-13-t-Bu), was selected to test its anti-cancer activity. KTH-13-t-Bu diminished the proliferation of C6 glioma, MDA-MB-231, LoVo, and HCT-15 cells. KTH-13-t-Bu induced morphological changes in C6 glioma cells in a dose-dependent manner. KTH-13-t-Bu also increased the level of early apoptotic cells stained with annexin V-FITC. Furthermore, KTH-13-t-Bu increased the levels of cleaved caspase-3 and -9. In contrast, KTH-13-t-Bu upregulated the levels of pro- and cleaved forms of caspase-3, -8, and -9 and Bcl- 2. Phospho-STAT3, phospho-Src, and phospho-AKT levels were also diminished by KTH13-t-Bu treatment. Therefore, these results strongly suggest that KTH-13-t-Bu can be considered a novel anti-cancer drug displaying pro-apoptotic activity.

• Korean Journal of Plant Resources
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• v.31 no.1
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• pp.16-23
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• 2018

Paeonia japonica is a perennial flowering plant used in traditional medicine therapy. The purpose of this study was to investigate the effect of water extract and solvent fractions obtained from P. japonica on anti-oxidative, anti-thrombin, anti-invasive and pro-apoptotic activities in YD-10B cells, human oral squamous carcinoma cell line. Water fraction revealed the highest extraction yield at 11.44% (w/w). Anti-oxidative activity was the highest in ethyl acetate fraction (85.13%). In the thrombin inhibitory activity test, ethyl fraction was the highest, with a value of 87.54%. Release and activation of MMP-2/pro-MMP-2 ratio in thrombin-treated YD-10B cells were significantly inhibited in the ethyl acetate fraction. At a concentration of $120{\mu}g/m{\ell}$ water extract and solvent fractions of P. japonica inhibited cell proliferation in YD-10B cells except water fraction. Pro-apoptotic effect on human oral squamous carcinoma cell using the Bax/Bcl-2 ratio analysis was higher in water extract than other fractions. These findings suggest that the ethyl acetate fraction of P. japonica potentiates a promising antioxidant, anti-thrombin and anti-invasive agents.

• Molecules and Cells
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• v.21 no.1
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• pp.1-6
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• 2006

Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is a mitochondrial pro-apoptotic protein that has a single Bcl-2 homology 3 (BH3) domain and a COOH-terminal transmembrane (TM) domain. Although it belongs to the Bcl-2 family and can heterodimerize with Bcl-2, its pro-apoptotic activity is distinct from those of other members of the Bcl-2 family. For example, cell death mediated by BNIP3 is independent of caspases and shows several characteristics of necrosis. Furthermore, the TM domain, but not the BH3 domain, is required for dimerization, mitochondrial targeting and pro-apoptotic activity. BNIP3 plays an important role in hypoxia-induced death of normal and malignant cells. Its expression is markedly increased in the hypoxic regions of some solid tumors and appears to be regulated by hypoxia-inducible factor (HIF), which binds to a site on the BNIP3 promoter. Silencing, followed by methylation, of the BNIP3 gene occurs in a significant proportion of cancer cases, especially in pancreatic cancers. BNIP3 also has a role in the death of cardiac myocytes in ischemia. Further studies of BNIP3 should provide insight into hypoxic cell death and may contribute to improved treatment of cancers and cardiovascular diseases.

• Journal of Microbiology and Biotechnology
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• v.31 no.10
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• pp.1343-1349
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• 2021

