• Journal of Ginseng Research
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• 제36권1호
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• pp.86-92
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• 2012

The glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Despite combination treatments of radiation and chemotherapy, the survival periods are very short. Therefore, this study was conducted to assess the potential of ginsenoside $F_2$ (F2) to treat GBM. In in vitro experiments with glioblastoma cells U373MG, F2 showed the cytotoxic effect with $IC_{50}$ of 50 ${\mu}g/mL$ through apoptosis, confirmed by DNA condensation and fragmentation. The cell population of cell cycle sub-G1 as indicative of apoptosis was also increased. In xenograft model in SD rats, F2 at dosage of 35 mg/kg weight was intravenously injected every two days. This reduced the tumor growth in magnetic resonance imaging images. The immunohistochemistry revealed that the anticancer activity might be mediated through inhibition of proliferation judged by Ki67 and apoptosis induced by activation of caspase-3 and -8. And the lowered expression of CD31 showed the reduction in blood vessel densities. The expression of matrix metalloproteinase-9 for invasion of cancer was also inhibited. The cell populations with cancer stem cell markers of CD133 and nestin were reduced. The results of this study suggested that F2 could be a new potential chemotherapeutic drug for GBM treatment by inhibiting the growth and invasion of cancer.

• Laboraroty Animal Research
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• 제34권4호
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• pp.264-269
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• 2018

Cell cycle dysfunction can cause severe diseases, including neurodegenerative disease and cancer. Mutations in cyclin-dependent kinase inhibitors controlling the G1 phase of the cell cycle are prevalent in various cancers. Mice lacking the tumor suppressors $p16^{Ink4a}$ (Cdkn2a, cyclin-dependent kinase inhibitor 2a), $p19^{Arf}$ (an alternative reading frame product of Cdkn2a,), and $p27^{Kip1}$ (Cdkn1b, cyclin-dependent kinase inhibitor 1b) result in malignant progression of epithelial cancers, sarcomas, and melanomas, respectively. Here, we generated knockout mouse models for each of these three cyclin-dependent kinase inhibitors using engineered nucleases. The $p16^{Ink4a}$ and $p19^{Arf}$ knockout mice were generated via transcription activator-like effector nucleases (TALENs), and $p27^{Kip1}$ knockout mice via clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRISPR/Cas9). These gene editing technologies were targeted to the first exon of each gene, to induce frameshifts producing premature termination codons. Unlike preexisting embryonic stem cell-based knockout mice, our mouse models are free from selectable markers or other external gene insertions, permitting more precise study of cell cycle-related diseases without confounding influences of foreign DNA.

• Archives of Pharmacal Research
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• 제21권3호
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• pp.298-304
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• 1998

Retinoids are applied to not only cancer prevention but also cancer chemotherapy by stimulating differentiation of cells. We studied differentiation inducing effect of all-trans retinoic acid (ATRA) by studying proportion of high dense fractions of stem-like cells and the size of S phase fraction in cell cycle. From mammary organoids obtained from 7- to 8-week old F344 female rat mammary gland, we cultured rat mammary epithelial cells (RMEC) and treated physiological doses of $10^{-6}$, $10^{-7}$, and $10^{-8}$ M ATRA from the first day and then cultured for 4, 7, and 14 days. After that, immunostaining was performed using peanut agglutinin (PNA) and anti-Thy-1.1 monoclonal antibody (Thy-1.1) that can be used as markers of differentiation. We separated four different cell subpopulations by flow cytometry: cells negative to both reagents (B-), PNA-positive cells (PNA+), Thy-1.1-positive cells (Thy-1.1+), and cells positive to both reagents (B+). We observed continuous decreases of high dense fractions of stem-like cells (PNA+ subpopulations) for 14 days and as much decreases as high doses of ATRA, which were thought to be proportional to doses of ATRA. We labeled RMEC with bromodeoxyuridine and investigated cell cycle fractions that went through S phase. We observed a tendency of decrease of S phase fraction with time in culture, which, is thought to be related to continuous decreases of PNA+ subpopulations and inhibitory role of ATRA on cell cycle. These results suggest that physiological doses of ATRA could stimulate differentiation of RMEC and convert stem-like RMEC to differentiated cells in SFM for a relatively long period of 14 days.

