• Korean Journal of Head & Neck Oncology
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• v.22 no.2
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• pp.130-136
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• 2006

Introduction : The sensitivity of tumor cells to radiotherapy is a critical determinant of local control and potential cure in advanced head and neck squamous cell carcinoma(HNSCC). The emergence of radioresistant tumor cells is an obstacle to cancer therapy. Most radioresistant cells have a higher proportion of cells in the Sphase of the cell cycle and a lower apoptotic fraction than radiosensitive cells. HSV replication is increased in cells that have higher S-phase fractions. NV1066 is an oncolytic herpes simplex virus type-1 mutant. We hypothesized that NV1066 replication and cytotoxicity are increased in radioresistant cells. The purpose of this study is to evaluate the antitumor efficacy of NV1066 to treat radioresistant HNSCC. Methods : Radioresistant cells were selected by treating five HNSCC cell lines with repeated conventional fractionated doses of radiation(2Gy/day), using a Cs-137 irradiator, up to a cumulative dose of 70Gy. Clonogenic cell survival and S-phase fractions were compared between radioresistant and parental radiosensitive cells. The two cell populations were then treated with NV1066 to examine viral replication, by the viral plaque assay and viral cytotoxicity. Results : Fractionated irradiation resulted in the selection of radioresistant cells. Radioresistant cells had a higher S-phase fraction(42.9%) compared to parental cells(26.2%). NV1066 replication in radioresistant cells was 7.4 times higher than in parental cells(p<0.01). Treatment with NV1066 resulted in increased cytotoxicity of 24.5% in radioresistant cells compared to parental cells(p<0.05). Conclusion : NV1066 showed increased viral replication and cytotoxicity in radioresistant HNSCC cell lines. These findings suggest a potential clinical application for this oncolytic viral therapy as treatment for radioresistant head and neck cancers.

• Biomolecules & Therapeutics
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• v.28 no.2
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• pp.184-194
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• 2020

Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents, which can be used to inhibit cell proliferation and induce apoptosis in several types of cancer cells. In this study, we investigated the anticancer activity of MHY4381, a newly synthesized HDAC inhibitor, against human prostate cancer cell lines and compared its efficacy with that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor. We assessed cell viability, apoptosis, cell cycle regulation, and other biological effects in the prostate cancer cells. We also evaluated a possible mechanism of MHY4381 on the apoptotic cell death pathway. The IC₅₀ value of MHY4381 was lower in DU145 cells (IC₅₀=0.31 µM) than in LNCaP (IC₅₀=0.85 µM) and PC-3 cells (IC₅₀=5.23 µM). In addition, the IC₅₀ values of MHY4381 measured in this assay were significantly lower than those of SAHA against prostate cancer cell lines. MHY4381 increased the levels of acetylated histones H3 and H4 and reduced the expression of HDAC proteins in the prostate cancer cell lines. MHY4381 increased G2/M phase arrest in DU145 cells, and G1 arrest in LNCaP cells. It also activated reactive oxygen species (ROS) generation, which induced apoptosis in the DU145 and LNCaP cells by increasing the ratio of Bax/Bcl-2 and releasing cytochrome c into the cytoplasm. Our results indicated that MHY4381 preferentially results in antitumor effects in DU145 and LNCaP cells via mitochondria-mediated apoptosis and ROS-facilitated cell death pathway, and therefore can be used as a promising prostate cancer therapeutic.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10949-10955
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• 2015

Liver cancer is one of leading digestive malignancies with high morbidity and mortality. There is an urgent need for the development of novel therapies for this deadly disease. It has been proven that asparagus polysaccharide, one of the most active derivates from the traditional medicine asparagus, possesses notable antitumor properties. However, little is known about the efficacy of asparagus polysaccharide as an adjuvant for liver cancer chemotherapy. Herein, we reported that asparagus polysaccharide and its embolic agent form, asparagus gum, significantly inhibited liver tumor growth with transcatheter arterial chemoembolization (TACE) therapy in an orthotopic hepatocellular carcinoma (HCC) tumor model, while significantly inhibiting angiogenesis and promoting tumor cell apoptosis. Moreover, asparagine gelatinous possessed immunomodulatory functions and showed little toxicity to the host. These results highlight the chemotherapeutic potential of asparagus polysaccharide and warrant a future focus on development as novel chemotherapeutic agent for liver cancer TACE therapy.

• Journal of Life Science
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• v.20 no.11
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• pp.1738-1741
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• 2010

Caliper measurements of tumor volume have been widely used in the assessment of tumors in animal models. However, experiments based on caliper data have resulted in unreliable estimates of tumor growth, due to necrotic areas of tumor mass. To overcome this systematic bias, we engineered a new luciferase-expressing rat prostate cancer cell line (MLL-Luc) that produces bioluminescence from viable cancer cells. MLL-Luc cells showed a strong correlation between bioluminescence intensity and cell number ($R^2$=0.99) and also accurately quantified tumor growth, with reduced bioluminescence signals caused by necrotic cells in a subcutaneous MLL-Luc xenograft model. The accurate quantification of tumor growth with bioluminescence imaging (BLI) was confirmed by a better antitumor effect of combination chemotherapy, compared to that based on caliper measurements with a correlation between the bioluminescence signal and tumor volume ($R^2$=0.84). These data suggest that bioluminescent MLL xenografts are a powerful and quantitative tool for monitoring tumor growth and are useful in evaluating the efficacy of anticancer drugs, with less systematic bias.

