Bak, Ye Sol;Ham, Sun Young;O, Baatartsogt;Jung, Seung Hyun;Choi, Kang Duk;Han, Tae Young;Han, Il Young;Yoon, Do-Young
Journal of Applied Biological Chemistry
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제57권2호
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pp.113-122
/
2014
A5E is complex of several medicinal herb ethanol extracts. The aim of this study is investigating the anticancer effect for non-small cell lung cancer. The antitumor effects of A5E on NCI-H460 were examined by regulation of cell proliferation, apoptosis, cell cycle arrest, mitochondrial membrane potential (${\Delta}{\Psi}_m$), and apoptosis-related protein. Cell proliferation was measured by MTS assay. Apoptosis induced by A5E was confirmed by Annexin V-fluorescein isothiocyanate (FITC)/Propidium Iodide (PI) staining, and cell cycle arrest was measured by PI staining. NF-${\kappa}B$ translocation was detected by immunofluorescence and MMP (${\Delta}{\Psi}_m$) was measured by JC-1 staining. The expression of extrinsic pathway molecules such as FasL and FADD were elevated, and procaspase-8 was processed by A5E. In addition, intrinsic pathway related molecules were altered. The Bcl-2 and Bcl-xl levels decreased, Bax increased, and cytochrome C was released. In addition, the mitochondrial membrane potential collapsed, and caspase-3 and poly-(ADP-ribose) polymerase were processed by A5E. Moreover, A5E affected the cellular survival pathway involving phosphatidylinositol 3-kinase (PI3K)/Akt and NF-${\kappa}B$. PI3K and Akt were downregulated, also NF-${\kappa}B$ expression was decreased, and nuclear translocalization was inhibited by A5E. These results suggested that A5E delays proliferation, inhibit cell cycle progression and induce apoptosis in human lung cancer cell. We conclude that A5E is a potential anticancer agent for human lung carcinoma.
The fractions of Capsosiphon fulvescens were studied to verify the anticancer and immunostimulating activity. The fractions from the ethanol extract of C. fulvescens were prepared by the systematic extraction procedure with the solvents such as hexane, ethyl ether, methanol, butanol and H$_2$O. The cytotoxic effects of C. fulvescens fractions against human leukemia cell line U937, mouse neuroblastoma cell line (NB41A3), human hepatoma cell line (HepG2)and rat glioma cell line (C6) were investigated. Ethyl ether fraction of C. fulvescens showed the highest cytotoxicity against all four cell lines tested. In addition, H$_2$O fraction also showed relatively high cytotoxicity. Dose dependent patterns were observed on all four cell lines. The immune-stimulating effects of C. fulvescens fractions on rat macrophage cell line (RAW 264.7) were also investigated. All five fractions of C. fulvescens extract stimulated NO production with concentration dependant manner. These results suggest that C. fulvescens may be a useful candidate for a natural antitumor and immune-stimulating agent.
To evaluate the renal toxicity of the antitumor agent, 5-(piperidonomethylphenyl)-2,3-dihydroimidazo[2,1-a]isoquinoline (SDZ-62-434), rats were treated with SDZ-62-434 of 50 mg/Kg, i.p., once and 10 mg/Kg, i.p., daily for 7 days. The kidney weights and urine volume after and during the treatment were observed. The concentrations of urinary creatinine, protein, and the activities of N-acetyl-$\beta $D-glucosaminidase (NAG), alanine aminopeptidase (AAP), $\gamma$-glutamyl transpeptidase (GGT) and lactate dehydrogenase (LDH) in 24 hr urine were also determined. The kidney weights after acute and subacute administration was not affected. The urine excretions were increased 5 days after the acute administration and increased after the daily 3rd day-administration. The excretion of creatinine was similar as that of urine excretion. The excretion of creatinine was increased 5 days after the acute and subacute administration. However, the protein excretion didn't changed in both treatment. Those indicate that SDZ-62-434 might induce the diuresis and also suggest that diuresis might be due to the some metabolites rather than the compound itself. The urinary activities of NAG and LDH were not affected after the acute treatment. However, the urinary activities of AAP and GGT were slightly increased 3 days after the acute administration but, returned to the control value. In subacute treatment, the activities of GGT was not changed. And the activities of NAG were declined after the 7th day-administration. However, the activities of AAP were significantly increased after the 5th day-administration. Furthermore, the urinary activities of LDH were continuously increased during the subacute administration. These results indicate that the high and subacute administration might induce a weak damage on the kidney cells. Furtherrnore, the present results suggest that SDZ-62-434 might have relatively slow-emerging and mild toxicity to the kidney.