• Asian Pacific Journal of Cancer Prevention
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• 제15권2호
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• pp.831-835
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• 2014

Background: Predictor factors determining complete response to treatment are still not clearly defined. We aimed to evaluate clinicopathological features, risk factors, treatment responses, and survival analysis of patient with advanced nonseminomatous GCTs (NSGCTs). Materials and Methods: Between November 1999 and September 2011, 140 patients with stage II and III NSGCTs were referred to our institutions and 125 patients with complete clinical data were included in this retrospective study. Four cycles of BEP regimen were applied as a first-line treatment. Salvage chemotherapy and/or high-dose chemotherapy (HDCT) with autologous stem cell transplantation were given in patients who progressed after BEP chemotherapy. Post-chemotherapy surgery was performed in selected patients with incomplete radiographic response and normal tumor markers. Results: The median age was 28 years. For the good, intermediate and poor risk groups, compete response rates (CRR) were, 84.6%, 67.9% and 59.4%, respectively. Extragonadal tumors, stage 3 disease, intermediate and poor risk factors, rete testis invasion were associated with worse outcomes. There were 32 patients (25.6%) with non-CR who were treated with salvage treatment. Thirty-one patients died from GCTs and 94% of them had stage III disease. Conclusions: Even though response rates are high, some patients with GCTs still need salvage treatment and cure cannot be achieved. Non-complete response to platinium-based first-line treatment is a negative prognostic factor. Our study confirmed the need for a prognostic and predictive model and more effective salvage approaches.

• Asian Pacific Journal of Cancer Prevention
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• 제15권22호
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• pp.9713-9717
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• 2014

Background: Colon cancer (CRC) is perhaps the second most common cause of cancer mortality. This study determined the clinical significance of serum vascular endothelial growth factor (VEGF) and serum complement 3a (C3a) levels in patients with CRC in Fars province, southern Iran. Materials and Methods: Between June 2010 and June 2012, 110 patients with CRC of both genders and different age groups were divided into 3 groups. Group A included patients who had just undergone surgery; Group B had undergone chemotherapy after surgery; and Group C had undergone chemotherapy and radiotherapy after surgery. Twenty one healthy subjects with normal colonoscopy were considered as a control group. ELISA was undertaken to determine VEGF and C3a levels before and after treatment measures. Results: The mean age of patients was $53.9{\pm}14.1$ years. Considering VEGF level, a significant decrease was visible after treatment measures in groups A and B, but not Group C. For VEGF level, the difference was not statistically significant between two genders and various age groups before and after treatment. No significant difference was found for VEGF level between patients and normal group before any treatment. Regarding C3a levels in 101 subjects, they significantly decreased after treatment measures. Before and after treatment, the difference was statistically significant between two genders, but was not statistically significant among various age groups. Conclusions: As VEGF and C3a levels were significantly lower in patients after treatment, these may be beneficial markers in assessment of CRC therapy especially in early stages.

• Journal of Applied Biological Chemistry
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• 제58권3호
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• pp.219-226
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• 2015

본 연구에서는 레몬 잎 메탄올 추출물(MLL)의 인간 유방암 줄기 세포인 MCF-7-SC에 대한 항암 활성을 조사하였다. MLL이 MCF-7-SC에서 apoptosis를 유도하였으며, 이를 apoptotic body의 형성, sub-G1 phase 및 annexin V-positive 세포와 Bax/Bcl-2 ratio의 증가, caspase-9과 caspase-3의 활성화 및 PARP의 절 단을 통하여 확인하였다. 동시에 MCF-7-SC에서 MLL은 acidic vesicular organelles의 형성, LC3-II의 축적 증가, Akt/mTOR/p70S6K의 활성 억제 등을 통하여 autophagy를 유도하였다. Epithelial-mesenchymal transition (EMT)는 세포가 전이 상태를 획득하기 위한 중요한 과정이며, 이 기작은 암세포가 전이되는 것을 억제함에 있어서 중요한 표적이 된다. 낮은 농도에서의 MLL은 epithelial 마커 단백질인 E-cadherin이 증가와 mesenchymal 마커 단백질인 Snail과 Slug의 발현 감소를 통해 EMT 과정을 저해함으로써 MCF-7-SC에서 항전이 활성을 나타내었다. 본 연구에서는 레몬 잎 메탄올 추출물이 농도 의존적으로 유방암 줄기세포에 대해 세포 독성과 항전이 활성을 나타내고 있으며, 따라서 레몬잎은 항암 소재로서의 개발 가능성이 높은 식물이라고 사료된다.