• BMB Reports
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• v.28 no.6
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• pp.556-561
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• 1995

The purpose of this study was to establish an in vitro culture method of tumor-specific T cells, and determine the efficacy of the cultured tumor-specific cytotoxic T-lymphocytes (CTL) as an agent of anti-tumor immunotherapy against a murine lymphoma, TIMI.4. Tumor-specific T-lymphocytes derived from C57BL/6 mice (thy-1.2) immune to TIMI.4 were activated by in vitro stimulation with the irradiated TIMI.4 cells, and expanded by restimulation with TIMI.4 in the presence of the concanavalin A-stimulated rat spleen culture supernatant, and splenic antigen-presenting cells. In vitro restimulation enhanced markedly the proportion of $CD8^+$, a predominant surface marker of CTL and the cytotoxic activity in the cultured immune T cell population. The resulting TIMI.4-specific T cells were adoptively transferred into nude mice. The tumor cells residing in the host after 7 days of adoptive transfer to B6.PL (thy-1.1) mice were quantified by use of an antibody directed to the thy-1.2 allele. The TIMI.4 cells in the recipient nude mice were decreased in a dose-dependent manner. Anti-tumor activity of the TIMI.4-specific T cells was also demonstrated by a survival test, where the tumor-bearing nu/nu mice which received the activated T-cells survived about 30% longer than the control mice which received the tumor cells alone. These suggest that adoptive transfer of TIMI.4-specific T cells could be a candidate for effective therapy of the murine lymphoma.

• Polymer(Korea)
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• v.26 no.5
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• pp.691-700
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• 2002

Interstitial therapy using biodegradable polymeric device loaded with anticancer agent can deliver the drug to the tumor site at high concentration, resulting in an increase of therapeutic efficacy. 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine) is most commonly used as chemotherapeutic agent for brain tumors. The design of implantable device is regarded as an important factor lot the efficient delivery of antitumor agent to targeting site. In order to control the release profile of drug, the release pattern of BCNU with the changes of various dimension and additives was investigated. The PLGA wafers containing 3.85, 10, 20 and 30% of BCNU were prepared in various shape (diameter of 3, 5 and 10 mm, thickness of 0.5, 1 and 2 mm) by direct compression method. In vitro drug release profile of BCNU-loaded PLGA wafers could be controlled by changing the dimension of wafers such as initial drug content, weight, diameter, thickness, volume and surface area of wafers, as well as PLGA molecular weight and additives. Drug release from BCNU-loaded PLGA wafers was facilitated with an increase of BCNU-loading amount or presence of poly(N-vinylpyrrolidone)(PVP) or sodium chloride (NaCl). The effects of various geometric factors and additives on the BCNU release pattern were confirmed by the investigation of mass loss and morphology of BCNU-loaded PLGA wafers.

• 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.

• Radiation Oncology Journal
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• v.21 no.3
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• pp.207-215
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• 2003

Purpose: Extracellular signal-regulated kinase (ERK), which is part of the mitogen-activated protin kinase cascade, opposes initiation of the apoptotic cell death which is programmed by diverse cytotoxic stimuli. In this regard, the inhibition of ERK may be useful in improving the therapeutic efficacy of established anticancer agents. Materials and Methods: Murine hepatocarcinoma, HCa-I is known to be highly radioresistant with a TCD50 (radiation dose yield in $50\%$ cure) of more than 80 Gy. Various anticancer drugs have been found to enhance the radioresponse of this particular tumor but none were successful. The objective of this study was to explore whether the selective inhibition of MEK could potentiate the antitumor efficacy of radiation in vivo, particularly in the case on radioresistant tumor. C3H/HeJ mice hearing $7.5\~8\;mm$ HCa-I, were treated with PD98059(intratumoral injection of $0.16\;\mug/50\;\mul$). Results: Downregulation on ERK by PD98059 was most prominent 1h after the treatment. In the tumor growth delay assay, the drug was found to Increase the effect of the tumor radioresponse with an enhancement factor (EF) of 1.6 and 1.87. Combined treatment of 25 Gy radiation with PD98059 significantly increased radiation induced apoptosis. The peak apoptotic index (number on apoptotic nuclei in 1000 nuclei X100) was $1.2\%$ in the case of radiation treatment alone, $0.9\%$ in the case of drug treatment alone and $4.9\%,\;5.3\%$ in the combination treatment group. An analysis of apoptosis regulating molecules with Western blotting showed upregulation of p53, p$p21^{WAF1/CIP1}\;and\;Bcl-X_s$ in the combination treatment group as compared to their levels in either the radiation alone or drug alone treatment groups. The level of other molecules such as $Bcl-X_L4, Bax and Bcl-2 were changed to a lesser extent. Conclusion: The selective inhibition of MEK in combination with radiation therapy may have potential benefit in cancer treatment.