To date many kinds of compounds have been obtained from plants kingdom as antineoplastic and anti-cancerous agents. However, there is no special type of compounds for cancer therapy. Various types of substances are effective for various types of cancers and tumors: for instance, alkaloids. lignans, terpenes and steroids etc. Curcumol obtained from Curcuma aromatica was tested and noticed to be effective against cancer of the uterine cervix clinically. Oridonin isolated from Rabdosia ssp. is now investigate for clinical trials in China. Moreover camptothecine isolated from Camptotheca acuminata is also antineoplastic alkaloid, but is very toxic. Chemical modification has been tried to decrease its toxicity This compound is now using as clinical agent. Harringtonin was investigated as an anticancerous drug in China. Taxol, a compound with a taxane ring isolated from the bark of Taxus brevifotia. has been demonstrated to have substantial anticancer activity in patients with solid tumors refractory standard chemotherapy. Supply of this drug has severely limited full exploration of its antineoplastic potential Some efforts are continued in National Cancer Institute(NCI) Washington for surveying various Taxus species for optimal taxol content, improvement in semi-synthesis from baccatin 111, improvement in method of extraction, and development of alternative renewable resources. Further, there are many compounds which have been reported as antineoplastic agents. On the other hand, we have screened on higher plants collected In Japan, China, Korea. Southeast Asia and South America for antineoplastic activity, which has been done using Sarcoma 180 ascites in mice, P388 Iymphocytic leukemia In mice, Chinese hamster lung V-79 cells, P388 cells and nasopharynx carcinoma(KB) cells in our laboratory, as primary screening. In this meeting, 1 will present on antitumor and cytotoxic substances of the higher plants(Rubis cordifolia, Ailanthus vilmoriniana, Aster tataricus, Taxus cuspidata var. nana, Cephalotaxus harringtonia var. drupacea, etc.) selected from above screening tests.
Mistletoe lectin has been reported to induce apoptosis in different cancer cell lines in vitro and to show antitumor activity against a variety of tumors in animal models. We previously demonstrated the Korean mistletoe lectin (Viscum album var. coloratum, VCA)-induced apoptosis by down-regulation of Bcl-2 and telomerase activity and by up-regulation of Bax through p53- and p21-independent pathway in hepatoma cells. In the present study, we observed the induction of apoptotic cell death through activation of caspase-3 and the inhibition of telomerase activity through transcriptional down-regulation of hTERT in the VCA-treated A253 cells. We also observed the inhibition of telomerase activity and induction of apoptosis resulted from dephosphorylation of Akt in the survival signaling pathways. In addition, combining VCA with the inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) upstream of Akt, wortmannin and LY294002 showed an additive inhibitory effect of telomerase activity. In contrast, the inhibitor of protein phosphatase 2A (PP2A), okadaic acid inhibited VCA-induced dephosphorylation of Akt and inhibition of telomerase activity. Taken together, VCA induces apoptotic cell death through Akt signaling pathway in correlated with the inhibition of telomerase activity and the activation of caspase-3. From these results, together with our previous studies, we suggest that VCA triggers molecular changes that resulting in the inhibition of cell growth and the induction of apoptotic cell death of cancer cells, which suggest that VCA may be useful as chemotherapeutic agent for cancer cells.
Aurora kinases inhibitors, including ZM447439 (ZM), which suppress cell division, have attracted a great deal of attention as potential novel anti-cancer drugs. Several recent studies have confirmed the anti-cancer effects of ZM in various cancer cell lines. However, there have been no studies regarding the cardiac safety of this agent. We performed several cytotoxicity, invasion and migration assays to examine the anti-cancer effects of ZM. To evaluate the potential effects of ZM on cardiac repolarisation, whole-cell patch-clamp experiments were performed with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cells with heterogeneous cardiac ion channel expression. We also conducted a contractility assay with rat ventricular myocytes to determine the effects of ZM on myocardial contraction and/or relaxation. In tests to determine in vitro efficacy, ZM inhibited the proliferation of A549, H1299 (lung cancer), MCF-7 (breast cancer) and HepG2 (hepatoma) cell lines with $IC_{50}$ in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect $I_{Na}$, $I_{Ks}$ or $I_{K1}$, but decreased $I_{hERG}$ in a dose-dependent manner ($IC_{50}$: $6.53{\mu}M$). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to $3{\mu}M$, but it at $10{\mu}M$ induced prolongation of AP duration. In summary, ZM showed potent broad-spectrum anti-tumor activity, but relatively low levels of cardiac side effects compared to the effective doses to tumor. Therefore, ZM has a potential to be a candidate as an anti-cancer with low cardiac toxicity.
