• Journal of Ginseng Research
• /
• v.44 no.5
• /
• pp.725-737
• /
• 2020

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a kind of aggressive hematological cancer, and the PI3K/Akt/mTOR signaling pathway is activated in most patients with T-ALL and responsible for poor prognosis. 20(S)-Ginsenoside Rh2 (20(S)-GRh2) is a major active compound extracted from ginseng, which exhibits anti-cancer effects. However, the underlying anticancer mechanisms of 20(S)-GRh2 targeting the PI3K/Akt/mTOR pathway in T-ALL have not been explored. Methods: Cell growth and cell cycle were determined to investigate the effect of 20(S)-GRh2 on ALL cells. PI3K/Akt/mTOR pathway-related proteins were detected in 20(S)-GRh2-treated Jurkat cells by immunoblotting. Antitumor effect of 20(S)-GRh2 against T-ALL was investigated in xenograft mice. The mechanisms of 20(S)-GRh2 against T-ALL were examined by cell proliferation, apoptosis, and autophagy. Results: In the present study, the results showed that 20(S)-GRh2 decreased cell growth and arrested cell cycle at the G1 phase in ALL cells. 20(S)-GRh2 induced apoptosis through enhancing reactive oxygen species generation and upregulating apoptosis-related proteins. 20(S)-GRh2 significantly elevated the levels of pEGFP-LC3 and autophagy-related proteins in Jurkat cells. Furthermore, the PI3K/Akt/mTOR signaling pathway was effectively blocked by 20(S)-GRh2. 20(S)-GRh2 suppressed cell proliferation and promoted apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway in Jurkat cells. Finally, 20(S)-GRh2 alleviated symptoms of leukemia and reduced the number of white blood cells and CD3 staining in the spleen of xenograft mice, indicating antitumor effects against T-ALL in vivo. Conclusion: These findings indicate that 20(S)-GRh2 exhibits beneficial effects against T-ALL through the PI3K/Akt/mTOR pathway and could be a natural product of novel target for T-ALL therapy.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.16
• /
• pp.7303-7307
• /
• 2015

Background: Leukemia is a common cancer among children and adolescents. Wilms' tumor gene (WT1) is highly expressed in patients with acute leukemia. It is found as a tumor associated antigen (TAA) in various types of hematopoietic malignancies and can be employed as a useful marker for targeted immunotherapy and monitoring of minimal residual disease (MRD). In this regard, WT1 is a transcription factor that promotes gene activation or repression depending on cellular and promoter context. The purpose of this study was assessment of WT1 gene expression in patients with acute leukemia, measurement of IL-12 and C3 levels in serum and evaluation of the relationship between them. Materials and Methods: We evaluated the expression of WT1 mRNA using real-time quantitative RT-PCR and serum levels of IL-12 and C3 using ELISA and nephelometry in peripheral blood of 12 newly diagnosed patients with acute leukemia and 12 controls. Results: The results of our study showed that the average wT1 gene expression in patients was 7.7 times higher than in healthy controls (P <0.05). In addition, IL-12 (P = 0.003) and C3 (P <0.0001) were significantly decreased in the test group compared to controls. Conclusions: WT1 expression levels are significantly higher in patients compared with control subjects whereas serum levels of interleukin-12 and C3 are significantly lower in patients. Wt1 expression levels in patients are inversely related with serum levels of IL-12 and C3.

• Radiation Oncology Journal
• /
• v.3 no.2
• /
• pp.137-144
• /
• 1985

Radiation therapy was the treatment of choice for CML in the past, in the form of SI or radioactive phosphorus. Its use has been replaced to a large extent by various chemotherapeutic agents. Recently SI in CML has been used, both to relieve painful splenomegaly and to take advantage of an indirect effect of SI on unirradiated bone marrow. We have treated 15 CML cases who had a huge spleen during chemotherapy or even after chemotherapy by 6 MV linear accelerator during the past two years at the Division of Radiation Therapy, Kang Nam St. Mary's Hospital, Catholic College. Response to SI has been rated according to the scoring system of Roger W. Byhardt, et al. which evaluated the splenic and hematologic response as well as the response of disease-related systems. According to this scoring system, most patients demonstrated a significant relief of splenomegaly along with improvement of hemogram. And we observed the change of Karnofsky Performance Status after SI, and survival after a confirmative diagnosis and SI.

• Journal of Chest Surgery
• /
• v.51 no.5
• /
• pp.350-355
• /
• 2018

Background: The complication rate of fungal disease is higher among patients with hematological malignancies. We investigated the clinicobacteriological outcomes of resected pulmonary fungal infections complicating hematological malignancies. Methods: Between 2001 and 2017, 21 patients with pulmonary fungal infections complicating hematological malignancies underwent resection, and their clinical records and survival were retrospectively reviewed. Results: The median age of the patients was 47 years, and 13 were male. The histological diagnoses were pulmonary aspergillosis (19 cases), mucormycosis (1 case), and cryptococcosis (1 case). The indications for surgery were resistance to antifungal therapy and the necessity of surgery before hematopoietic stem cell transplantation in 13 and 8 cases, respectively. The diagnoses of the hematological malignancies were acute myelogenous leukemia (10 cases), acute lymphocytic leukemia (5 cases), myelodysplastic syndrome (3 cases), and chronic myelogenous leukemia, malignant lymphoma, and extramedullary plasmacytoma (1 case each). The surgical procedures were partial resection (11 cases), segmentectomy (5 cases), lobectomy (4 cases), and cavernostomy (1 case). The size of the lesions was 0.9-8.5 cm. Fourteen cases had cavitation. There were no surgical-related deaths or fungal progression. Conclusion: Pulmonary fungal infections are resistant to treatments for hematological malignancies. Since the treatment of the underlying disease is extended and these infections often recur and are exacerbated, surgery should be considered when possible.

