• Asian Pacific Journal of Cancer Prevention
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• 제17권5호
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• pp.2637-2641
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• 2016

Tumor necrosis factor ($TNF-{\alpha}$), an inflammatory cytokine that plays an important role in the control of cell proliferation, differentiation, and apoptosis, has previously been used in anti-cancer therapy. However, the therapeutic applications of $TNF-{\alpha}$ are largely limited due to its general toxicity and anti-apoptotic influence. To overcome this problem, the present study focused on the effect of active constituents isolated from a medicinal plant on $TNF-{\alpha}$-induced apoptosis in human colon adenocarcinoma (HT-29) cells. Nimbolide from Azadirachta indica was evaluated for cytotoxicity by methyl tetrazolium 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay and phase contrast microscopy. Effects on apoptotic signaling proteins were investigated using Western blot analysis. Nimbolide showed cytotoxicity against HT-29 cells that was significantly different from the control group (p<0.01), a concentration of $10{\mu}M$ significantly inducing cell death (p<0.01). In combination with $TNF-{\alpha}$, nimbolide significantly enhanced-induced cell death. In apoptotic pathway, nimbolide activated c-Jun N-terminal kinase (JNK) phosphorylation, BH3 interacting-domain death agonist (Bid) and up-regulated the death receptor 5 (DR5) level. In the combination group, nimbolide markedly sensitized $TNF-{\alpha}$-induced JNK, Bid, caspase-3 activation and the up-regulation of DR5. Our findings overall indicate that nimbolide may enhance $TNF-{\alpha}$-mediated cellular proliferation inhibition through increasing cell apoptosis of HT-29 cells by up-reglation of DR5 expression via the JNK pathway.

• Asian Pacific Journal of Cancer Prevention
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• 제13권4호
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• pp.1333-1340
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• 2012

Epithelial ovarian cancer represents the most lethal gynecological cancer, and the high mortality rate makes this malignancy a major health concern. Poor prognosis results from an inability to detect ovarian cancers at an early, curable stage, as well as from the lack of an effective therapy. Thus, effective and novel strategies for prevention and treatment with non-toxic agents merit serious consideration. Resveratrol, obtained from grapes, berries, peanuts and red wine, has been shown to have a potent growth-inhibitory effect against various human cancer cells as well as in in vivo preclinical cancer models. The objective here was to evaluate potential antitumor effects of resveratrol in both in vitro and in vivo NuTu-19 ovarian cancer models. In vitro an invasion assay was performed. After 48 h, the numbers of viable cells that invaded the extracellular matrix layer were reduced by 94% with resveratrol in comparison to control. For the in vivo anti-tumor assessment, 10 rats were injected with NuTu-19 cells into the ovarian bursa. Thereafter, half were provided with a diet mixed with a dose of 100 mg resveratrol/kg body weight/day for 28 days. Following sacrifice, anticancer effects were assessed by histological evaluation of ovarian as well as surrounding tissues, and immunohistochemical detection of cell proliferation and apoptosis, but there were no observable differences between the control and resveratrol-treated groups for any of the biological endpoints. While resveratrol is effective in suppressing the in vitro cellular invasion of NuTu-19 ovarian cancer cells, these effects do not appear to impact on in vivo NuTu-19 ovarian cancers in rats.

• 동의생리병리학회지
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• 제21권3호
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• pp.721-727
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• 2007

Scorpion (SCP) has been clinically used for the treatment of endogenous wind to relieve convulsion, clearing away toxins, resolving hard masses and removing obstruction in the collaterals to relieve pain. Recent studies showed that scorpion toxins that affect the activating mechanism of sodium channels and indian black scorpion venom induced anti-proliferative and apoptogenic activity against human leukemic cell lines U937 and K562. There is lack of studies regarding the effects of SCP on the immunological activities. The present study was conducted to evaluate the effect of SCP on the regulatory effects of cytokines and nitric oxide (NO) for the immunological activities in Raw 264.7 cells. After the treatment of SCP MeOH extract dissolved in media for 1 h prior to the addition of lipopolysaccharide (LPS: 1 ${\mu}$g/ml), cell viability was measured by MTT assay, NO production was monitored by measuring the nitrite content in culture medium. Inducible nitric oxide synthase (iNOS) was determined by immunoblot analysis, and levels of cytokine were analyzed by sandwich immunoassays. As results, SCP inhibited the production of nitrite and nitrate (0.3 and 1.0 mg/ml), iNOS and p-$I_KB_{\alpha}$ protein, tumor necrosis factor-${\alpha}$ (0.3 and 1.0 mg/ml), interleukin-1${\beta}$ (0.3 and 1.0 mg/ml) and interleukin-6 (1.0mg/ml) in Raw 264.7 cells activated with LPS. These findings suggest that SCP can produce anti-inflammatory effect, which may play a role in adjunctive therapy in Gram-negative bacterial infections.

