• 생명과학회지
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• 제21권11호
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• pp.1641-1651
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• 2011

TNF ligand 군에 속하는 Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L)은 death receptor를 통한 세포사멸을 유도하는 것으로 알려졌다. TRAIL은 정상세포에서는 세포사를 일으키지 않고 암세포에서만 특이적으로 세포사멸을 유도함으로써 잠재력 있는 항암제로 주목을 받고 있다. 그러나, 최근 연구에 의하면 악성 신장암과 간암과 같은 일부 암에서는 TRAIL에 의한 세포사에 저항성을 가지는 것으로 알려져 있다. 그러므로, TRAIL 만으로는 다양한 악성종양을 위한 치료법으로 적절하지 않다. TRAIL에 대한 저항성을 가지는 분자적 기전을 이해하고, TRAIL 저항성을 극복할 수 있는 증감제를 밝혀내는 것이 보다 효율적인 TRAIL을 이용한 암세포 치료 전략에 필요하다. 화학치료제들이 TRAIL 수용체인 death receptor의 발현을 증가시키고, 세포 내의 TRAIL에 의한 신호전달 체계를 활성화 시키는 것으로 알려져 있고, 이러한 기전을 통하여 다양한 화학치료제들이 TRAIL에 의한 세포사멸을 증가시키는 것을 확인하였다. 이 논문에서, 우리는 TRAIL에 의한 세포 사멸을 증가시키기 위한 생물학적 약물을 정리하고, 그 분자적 기전을 고찰한다.

• Biomolecules & Therapeutics
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• 제20권1호
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• pp.62-67
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• 2012

TNF-related apoptosis-inducing ligand (TRAIL) is a promising agent for management of cancer because of its selective cytotoxicity to cancer cells. However, some cancer cells have resistance to TRAIL. Accordingly, novel treatment strategies are required to overcome TRAIL resistance. Here, we examined the synergistic apoptotic effect of apigenin in combination with TRAIL in Huh-7 cells. We found that combined treatment of TRAIL and apigenin markedly inhibited Huh-7 cell growth compared to either agent alone by inducing apoptosis. Combined treatment with apigenin and TRAIL induced chromatin condensation and the cleavage of poly (ADP-ribose) polymerase (PARP). In addition, enhanced apoptosis by TRAIL/apigenin combination was quantified by annexin V/PI flow cytometry analysis. Western blot analysis suggested that apigenin sensitizes cells to TRAIL-induced apoptosis by activating both intrinsic and extrinsic apoptotic pathway-related caspases. The augmented apoptotic effect by TRAIL/apigenin combination was accompanied by triggering mitochondria-dependent signaling pathway, as indicated by Bax/Bcl-2 ratio up-regulation. Our results demonstrate that combination of TRAIL and apigenin facilitates apoptosis in Huh-7 cells.

• 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.

• Asian Pacific Journal of Cancer Prevention
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• 제13권4호
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• pp.1471-1476
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• 2012

Background and Aim: Currently available systemic therapies for malignant melanoma produce low response rates in patients, and more effective treatment modalities are clearly needed. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand has a significant impact on therapy for patients with X-linked inhibitor of apoptosis protein-downregulation malignant melanoma. The primary objective of this study was to assess its therapeutic potential. Materials and Methods: We employed a conditionally replicating oncolytic adenoviral vector, named CRAd5.TRAIL/siXIAP, with the characteristics of over-expression of the therapeutic gene TRAIL and downregulation of XIAP in one vector. B16F10-luc cells were employed to detect anti-tumor activity of CRAd5.TRAIL/siXIAP in vitro and in vivo. Results: CRAd5.TRAIL/siXIAP enhanced caspase-8 activation and caspase-3 maturation in B16F10 cells in vitro. Furthermore, it more effectively infected and killed melanoma cells in vitro and in vivo than other adenoviruses. Conclusion: Taken together, the combination of upregulation of TRAIL and downregulation of siXIAP with one oncolytic adenoviral vector holds promise for development of an effective therapy for melanomas and other common cancers.

