• Journal of Physiology & Pathology in Korean Medicine
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• v.18 no.4
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• pp.1089-1097
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• 2004

This study was designed to elucidate the synergistic cytotoxic mechanisms of the cotreatment of Gagamsibjeondaebo-tang (GSD) and AS₂O₃ in human lung cancer cell line, H-460. The combination of GSD and AS₂O₃ synergistically augmented the cytotoxicity of GSD and AS₂O₃ in H-460 cells. The nature of cytotoxicity was revealed as apoptosis which was characterized by chromatin condensation and fragmentaton in DAPI staining. The apoptotic cytotoxicity of GSD and AS₂O₃ was accompanied by the cleavage of PARP. Of note, the expression of pro-apoptotic BclXS protein was increased, but the expressions of Sax and BclXL was not affected in H-460 cells treated with GSD and AS₂O₃. In addition, antioxidant NAC completely blocked the apoptotic death of H-460 cells by GSD and AS₂O₃. In conclusion, this results suggest that the cotreatment of GSD and AS203 induces the synergistic apoptotis of human large cell lung cancer cell line, H-460 via the induction of BclXS and reactive oxygen species (ROS).

• The Journal of Korean Medicine
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• v.25 no.3
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• pp.191-202
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• 2004

Objectives : This study was designed to elucidate the synergistic cytotoxic mechanisms of the co-treatment of Gagamjengac-tang (GGJAT) and As₂O₃ in human lung cancer cell line, H-157. Methods : The combination of GGJAT and As₂O₃ synergistically augmented the cytotoxicity of GGJAT and As₂O₃ in H­157 cells. The cytotoxicity by the combination of these two drugs was revealed as apoptosis which was characterized by chromatin condensation and fragmentation in DAPI staining. Results : Antioxidant NAC completely blocked the apoptotic death of H-157 cells by GGJAT and As₂O₃. The apoptotic cytotoxicity of GGJAT and As₂O₃ was accompanied by the induction of DR4 and DR5 in RT-PCR. In addition, antioxidant enzymes such as SOD1, GSH synthetase and GSH reductase were also increased in H-157 cells treated with GGJAT and As₂O₃. However, of note, p53, Fas, FasL and TRAIL were not detected in H-157 cells treated with GGJAT and As₂O₃ by RT-PCR. Conclusions : These results suggest that the synergistic cytotoxicity of the co-treatment of H-457 cells treated with GGJAT and As₂O₃ may cause induction of death receptors DR4 and DR5 as well as reactive oxygen species.

• Development and Reproduction
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• v.21 no.2
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• pp.139-150
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• 2017

Metformin is the most commonly prescribed anti-diabetic drug with relatively minor side effect. Substantial evidence has suggested that metformin is associated with decreased cancer risk and anticancer activity against diverse cancer cells. The tyrosine kinase inhibitor imatinib has shown powerful activity for treatment of chronic myeloid leukemia and also induces growth arrest and apoptosis in colorectal cancer cells. In this study, we tested the combination of imatinib and metformin against HCT15 colorectal cancer cells for effects on cell viability, cell cycle and autophagy. Our data show that metformin synergistically enhances the imatinib cytotoxicity in HCT15 cells as indicated by combination and drug reduction indices. We also demonstrate that the combination causes synergistic down-regulation of pERK, cell cycle arrest in S and $G_2/M$ phases via reduction of cyclin B1 level. Moreover, the combination resulted in autophagy induction as revealed by increased acidic vesicular organelles and cleaved form of LC3-II. Inhibition of autophagic process by chloroquine led to decreased cell viability, suggesting that induction of autophagy seems to play a cell protective role that may act against anticancer effects. In conclusion, our present data suggest that metformin in combination with imatinib might be a promising therapeutic option in colorectal cancer.

• The Journal of the Korean bone and joint tumor society
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• v.4 no.1
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• pp.13-21
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• 1998