• Clinical and Experimental Pediatrics
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• 제50권7호
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• pp.601-605
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• 2007

The cure rate of acute lymphoblastic leukemia (ALL) in children dramatically improved over past 5 decades from zero to about 80%. The main cause of improvement is owing to the development of chemotherapy by multicenter clinical trial of large study groups with the understanding of leukemia biology. Recently, pediatric ALL protocols were applied to the treatment of adolescent and even adult ALL patients. For nearly 30 years, clinical factors have been used to risk-stratify therapy for children with ALL, so that the most intensive therapies are reserved for those patients at the highest risk of relapse. The risk groups of ALL are divided as standard- (low- plus intermediate-), high- and very high-risk group according to the prognostic factors, and treatment results improved by this risk based treatment. The factors used to risk-stratify therapy include age, gender, presenting leukocyte count, immunophenotype, cytogenetic aberrations including ploidy and translocations, and initial response after 1 to 2 weeks of therapy. But treatment efficacy is the most important determinant and can abolish the clinical significance of most, if at all, prognostic factors. Today, in the era of intensive, multiagent regimens, there is increasing evidence that we have reached the limits of prognostic significance of currently applied clinical risk factors in childhood ALL. As the cure rate of ALL is about 80%, introducing new prognostic factors such as new molecular prognostic markers, new methods of assessment about minimal residual disease, and pharmacogenetic study, with the development of stem cell transplantation and molecular targeted therapy are needed to cure residual 20% of childhood ALL patients without short and long term complications.

• IMMUNE NETWORK
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• 제1권1호
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• pp.1-6
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• 2001

The identification of tumor-specific antigens has represented a critical milestone in cancer diagnosis and therapy. Clinical research in this area for leukemia has also been driven over the past few decades by the hope that surface antigens with restricted tissue expression would be identified. Disappointingly, only a small number of the leukemic antigens identified to date, meet sufficient criteria to be considered viable immunophenotypic markers. In this paper, we nominate anti-JL1 monoclonal antibody as an immunodiagnostic and immunotherapeutic candidate for leukemia. The JL1 molecule appears to be a novel cell surface antigen, which is strictly confined to a subpopulation of limited stages during the hematopoietic differentiation process. Despite the restricted distribution of the JL1 antigen in normal tissues and cells, anti-JL1 monoclonal antibody specifically recognizes various types of leukemia, irrespective of immunophenotypes. On the basis of these findings, we propose JL1 antigen as a tumor-specific marker, which shows promise as a candidate molecule for diagnosis and immunotherapy in leukemia, and one that spares normal bone marrow stem cells.

• Journal of Nutrition and Health
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• 제52권1호
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• pp.17-25
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• 2019

본 연구에서는 댕댕이나무 열매 추출물이 3T3-L1과 마우스 지방유래줄기세포의 지방 분화유도 및 지방생성에 미치는 영향을 살펴보았다. 3T3-L1에 댕댕이나무 열매 추출물을 처리하였을 때, 농도의존적으로 지방구의 생성을 줄였고 지방세포 분화에 있어서 중요한 전사인자인 $PPAR{\gamma}$, $C/EBP{\alpha}$, SREBP1의 발현을 억제시켜 지방 합성이 감소됨을 확인하였다. 또한, 마우스 지방에서 분리한 줄기세포의 지방 분화과정에서도 댕댕이나무 열매 추출물이 $PPAR{\gamma}$, $C/EBP{\alpha}$, SREBP1의 단백질 발현을 감소시켜 지방 축적을 농도 의존적으로 억제하였다. 이상의 결과로 댕댕이나무 열매 추출물은 세포독성이 없는 농도에서 지방 세포의 분화를 억제 하는 것으로 확인되어 항비만 기능성 소재로서의 활용 가능성이 있을 것으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권11호
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• pp.5469-5475
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• 2012

Background and Objectives: Acute lymphoblastic leukemia (ALL) is a complex genetic disease involving many fusion oncogenes (FO) having prognostic significance. The frequency of various FO can vary in different ethnic groups, with important implications for prognosis, drug selection and treatment outcome. Method: We studied fusion oncogenes in 101 pediatric ALL patients using interphase FISH and RT-PCR, and their associations with clinical features and treatment outcome. Results: Five most common fusion genes i.e. BCR-ABL t (22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 89/101 (88.1%) patients. Frequency of BCR-ABL was 44.5% (45/101). BCR-ABL positive patients had a significantly lower survival ($43.7{\pm}4.24$ weeks) and higher white cell count as compared to others, except patients with MLL-AF4. The highest relapse-free survival was documented with ETV6-RUNX1 (14.2 months) followed closely by those cases in which no gene was detected (13.100). RFS with BCR-ABL, MLL-AF4, TCF3-PBX1 and SIL-TAL1 was less than 10 months (8.0, 3.6, 5.5 and 8.1 months, respectively). Conclusions: This is the first study from Pakistan correlating molecular markers with disease biology and treatment outcome in pediatric ALL. It revealed the highest reported frequency of BCR-ABL FO in pediatric ALL, associated with poor overall survival. Our data indicate an immediate need for incorporation of tyrosine kinase inhibitors in the treatment of BCR-ABL+ pediatric ALL in this population and the development of facilities for stem cell transplantation.