• Journal of Ginseng Research
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• 제44권5호
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• pp.725-737
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• 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
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• 제16권16호
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• pp.7303-7307
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• 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
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• 제3권2호
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• pp.137-144
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• 1985

전신질환인 만성골수성백혈병(Chronic Myelogenous Leukemia: CML)에 있어서, 비장에만 국소적으로 방사선을 조사(Splenic Irradiation; SI)함으로써, 임상적 증상의 호전과 혈액소견상에 완해를 일으킨다는 것은 1903년대 이후로 알러져 있는 사실이다. 최근에 와서 Busulfan에 의한 화학요법이 주치료로서 도입되기 전까지는 SI가 CML치료에 광범위하게 사용되어 왔었다. 요즈음엔 비장의 방사선치료는 화학요법보다 그 결과가 좋지 못하지만, 통증을 동반한 비종대에서 증상의 완화를 위하거나, 가속기(accelerated phase)에 들어섰거나, 화학요법에 반응하지 않을 때 사용되고 있다. SI의 효과는 백혈구수의 감소, 헤모글로빈치의 상승등의 직접, 간접효과가 있으며 이 효과는 방사선치료를 끝낸 후에도 어느 기간 지속되며, 만족스런 반응을 보일 경우엔 반복치료도 시도되고 있다. 그리고 약물치료에 반응이 없었던 판자에서도 에로는 SI로 임상적 호전을 관찰할 수 있으며, SI전에 많은 치료를 받지 않았던 경우에 더 좋은 반응을 기대할 수 있음은 잘 알려져 있다. 가톨릭의대 방사선치료실에서는 화학요법도중 통증을 동반한 심한 비종대를 호소하거나, 화학요법에 반응이 없었던 15례의 CML환자에서 SI를 실시하였다. 저자들은 대상환자들의 SI전후의 임상적 증상, 이학적 소견 혈액학적 소견등의 변화 및 생존기간을 추적하였기에 문헌고찰과 함께 보고하는 바이다.

• Journal of Chest Surgery
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• 제51권5호
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• pp.350-355
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• 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
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• 제13권7호
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• pp.3461-3464
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• 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
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• 제15권13호
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• pp.5455-5461
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• 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
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• 제15권22호
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• pp.9885-9889
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• 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
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• 제48권4호
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• pp.448-463
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• 2000

연구배경 : 백혈병 환자에서 발생한 폐침윤은 진행속도가 빠르고 이로 인한 사망률이 매우 높아 이에 대한 정확한 진단과 신속한 치료 개시가 필요하지만 비침습적인 방법만으로 확진이 어려운 경우가 많다. 이에 저자들은 새롭게 폐침윤이 발생한 백혈병 환자에서 침습적 진단법인 기판지내시경 검사와 외파적 폐생검술의 유용성을 알아보고자 후향적 연구를 시행하였다. 방 법 : 1994년 12월부터 1999년 3월까지 삼성서울병원에 입원한 백혈병 환자중 새로운 폐침윤이 발생한 102례 총 90명 환자를 대상으로 진료 기록과 방사선 소견등을 후향적으로 조사하였다. 결 과 : 1) 총 102례중 경험적 치료군이 58례, 침습적 검사군이 44례였다. 폐침윤 발생 당시 경험적 치료군에서 평균연령이 많았고(p=0.035), 호중구 감소증이 더 흔히 관찰되었으며(p=0.047) 혈소판 수치는 침습적 검사군에서 더 높았다(p=0.043). 그 외 폐침윤 분포양상 및 기계환기 여부등은 두 군간에 유의한 차이가 없었다. 골수이식은 침습적 검사군에서(p=0.036), 관해유도 항암화학요법을 시행중인 환자는 경험적 치료군에서 많았으나(p=0.021) 28일째 완전관해율은 두 군간에 유의한 차이가 없었다. 2) 첨습적 검사군 44례중 기관지내시경 검사를 시행한 경우가 22례, 외과적 폐생검술이 17례, 모두 시행한 경우가 5례였다. 침습적 검사로 원인이 확진된 환자 32례(72.7%) 중 감염성 원인이 25례(78.1%)였고 검사후 치료방침의 변화를 가져온 경우는 23례(52.3%)였으며 시술과 관련된 사망은 없었다. 3) 전체 환자의 입원기간중 생존률은 62.7%(64/102)였고 침습적 경사군이 79.5%(35/44)의 생존률을 보여 경험적 치료군의 50.0%(32/66)보다 의미있게 높았다(p=0.002). 4) 다변량 통계 분석상 침습적 검사 시행(p=0.007), 기계환기 미시행(p<0.001), 28일째 완전관해 달성(p=0.005)의 3가지가 전체 환자에서 생존을 예측할 수 있는 독립적 예후 인자였다. 결 론 : 결론적으로 기관지내시경 검사와 외과적 폐생검은 백혈병 환자에서 발생한 폐침윤의 진단에는 유용하나 생존률 향상에 기여하는지 여부는 백혈병 치료상태 및 호흡부전 여부가 동시에 고려되어야 하므로 향후 대규모 무작위 전향적 연구가 이루어져야 결론이 날 것으로 사료된다.

• 한국식품영양과학회지
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• 제40권9호
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• pp.1201-1207
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• 2011

TRAIL은 최근 암세포의 apoptosis 유도를 위한 효율적인 도구로 제시되었으나 많은 암세포들이 TRAIL 저항성을 획득한 것으로 알려져 TRAIL 저항성 극복을 위한 새로운 방법론의 제시가 요구되어지고 있다. Genistein은 대두의 대표적인 생리활성 물질인 isoflavonoid의 일종으로 많은 암세포에서 G2/M arrest를 유발하면서 apoptosis를 유도하는 것으로 알려져 있다. 본 연구에서는 U937 인체백혈병세포를 대상으로 genistein에 의한 TRAIL 유도 apoptosis의 감수성 증대 여부를 조사하였다. 본 연구의 결과에 의하면 U937 세포에서 세포독성이 없는 범위의 genistein 처리는 TRAIL에 의한 apoptosis 유도를 매우 증진시켰으며, 이는 tBid의 발현 증가와 cFLIPL의 발현 감소와 연계된 caspase의 활성 증가와 연관성이 있었다. 또한 caspase의 활성 저해제는 genistein과 TRAIL의 복합처리에 의한 apoptosis를 유의적으로 감소시켜 복합 처리에 의한 apoptosis의 유도에 caspase의 활성 증대가 필수적임을 알 수 있었다. 따라서 genistein은 TRAIL 저항성을 획득한 암세포의 효율적인 combined therapy approach를 위해 유용하게 사용될 수 있음을 알 수 있었다.

• Asian Pacific Journal of Cancer Prevention
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• 제16권18호
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• pp.8533-8539
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• 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.