• Journal of Gynecologic Oncology
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• 제29권6호
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• pp.93.1-93.11
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• 2018

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human anti-programmed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that BRCA mutation could be a predictor of improved response in OC. The underlying DNA-repair-deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression.

• Nutrition Research and Practice
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• 제17권6호
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• pp.1070-1083
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• 2023

BACKGROUND/OBJECTIVES: Sanghuangporus sanghuang (SS) has various medicinal effects, including anti-inflammation and anticancer activities. Despite the extensive research on SS, its molecular mechanisms of action on lung cancer are unclear. This study examined the impact of an SS alcohol extract (SAE) on lung cancer using in vitro and in vivo models. MATERIALS/METHODS: Different concentrations of SAE were used to culture lung cancer cells (A549 and H1650). A cell counting kit-8 assay was used to detect the survival ability of A549 and H1650 cells. A scratch assay and transwell cell invasion assay were used to detect the migration rate and invasive ability of SAE. Western blot analysis was used to detect the expression of B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax), cyclin D1, cyclin-dependent kinases 4 (CDK4), signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3). Lung cancer xenograft mice were used to detect the inhibiting ability of SAE in vivo. Hematoxylin and eosin staining and immunohistochemistry were used to detect the effect of SAE on the structural changes to the tumor and the expression of Bcl-2, Bax, cyclin D1, CDK4, STAT3, and p-STAT3 in lung cancer xenograft mice. RESULTS: SAE could inhibit lung cancer proliferation significantly in vitro and in vivo without cytotoxicity. SAE suppressed the viability, migration, and invasion of lung cancer cells in a dose and time-dependent manner. The SAE treatment significantly decreased the proapoptotic Bcl-2/Bax ratio and the expression of pro-proliferative proteins Cyclin D1 and CDK4 in vitro and in vivo. Furthermore, SAE also inhibited STAT3 expression. CONCLUSIONS: SAE reduced the cell viability and suppressed cell migration and invasion in human lung cancer cells. Moreover, SAE also exhibited anti-proliferation effects in vivo. Therefore, SAE may have benefits in cancer therapy.

• Asian Pacific Journal of Cancer Prevention
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• 제15권16호
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• pp.6679-6683
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• 2014

Background: Carcinoid crisis is a life-threating syndrome of neuroendocrine tumors (NETs) characterized by dramatic blood pressure fluctuation, arrhythmias, and bronchospasm. In the era of booming anti-tumor therapeutics, this has become more important since associated stresses can trigger carcinoid crisis. Somatostatin analogues (SSTA) have been recommended for prophylactic administration before intervention procedures for functioning NETs. However, the efficacy is still controversial. The aim of this article is to review efficacy of SSTA for preventing carcinoid crisis. Materials and Methods: PubMed, Cochrane Controlled trials Register, and EMBASE were searched using 'carcinoid crisis' as a search term combining terms with 'somatostatin'; 'octreotide'; 'lanreotide' and 'pasireotide' until December 2013. Results: Twenty-eight articles were retrieved with a total of fifty-three unique patients identified for carcinoid crisis. The most common primary sites of NETs were the small intestine and respiratory tract. The triggering factors for carcinoid crisis included anesthesia/surgery (63.5%), interventional therapy (11.5%), radionuclide therapy (9.6%), examination (7.7%), medication (3.8%), biopsy (2%) and spontaneous (2%). No randomized controlled trials (RCTs) were identified and two case-control studies were included to assess the efficacy of SSTA for preventing carcinoid crisis by meta-analysis. The overall pooled risk of perioperative carcinoid crisis was similar despite the prophylactic administration of SSTA (OR 0.44, 95% CI: 0.14 to 1.35, p=0.15). Conclusions: SSTA wasnot helpful for preventing carcinoid crisis based on a meta-analysis of retrospective studies. Attentive monitoring and careful intervention are essential. Future studies with better quality are needed to clarify any effect of SSTA for preventing carcinoid crisis.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제29권1호
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• pp.10-23
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• 2007

Hallmarks of clinical behaviors of adenoid cystic carcinoma(ACC) of salivary glands are the delayed onset of vascular metastasis and poor responses to classical chemotherapeutic agents. Poor prognoses from salivary ACC are caused by lung metastases that are resistant to conventional therapy. Therefore, cellular and molecular characteristics that influence the dissemination of metastatic cells are important for the design of more effective treatment of salivary ACC. Tumor angiogenesis has been known to be essential for the distant metastasis of malignant cells. So, we determined expressions of angiogenic proteins in benign (pleomorphic adenoma) and malignant (ACC, mucoepidermoid carcinoma) tumors of salivary glands and compared each other and to those in oral squamous cell carcinoma. Using surgical specimens, we performed immunohistochemical assays with anti-vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), phosphorylated VEGFR-2 (pVEGFR-2), matrix metalloproteinase (MMP)-9, and interleukin (IL)-8 antibodies. Most angiogenic factors were overexpressed in malignant salivary tumors than in pleomorphic adenoma which is benign nature. Moreover, ACC demonstrated more expression of VEGFR-2 than that of squamous cell carcinoma which used as control. Conclusively, these data show those angiogenic factors produced by salivary gland tumors may affect the propagation and metastasis of malignant cells of salivary tumors, and could be used as biomarkers for the malignant transformation of salivary gland tumors. Prospectively, although further studies will be needed, these biomarkers related to angiogenesis can be molecular targets for the therapy of salivary ACC, which has propensity for delayed vascular metastasis.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.69-73
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• 2014