Cockroaches live in places where various pathogens exist and thus are more likely to use antimicrobial compounds to defend against pathogen intrusions. We previously performed an in silico analysis of the Periplaneta americana transcriptome and detected periplanetasin-5 using an in silico antimicrobial peptide prediction method. In this study, we investigated whether periplanetasin-5 has anticancer activity against the human leukemia cell line K562. Cell growth and survival of K562 cells treated with periplanetasin-5 were decreased in a dose-dependent manner. By using flow cytometric analysis, acridine orange/ethidium bromide (AO/EB) staining and DNA fragmentation, we found that periplanetasin-5 induced apoptotic and necrotic cell death in leukemia cells. In addition, these events were associated with increased levels of the pro-apoptotic proteins Fas and cytochrome c and reduced levels of the anti-apoptotic protein Bcl-2. Periplanetasin-5 induces the cleavage of pro-caspase-9, pro-caspase-8, pro-caspase-3, and poly (ADP-ribose) polymerase (PARP). The above data suggest that periplanetasin-5 induces apoptosis via both the intrinsic and extrinsic pathways. Moreover, caspase-related apoptosis was further confirmed by using the caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK), which reversed the periplanetasin-5-induced reduction in cell viability. In conclusion, periplanetasin-5 caused apoptosis in leukemia cells, suggesting its potential utility as an anticancer therapeutic agent.

• Toxicological Research
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• v.22 no.1
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• pp.31-37
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• 2006

It was previously found that melittin inhibited $NF-{\kappa}B$ activity by reacting with signal molecules of $NF-{\kappa}B$ which is critical contributor in cancer cell growth by induction of apoptotic cell death. We here investigated whether melittin inhibits cell growth of human prostate cancer cells through induction of apoptotic cell death, and the possible signal pathways. Melittin ($0{\sim}1\;{\mu}g/ml$) inhibited prostate cancer cell growth in a dose dependent manner. Conversely related to the growth inhibitory effect, melittin increased the induction of apoptotic cell death in a dose dependent manner. Melittin also inhibited DNA binding activity of $NF-{\kappa}B$, an anti-apoptotic transcriptional factor. Consistent with the induction of apoptotic cell death and inhibition of $NF-{\kappa}B$, melittin increased the expression of pro-apoptotic proteins caspase-3, and Bax but down-regulated anti-apoptotic protein Bcl-2. These findings suggest that melittin could inhibit prostate cancer cell growth, and this effect may be related with the induction of apoptotic cell death via inactivation of $NF-{\kappa}B$.

• 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.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.617-622
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• 2014

Voacanga globosa (Blanco), a plant endemic to the Philippines, is traditionally used especially by indigenous people of Bataan in the treatment of ulcers, wounds and tumorous growths. This study aimed to provide scientific evidence to therapeutic properties by determining cytotoxic and pro-apoptotic activity of HPLC fractions from leaves on HCT116 human colon carcinoma and A549 human lung carcinoma cell lines. Ethanolic extraction was performed on V globosa leaves followed by hexane and ethyl acetate partitioning. Silica gel column chromatography and high performance liquid chromatography (HPLC) produced MP1, MP2 and MP3 fractions. Cytotoxic activity of the fractions was determined through MTT assay against the cancer cell lines HCT116 and A549 and the non-cancer AA8 Chinese hamster ovarian cell line. Pro-apoptotic activities of the most active fractions were further assessed through DAPI staining, TUNEL assay and JC-1 mitochondrial membrane potential assay with HCT116 cells. While the MPI fraction exerted no significant activity against all cell lines tested, MP2 and MP3 fractions demonstrated high toxicity against HCT116 and A549 cells. The MP3 fraction induced formation of apoptotic bodies, condensed DNA and other morphological changes consistent with apoptosis of HCT116 cells and TUNEL assay showed significant increase in DNA fragmentation over time. In these cells, the MP3 fraction also induced mitochondrial membrane destabilization, which is generally associated with the beginning of apoptosis. Phytochemical analysis demonstrated the presence only of saponins and terpenoids in the MP3 fraction. The results indicate that the MP3 fraction exerts cytotoxic activity on HCT116 cells via induction of apoptosis triggered by loss of mitochondrial membrane potential crucial for cell survival.