• Asian Pacific Journal of Cancer Prevention
• /
• v.13 no.7
• /
• pp.3461-3464
• /
• 2012

Methotrexate (MTX) is an important drug for the treatment of childhood acute lymphoblastic leukemia (ALL). However, related toxicity occurs in many organs which may cause interruption of treatment, morbidity, and mortality. Single nucleotide polymorphisms (SNPs) of dihydrofolate reductase (DHFR) and gamma glutamyl hydrolase (GGH) are known to alter their enzymatic activity and thus affect the metabolism of MTX and influence the effectiveness. Therefore, we hypothesized that genetic variations of DHFR and GGH genes may influence the risk of toxicity after high dose MTX. The study population comprised of 105 children with ALL who were treated according to the modified St Jude Total XV protocol. The patients received 2.5 or $5g/m^2$ of MTX for 5 doses during the consolidation phase. Genotyping of DHFR 829C>T and GGH-401C>T was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The GGH-401CT and TT genotypes were associated with increased risk of leukopenia and thrombocytopenia after high dose MTX (OR 2.97, 95%CI; 1.24-7.13 and OR 4.02, 95%CI; 1.58-10.26). DHFR 829C>T was not associated with toxicity. In conclusion, the GGH-401CT and TT genotypes were found to increase the risk of severe leukopenia and thrombocytopenia after exposure to high dose MTX for childhood ALL therapy.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.13
• /
• pp.5455-5461
• /
• 2014

Background: Saponins are a major active component for the traditional Chinese medicine, Rubus parvifolius L., which has shown clear antitumor activities. However, the specific effects and mechanisms of saponins of Rubus parvifolius L. (SRP) remain unclear with regard to human chronic myeloid leukemia cells. The aim of this study was to investigate inhibition of proliferation and apoptosis induction effects of SRP in K562 cells and further elucidate its regulatory mechanisms. Materials and Methods: K562 cells were treated with different concentrations of SRP and MTT assays were performed to determine cell viability. Apoptosis induction by SRP was determined with FACS and DAPI staining analysis. Western blotting was used to detect expression of apoptosis and survival related genes. Specific inhibitors were added to confirm roles of STAT3 and AMPK pathways in SRP induction of apoptosis. Results: Our results indicated that SRP exhibited obvious inhibitory effects on the growth of K562 cells, and significantly induced apoptosis. Cleavage of pro-apoptotic proteins was dramatically increased after SRP exposure. SRP treatment also increased the activities of AMPK and JNK pathways, and inhibited the phosphorylation expression level of STAT3 in K562 cells. Inhibition of the AMPK pathway blocked the activation of JNK by SRP, indicating that SRP regulated the expression of JNK dependent oon the AMPK pathway. Furthermore, inhibition of the latter significantly conferred resistance to SRP pro-apoptotic activity, suggesting involvement of the AMPK pathway in induction of apoptosis. Pretreatment with a STAT3 inhibitor also augmented SRP induced growth inhibition and cell apoptosis, further confirming roles of the STAT3 pathway after SRP treatment. Conclusions: Our results demonstrated that SRP induce cell apoptosis through AMPK activation and STAT3 inhibition in K562 cells. This suggests the possibility of further developing SRP as an alternative treatment option, or perhaps using it as adjuvant chemotherapeutic agent for chronic myeloid leukemia therapy.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.22
• /
• pp.9885-9889
• /
• 2014

Background: Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) is an antitumor candidate in cancer therapy. This study focused on effects of TRAIL, as a proapototic ligand that causes apoptosis, in B-CELL chronic lymphocytic leukemia cells (B-CLL). Materials and Methods: A population of HEK 293 cells was transducted by lentivirus that these achieved ability for producing the TRAIL protein and then HEK 293 cells transducted were placed in the vicinity of CLL cells. After 24 hours of co-culture, apoptosis of CLL cells was assessed by annexin V staining. Results: The amount of Apoptosis was examined separately in four groups: 293 HEK TRAIL ($16.17{\pm}1.04%$); 293 HEK GFP ($2.7{\pm}0.57%$); WT 293 HEK ($2{\pm}2.6%$); and CLL cells ($0.01{\pm}0.01%$). Among the groups studied, the maximum amount of apoptosis was in the group that the vector encoding TRAIL was transducted. In this group, the mean level of soluble TRAIL in the culture medium was 253pg/ml; also flow cytometry analyzes showed that proapotosis in this group was $32.8{\pm}1.6%$, which was higher than the other groups. Conclusions: In this study, we have demonstrated that TNF secreted from HEK 293 cells are effective in death of CLL cells.