Taxol, the extract from the Taxus brevifolia which is a Pacific yew tree has aroused the interest of the tumor investigators since the 1960s. As well, it is shown to have broad antitumor activity in preclinical experimental models. Its action mechanism is an anti-microtubule effect by duplication of tubulin. The most impressive antitumor activity of taxol has been observed in advanced ovarian cancer and metastatic breast cancer. The purpose of this study was to determine how taxol acts on malignant bone tumor cell lines, to compare its cytotoxic effect with those of other chemotherapeutic agents, and to ascertain the its combination effect with adriamycin. Cell lines used in this study were G-292(osteosarcoma, human), SaOS-2(osteosarcoma, primary, human), and HT-1080(fibrosarcoma, human). Methotrexate, adriamycin, cisplatinum, ifosfamide and taxol were used as testing chemotherapeutic agents and their maximum test concentration were $500{\mu}g/ml$, $200{\mu}g/ml$, $500{\mu}g/ml$, $1000{\mu}g/ml$, and $600{\mu}g/ml$, respectively. The media for cell culture was RPMI-1640 with 10% fetal bovine serum and gentamycin. The results were as follows. The $IC_{50}$ of methotrexate, ifosfamide, cisplatinum, adriamycin and Taxol in G-292 were $2.3{\times}10^{-1}{\mu}g/ml$, $8.0{\times}10^0{\mu}g/ml$, $3.5{\times}10^0{\mu}g/ml$, $9.8{\times}10^{-1}{\mu}g/ml$, $2.7{\times}10^{-2}{\mu}g/ml$ respectively, in SaOS-2 $3.5{\times}10^{-1}{\mu}g/ml$, $1.5{\times}10^1{\mu}g/ml$, $2.8{\times}10^0{\mu}g/ml$, $9.9{\times}10^{-2}{\mu}g/ml$, $1.0{\times}10^{-2}{\mu}g/ml$, respectively, in HT-1080 $4.2{\times}10^{-2}{\mu}g/ml$, $5.4{\times}10^1{\mu}g/ml$, $3.8{\times}10^0{\mu}g/ml$, $5.5{\times}10^{-3}{\mu}g/ml$, $1.1{\times}10^{-3}{\mu}g/ml$, respectively. In conclusion, taxol had very potent cytotoxic effect on the malignant bone tumor cell lines with adriamycin, and was more potent than methotrexate, cisplatinum and ifosfamide. There were synergistic antitumor effects on G-292 and SaOS-2 cell lines in combination test of taxol and adriamycin. From the above results, it would be estimated that taxol could be a new antitumor drug for the malignant bone tumors, providing measures against the side effects and followed by the clinical tests.

• Development and Reproduction
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• v.22 no.2
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• pp.133-142
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• 2018

Patients with type II diabetes mellitus are more susceptible to colorectal cancer (CRC) incidence than non-diabetics. The anti-diabetic drug metformin is most commonly prescribed for the treatment of this disease and has recently shown antitumor effect in preclinical studies. The aberrant mutational activation in the components of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathway is very frequently observed in CRC. We previously reported that metformin inhibits the phosphorylation of ERK and BEZ235, a dual inhibitor of PI3K and mTOR, has anti-tumor activity against HCT15 CRC cells harboring mutations of KRAS and PIK3CA. Therefore, we hypothesized that simultaneous inhibition of two pathways by combining metformin with BEZ235 could be more effective in the suppression of proliferation than single agent treatment in HCT15 CRC cells. Here, we investigated the combinatory effect of metformin and BEZ235 on the cell survival in HCT15 CRC cells. Our study shows that both of the two signaling pathways can be blocked by this combinational strategy: metformin suppressed both pathways by inhibiting the phosphorylation of ERK, 4E-BP1 and S6, and BEZ235 suppressed PI3K/AKT/mTOR pathway by reducing the phosphorylation of 4E-BP1 and S6. This combination treatment synergistically reduced cell viability. The combination index (CI) values ranged from 0.44 to 0.88, indicating synergism for the combination. These results offer a preclinical rationale for the potential therapeutic option for the treatment of CRC.

• Korean Journal of Head & Neck Oncology
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• v.14 no.2
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• pp.151-155
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• 1998

Background and Objectives: Numerous studies were conducted to develop radiosensitizers to increase antitumor effect and decrease systemic toxicity of ionizing radiation. In current study, the authors tested the synergistic effect of mutant $TNF-{\alpha}(M_3S)$ with radiation therapy on heterotransplanted hypoparyngeal squamous cell carcinoma. Materials and Method: SNU-1041 cell line was heterotransplanted to nude mice. When the tumors grew up to $70mm^3$ or more, the animals were randomly placed into 4 groups(n=10/group). Group I : 0.1ml of normal saline injected intraperitoneally once a day for 5 days. Group II : 10ug of $TNF-{\alpha}$ injected intraperitoneally once a day for 5 days. Group III : a single radiation dose of 10 Gy per animal delivered. Group IV : single radiation dose of 10 Gy was delivered 1 hour after intraperitoneal injection of $TNF-{\alpha}$ 10 ug. Results: Four weeks after treatment, group IV showed the least tumor growth during the 4 weeks follow up and the relative tumor growth rate(RTG) of each groups after 4 weeks were 31, 5.8, 10, and 3.2 respectively(p<0.05). Conclusion: These study suggests that pretreatment with $TNF-{\alpha}$ can significantly enhance the effects of radiation therapy and further studies may be needed for clinical trials of combination treatment of $TNF-{\alpha}$ and radiation.