• Journal of Acupuncture Research
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• v.23 no.2
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• pp.47-59
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• 2006

We previously found that cobrotoxin inhibited $NF-{\kappa}B$ activity by reacting with signal molecules of $NF-{\kappa}B$ which is critical contributor in cancer cell growth by induction of apoptotic cell death. We here investigated whether cobrotoxin inhibits cell growth of human prostate cancer cells through induction of apoptotic cell death, which is related with the suppression of the $NF-{\kappa}B$ activity. Cobrotoxin $(0{\sim}8\;nM)$ inhibited prostate cancer cell growth through increased apoptosis in a dose dependent manner. Cobrotoxin inhibited DNA binding activity of $NF-{\kappa}B$, an anti-apoptotic transcriptional factor. Consistent with the induction of apoptosis and inhibition of $NF-{\kappa}B$, cobrotoxin increased the expression of pro-apoptotic proteins caspase 3. Cobrotoxin, a venom of Vipera lebetina turanica, is a group of basicpeptides composed of 233 amino acids with six disulfide bonds formed by twelve cysteins. NF-kB is activated by subsequent release of inhibitory IkB and translocation of p50. Since sulfhydryl group is present in kinase domain of p50 subunit of NF-kB, cobrotoxin could modify NF-kB activity by protein-protein interaction. And Cobrotoxin down regulated Akt signals. Salicylic acid as a reducing agent of Sulf-hydryl group and LY294002 as a Akt inhibitor abrogated cobrotoxin-induced cell growth and DNA binding activity of $NF-{\kappa}B$. These findings suggest that nano to pico molar range of cobrotoxin could inhibit prostate cancer cell growth, and the effect may be related with the induction of apoptotic cell death through Akt dependent inhibition of $NF-{\kappa}B$ signal.

• Journal of the Korean Society of Food Science and Nutrition
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• v.45 no.6
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• pp.911-917
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• 2016

Lespedeza cuneata G. Don is an edible perennial herb used in traditional Korean medicine. We investigated the anti-proliferative properties and mechanism of L. cuneata extract. The ethanolic extract of L. cuneata dose-and time-dependently inhibited human colorectal cancer cell proliferation. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to test the effect of the extract on proliferation of HT-29 colorectal cancer cells. The extract inhibited HT-29 cell proliferation with an $IC_{50}$ value of $554.26{\pm}8.81{\mu}g/mL$. L. cuneata extract suppressed production of pro-inflammatory cytokines interleukin-6 and tumor necrosis $factor-{\alpha}$. Apoptosis was evaluated by analysis of DNA fragmentation, poly(ADP-ribose) polymerase cleavage, caspase-3 activity, and protein expression of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2). Our results demonstrated that the extract induced DNA fragmentation and characteristic morphological changes associated with apoptosis in HT-29 colorectal cancer cells. The extract also time- and dose-dependently up-regulated expression of the Bax and down-regulated expression of the Bcl-2. Furthermore, the extract dose- and time-dependently enhanced caspase-3 activity. Our findings provide evidence that L. cuneata extract may mediate its anti-proliferative effect via modulation of apoptosis.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6791-6795
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• 2013

Apoptotic and cytotoxic activity of plant extracts obtaining from naturally growing Cynara syriaca in Turkey and cultivated C cardunculus against DLD1 colorectal cancer cells was determined. Extracts from wild and cultivated Cynara species were obtained from their vegetative parts and receptacles using hexane and applied with five different dose (0.1-1 mg/ml) as well as apigenin for MTT tests for three time periods (24, 48 and 72 hours). After cells were treated with $IC_{50}$ doses for each extract total DNA and RNA were isolated for determination of the cause of cell death. From isolated RNAs, cDNA were synthesized and amplification of p21, BCL-2 and BAX gene regions was carried out. Consequently, we found that pro-apoptotic (BAX) gene expression and a cell cycle inhibitor (p21) were induced in the presence of our artichoke extracts. In contrast, anti-apoptotic BCL-2 gene expression was reduced compared to the control group. In addition DNA fragmentation results demonstrated DLD1 cell death via apoptosis.