• Tuberculosis and Respiratory Diseases
• /
• v.48 no.4
• /
• pp.448-463
• /
• 2000

Background : Pulmonary infiltrate is a frequent cause of morbidity and mortality in patients with leukemia. It is often hard to obtain a reliable diagnosis by clinical and radiologic findings alone. The aim of this study was to evaluate diagnostic and therapeutic benefits of invasive procedures for new lung infiltrates in leukemia. Methods : Patients with leukemia who developed new lung infiltrates from December 1994 to March 1999 were included in this study. These patients were classified into the empirical group who received empirical therapy only and into the invasive group who underwent bronchoscopy or surgical lung biopsy for the diagnostic purpose of new lung infiltrates. A retrospective chart review was done to find the etiologies of new lung infiltrates, the yield of invasive procedures, outcome as well as predicting factors for survival. Results : 1) One hundred-two episodes of new lung infiltrates developed in 90 patients with leukemia. Invasive procedures were performed in 44 episodes while 58 episodes were treated with empirical therapy only. 2) Invasive procedures yielded a specific diagnosis in 72.7%(32/44), of which 78.1% had infectious etiology. Therapeutic plan was changed in 52.3%(23/44) of patients after invasive procedures. None of them showed procedure-related mortality. 3) The overall survival rate was 62.7%(64/102). Survival rate in the invasive group (79.5%) was significantly better than that in the empirical group (50.0%) (p=0.002). 4) Upon multivariate analysis, the performance of invasive procedures, no need for mechanical ventilation and achievement of complete remission of leukemia after induction chemotherapy were the independent predicting factors for survival in patients with leukemia and new lung infiltrates. Conclusion : Bronchoscopy and surgical lung biopsy are useful in the diagnosis of new lung infiltrates in patients with leukemia. However, survival benefits of invasive procedures should be considered together with disease status of leukemia and severity of respiratory compromise.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.40 no.9
• /
• pp.1201-1207
• /
• 2011

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a potent tool to trigger apoptosis in cancer therapy. However, as many types of cancer cells remain resistant towards TRAIL-induced cytotoxicity, several combined therapy approaches aimed to sensitize cells to TRAIL have been developed. Genistein, a natural isoflavonoid phytoestrogen, has been shown to have anticancer activity by inducing cell cycle arrest at G2M phase as well as apoptosis in various cancer cell lines. In the present study, we showed that treatment with TRAIL in combination with subtoxic concentrations of genistein sensitized U937 human leukemia cells to TRAIL-mediated apoptosis. Combined treatment with genistein and TRAIL effectively activated caspases through Bid truncation (tBid) and down-regulation of cellular caspase-8 (FLICE)-like inhibitory proteinL ($cFLIP_L$). However, the apoptotic effects of co-treatment with genistein and TRAIL were significantly inhibited by specific caspase inhibitors, which demonstrates the important role of caspases in apoptosis induced by genistein and TRAIL. Overall, our results indicate that genistein can potentiate TRAIL-induced apoptosis through down-regulation of $cFLIP_L$ and up-regulation of pro-apoptotic tBid proteins.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.18
• /
• pp.8533-8539
• /
• 2016

Background: B-cell chronic lymphocytic leukemia B (B-CLL), the most common type of leukemia, may be caused by apoptosis deficiency in the body. Adipose tissue-derived mesenchymal stem cells (AD-MSCs) as providers of pro-apoptotic molecules such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), can be considered as an effective anti-cancer therapy candidate. Therefore, in this study we assessed the role of tumor necrosis factor-producing mesenchymal stem cells oin apoptosis of B-CLL cells resistant to fludarabine-based chemotherapy. Materials and Methods: In this study, after isolation and culture of AD-MSCs, a lentiviral LeGO-iG2-TRAIL-GFP vector containing a gene producing the ligand pro-apoptotic with plasmid PsPAX2 and PMDG2 virus were transfected into cell-lines to generate T293HEK. Then, T293HEK cell supernatant containing the virus produced after 48 and 72 hours was collected, and these viruses were transduced to reprogram AD-MSCs. Apoptosis rates were separately studied in four groups: group 1, AD-MSCs-TRAIL; group 2, AD-MSCs-GFP; group 3, AD-MSCs; and group 4, CLL. Results: Observed apoptosis rates were: group 1, $42{\pm}1.04%$; group 2, $21{\pm}0.57%$; group 3, $19{\pm}2.6%$; and group 4, % $0.01{\pm}0.01$. The highest rate of apoptosis thus occurred ingroup 1 (transduced TRAIL encoding vector). In this group, the average medium-soluble TRAIL was 72.7pg/m and flow cytometry analysis showed a pro-apoptosis rate of $63{\pm}1.6%$, which was again higher than in other groups. Conclusions: In this study we have shown that tumor necrosis factor (TNF) secreted by AD-MSCs may play an effective role in inducing B-CLL cell apoptosis.