• Journal of Ginseng Research
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• v.39 no.1
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• pp.22-28
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• 2015

Background: Sun ginseng (SG), a specific formulation of quality-controlled red ginseng, contains approximately equal amounts of three major ginsenosides (RK1, Rg3, and Rg5), which reportedly has antitumor-promoting activities in animal models. Methods: MTT assay was used to assess whether SG can potentiate the anticancer activity of epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells; apoptosis status was analyzed by annexin V-FITC and PI and analyzed by flow cytometry; and apoptosis pathway was studied by analysis of caspase-3, -8, and -9 activation, mitochondrial accumulation of Bax and Bak, and cytochrome c release. Results: SG remarkably enhances cancer cell death induced by epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells. Results of the mechanism study highlighted the cooperation between SG and epirubicin or paclitaxel in activating caspase-3 and -9 but not caspase-8. Moreover, SG significantly increased the mitochondrial accumulation of both Bax and Bak triggered by epirubicin or paclitaxel as well as the subsequent release of cytochrome c in the targeted cells. Conclusion: SG significantly potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. Treating cancer cells by combining epirubicin and paclitaxel with SG may prove to be a novel strategy for enhancing the efficacy of the two drug types.

• Biomolecules & Therapeutics
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• v.30 no.3
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• pp.274-283
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• 2022

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

• The Journal of Internal Korean Medicine
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• v.21 no.1
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• pp.65-73
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• 2000

Objectives : The effects of cotreatment of adriamycin and ethanol extract of herb (Palgin-tang hab Hwajuck-hwan a traditional medicine for cancer treatment in oriental medicine) on the induction of apoptotic cell death were investigated in human liver origin cell lines, Chang. Methods : Chang(ATCC) liver cells were cultured in RPMI-1640(Gibco SRL Co, Gaithersburg, MD) badge including 10% fetal bovine serum. Chang liver cells were treated with various concentrations(from 10 to $0.16{\mu}l$) of adriamycin and herb extract(from 500 to $31.25{\mu}l$) After 48h later, the cells were tested for viability by Crystal violet staining assay. Adriamycin and Herb extract induced ladder pattern of DNA fragmentation in Chang cells. Genomic DNA was isolated and separated on 1.5% agarose gels. The DNA was stained with ethidium bromide and visualized under UV light. Results : The death of Chang cells was synergistically induced by the cotreatment of adriamycin and ethanol extract of herb. In addition, the cotreatment-induced cell death of Chang cells was mediated by apoptotic death signal processes. The phosphotransferase activity of JNK1 remained in a basal level in Chang cells which was treated individually with the adriamycin and ethanol extract of herb. However, it was markedly increased in Chang cells which was cotreated with adriamycin and ethanol extract of herb. In addition, the expression of Fas and FasL was markedly induced by the cotreatment of adriamycin and herb extract. For a while, the expression of Sax was a eminently increased by the ethanol extract of herb. However, Scl2 expression was not affected by the individual or cotreatment of adriamycin and herb extract. Conclusions : our results suggest that the cotreatment of adriamycin aM ethanol extract of herb induces synergistic apoptotis of human liver origin Chang cells via the upregulation of JNK, Fas, FasL and Bax.

• International Journal of Oral Biology
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• v.39 no.3
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• pp.159-167
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• 2014

Curcumin is a widely used flavoring agent in food, and it has been reported to inhibit cell growth, to induce apoptosis, and to have antitumor activity in many cancers. Cisplatin is one of the most potent known anticancer agents and shows significant clinical activity against a variety of solid tumors. This study was undertaken to investigate the synergistic apoptotic effects of co-treatment with curcumin and cisplatin on human tongue SCC25 cells. To investigate whether the co-treatment efficiently reduced the viability of the SCC25 cells compared with the two treatments separately, an MTT assay was conducted. The induction and the augmentation of apoptosis were confirmed by DNA electrophoresis, Hoechst staining, and an analysis of DNA hypoploidy. Western blot, MMP and immunofluorescence tests were also performed to evaluate the expression levels and the translocation of apoptosis-related proteins following the co-treatment. In this study, following the co-treatment with curcumin and cisplatin, the SCC25 cells showed several forms of apoptotic manifestation, such as nuclear condensation, DNA fragmentation, reduction of MMP, increased levels of Bax, decreased levels of Bcl-2, and decreased DNA content. In addition, they showed a release of cytochrome c into the cytosol, translocation of AIF and DFF40 (CAD) to the nuclei, and activation of caspase-7, caspase-3, PARP, and DFF45 (ICAD). In contrast, separate treatments of $5{\mu}M$ of curcumin or $4{\mu}g/ml$ of cisplatin, for 24 hours, did not induce apoptosis. Therefore, our data suggest that combination therapy with curcumin and cisplatin could be considered as a novel therapeutic strategy for human oral squamous cell carcinoma.