Background: Ginsenosides have been widely used clinically for many years and were regarded as very safe. However, a few researches on the toxicities of these kinds of agents showed that some ginsenosides may have side-effect on the rats or dogs. So it is extremely necessary to further clarify the potential toxicity of ginsenosides. This study was carried out to investigate long-term toxicity and genotoxicity of 25-methoxydammarane-3, 12, 20-triol ($25-OCH_3-PPD$), a new derivative of ginsenoside, in beagle dogs. Methods: Twenty-four beagle dogs were divided randomly into four treatment groups and repeatedly orally administered with $25-OCH_3-PPD$ capsule at 60, 120, and 240 mg/kg/day for 91 consecutive days. Ames, micronucleus, and chromosomal aberration tests were established to analyze the possible genotoxicity of $25-OCH_3-PPD$. Results: There was no $25-OCH_3-PPD$einduced systemic toxicity in beagle dogs at any doses. The level of $25-OCH_3-PPD$ at which no adverse effects were observed was found to be 240 mg/kg/day. The result of Ames test showed that there was no significant increase in the number of revertant colonies of $25-OCH_3-PPD$ administrated groups compared to the vehicle control group. There were also no significant differences between $25-OCH_3-PPD$ administrated groups at all dose levels and negative group in the micronucleus test and chromosomal aberration assay. Conclusion: The highest dose level of $25-OCH_3-PPD$ at which no adverse effects were observed was found to be 240 mg/kg per day, and it is not a genotoxic agent either in somatic cells or germs cells. $25-OCH_3-PPD$ is an extremely safe candidate compound for antitumor treatment.
Current studies have been reported that fruits such as berries may contain both antioxidant and antitumor polyphenols that may be important in this regard. We investigated the immunostimulatory effect of fermented blueberry (Vaccinium corymbosum L.) on cyclophosphamide-induced immunosuppression in animal model. Rats were administered blueberry yeast fermented powder (BYFP) at doses 30, 100, and 300 mg/kg for 4 weeks after cyclophosphamide (Cy) treatment, respectively. The immunomodulatory effect of BYFP were measured both in vitro and in vivo, and the changes of blood components were also analyzed. We found that BYFP recovered immunosuppression-mediated decreased liver, spleen, and thymus weights as well as up regulation of white blood cell, lymphocyte, and neutrophil in blood. Moreover, BYFP up-regulated IL-2, TNF-${\alpha}$, and IFN-${\gamma}$ pro-inflammatory cytokine production compared to immune suppressed control group, respectively. According to histological studies, BYFP regenerated significantly on Cy-mediated injured spleen at the high doses (BYFP 300) comparison with Cy-treated groups (immunosuppression). Collectively, these findings suggest that BYFP may have the potential as a dietary immunostimulatory agent.
Shea butter (Vitellaria paradoxa) is a fat extracted from shea tree nuts and contains relatively high levels of non-glycerides. Triterpenes, the main non-glyceride component, exhibit a variety of biological activities such as antitumor, antibacterial, and anti-inflammatory. Shea butter extract (SBE) has been used to treat various skin problems such as burns, eczema, and rash in human medicine, but little is known about the activity of SBE on canine skin. This study evaluated the cytotoxicity and anti-inflammatory effect of SBE in canine keratinocytes. Cytotoxicity of lipopolysaccharide (LPS, 5-50 ng/mL) and SBE (50-200 ㎍/mL) was evaluated using the CCK-8 assay. Non-cytotoxic concentrations of LPS and SBE were administered to canine cell cultures to evaluate anti-inflammatory effects. To evaluate the anti-inflammatory activity of SBE, the levels of IL-1β, IL-8, IL-12, and TNF-α were measured using ELISA kits. The concentration of each cytokine was quantified in control, LPS-treated, LPS + SBE-treated groups. Increased levels of IL-1β, IL-8, and IL-12 were found in LPS-treated groups relative to control groups. LPS + SBE-treated groups showed a lower level of IL-1β, IL-8, and IL-12 than LPS-treated groups. These results suggest that SBE may have application as a topical agent for canine inflammatory skin diseases. However, further in vivo study is needed to evaluate the safety and efficacy of SBE in dogs.
Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.
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