The effects of erlotinib combined with celecoxib in a lung cancer xenograft model were here explored with a focus on possible mechanisms. A xenotransplanted lung cancer model was established in nude mice using the human lung cancer cell A549 cell line and animals demonstrating tumour growth were randomly divided into four groups: control, erlotinib, celecoxib and combined (erotinib and celecoxib). The tumor major axis and short diameter were measured twice a week and after 40 days tissues were collected for immunohistochemical analyses of Bcl-2 and Bax positive cells and Western-blotting analyses for the epidermal growth factor recepto (EGFR), P-EGFR, and cyclooxygenase-2 (COX-2). Tumor size in the combined group was smaller than in the others (p<0.01) and the percentage of Bcl-2 positive cells was fewer in most cases (p<0.01), while that of Bax positive cells was greater than in the erlotinib and celecoxib groups (P>0.05). Western blotting showed decreased expression of P-EGFR and COX-2 with both erlotinib and celecoxib treatments, but most pronouncedly in the combined group (P<0.05). Simultaneous blockage of the EGFR and COX-2 signal pathways exerted stronger growth effects in our human xenotransplanted lung cancer model than inhibition of either pathway alone. The anti-tumor effects were accompanied by synergetic inhibition of tumor cell apoptosis, activation of p-EGFR and expression of COX-2.

• 생명과학회지
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• 제29권5호
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• pp.530-536
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• 2019

교모세포종은 형질 전환된 신경 교세포로부터 유래한 악성 종양이다. 교모세포종의 치료는 외과적 수술을 포함한 약물 및 방사선 치료를 통해 진행된다. 그러나 이러한 치료 과정이 환자의 예후에 크게 기여하지 못하는 실정이다. 교모세포종 치료의 어려움 중 하나로 뇌종양줄기세포의 존재를 들 수 있다. 주요하게 proneural (PN) 아형과 mesenchymal (MES) 아형으로 나누어지는 뇌종양줄기세포는 교모세포종의 발달, 유지 및 항암 치료 후 재발의 원인이 되는 암세포로 이해되고 있다. 본 연구에서는 PN 아형 뇌종양줄기세포들이 특정 사이토카인에 선택적으로 MES 아형으로 전이가 될 수 있다는 것에 중점을 두고 실험을 진행하였다. PN 아형 뇌종양줄기세포 중 GSC11 세포는 $TNF-{\alpha}$ 사이토카인에 의해, 그리고 GSC23 세포는 $TGF-{\beta}1$ 사이토카인에 노출이 될 때 MES 아형 뇌종양줄기세포의 표지 인자인 CD44의 발현 증가가 관찰되었다. 또한, Ivy Glioblastoma Atlas Project (Ivy GAP) 데이터 베이스를 통해, $TNF-{\alpha}$와 $TGF-{\beta}1$은 종양미세환경을 구성하는 요소 중 각각 괴사 부위와 미세혈관 주위에서 높은 발현을 보임을 확인하였다. 따라서 본 연구 결과는 PN 아형의 뇌종양줄기세포가 특정 종양미세환경에서 조절되는 다양한 종류의 사이토카인 신호에 의해 MES 아형으로의 전이가 결정될 수 있다는 가능성을 시사한다.

• BMB Reports
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• 제40권6호
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• pp.1069-1076
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• 2007

Cancer cells, characterized by local invasion and distant metastasis, are very much dependant on the extracellular matrix. The expression of matrix metalloproteinases (MMPs) has been implicated in the invasion and metastasis of cancer cells. In this study, we reported the effects of disulfiram, a clinically used anti-alcoholism drug, on tumor invasion suppression, as well as its effects on the activity of MMP-2 and MMP-9 in human osteosarcoma cells (U2OS). Disulfiram has been used for alcohol aversion therapy. However, recent reports have shown that disulfiram may have potential in the treatment of human cancers. Herewith, we showed that the anti-tumor effects of disulfiram, in an invasion assay using U2OS cells and that disulfiram has a type IV collagenase inhibitory activity that inhibits expression of genes and proteins responsible for both cell and non-cell mediated invasion on pathways. In conclusion, disulfiram inhibited expression of MMP-2 and MMP-9 and it regulated the invasion of human osteosarcoma cells. These observations raise the possibility of disulfiram being used clinical for the inhibition of cancer invasion.