• 생명과학회지
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• 제19권8호
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• pp.1023-1032
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• 2009

TNF-related apoptosis-inducing ligand (TRAIL) 는 암세포에만 작용하고 정상세포에는 영향을 주지 않는 항암제로서 알려져 있지만, TRAIL에 내성을 나타내는 암세포의 출현이 문제점으로 지적되고 있다. 사람 백혈병세포인 K562 및 CEM 세포는 TRAIL에 내성을 나타낸다. 본 연구에서는 이러한 백혈병 세포의 TRAIL 내성에 대한 새로운 표적 분자의 발굴과 이를 토대로 한 새로운 내성극복 방법을 연구하였다. 새로운 TRAIL sensitizer로서 quercetin을 발굴하고, 이를 K562 세포에 TRAIL과 병용 투여하므로서 TRAIL의 효과 증강에 의한 내성극복을 시도하였다. Quercetin은 DNA-PK/Akt 신호전달경로를 억제하므로서, caspases 활성 증강과 PARP cleavage, 이에 따른 Bax의 발현을 증강시키는 기전으로 K562 세포의 TRAIL에 의한 apoptosis를 증대시키는 활성이 있음을 밝혔다. 이러한 quercetin 병용 처리에 의한 TRAIL의 활성 증강으로 TRAIL 내성이 극복됨을 CEM 세포에서도 확인하였다. 이러한 연구 결과는 DNA-PK 발현 증강에 의한 Akt의 활성화가 TRAIL 내성을 유발하는 기전을 토대로 함을 밝힘으로써, DNA-PK 활성 억제제를 TRAIL과 병용하므로서 TRAIL 내성을 나타내는 암세포에 내성 극복 효과를 얻을 수 있는 새로운 약제 병용 방법을 제시하였다.

• 대한한의학방제학회지
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• 제25권2호
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• pp.145-154
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• 2017

Objectives : Bufalin is one of the bioactive component of 'Sum Su (蟾酥)', which is obtained from the skin and parotid venom gland of toad. Bufalin has been known to possess the inhibitory effects on cell proliferation and inducing apoptosis in various cancer cells. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has concerned, because it can selectively induce apoptotic cell death in many types of malignant cells, while it is relatively non-toxic to normal cells. Here, we investigated whether bufalin can trigger TRAIL-induced apoptotic cell death in EJ human bladder cancer cells. Methods : Effects on the cell viability and apoptotic activity were quantified using MTT assay and flow cytometry analysis, respectively. To investigate the morphological change of nucleus, DAPI staining was performed. Protein expressions were measured by immunoblotting. Results : A combined treatment with bufalin (10 nM) and TRAIL (50 ng/ml) significantly promoted TRAIL-mediated growth inhibition and apoptosis in EJ cells. The apoptotic effects were associated with the up-regulation of death receptor proteins, and the down-regulation of cFLIP and XIAP. Moreover, our data showed that bufalin and TRAIL combination activated caspases and subsequently increased degradation of poly(ADP-ribose) polymerase. Conclusions : Taken altogether, the nontoxic doses of bufalin sensitized TRAIL-mediated apoptosis in EJ cells. Therefore, bufalin might be an effective therapeutic strategy for the safe treatment of TRAIL-resistant bladder cancers.

• 대한수의학회지
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• 제44권2호
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• pp.195-200
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• 2004

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family and potent inducer of apoptosis. TRAIL has been shown to effectively limit tumor growth in vivo without detectable cytotoxic side effects. Interferon (IFN)-${\gamma}$ often modulates the anti-cancer activities of TNF family members including TRAIL. We previously reported that IFN-${\gamma}$ enhanced TRAIL-induced Apoptosis in HeLa cells without the unknown mechanism. In this study, we investigated whether IRF-1 involves in IFN-${\gamma}$-enhanced TRAIL-induced apoptosis. We exposed HeLa cells to IFN-${\gamma}$ for 12 hours and then treated with recombinant TRAIL protein. No apoptosis was induced in cells pretreated with IFN-${\gamma}$, and TRAIL only induced 30% apoptosis after 3 hours treatment. In HeLa cells pretreated with IFN-${\gamma}$, TRAIL induced cell death to more than 75% at 3 hours, showed that IFN-${\gamma}$-pretreatment enhanced HeLa cell death to TRAIL-induced apoptosis. To investigate the functional role of IRF-1 in IFN-${\gamma}$-enhanced TRAIL-induced apoptosis, IRF-1 was overexpressed by using an adenoviral vector AdIRF-1. IRF-1 overexpression increased apoptotic cell death and significantly enhanced apoptotic cell death induced by TRAIL when infected cells were treated with TRAIL. Our findings show that IFN-${\gamma}$ enhances TRAIL-induced apoptosis by IRF-1 in HeLa cells.

• BMB Reports
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• 제52권2호
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• pp.119-126
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• 2019

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) initiates the extrinsic apoptotic pathway through formation of the death-inducing signaling complex (DISC), followed by activation of effector caspases. TRAIL receptors are composed of death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and osteoprotegerin. Among them, only DRs activate apoptotic signaling by TRAIL. Since the levels of DR expressions are higher in cancer cells than in normal cells, TRAIL selectively activates apoptotic signaling pathway in cancer cells. However, multiple mechanisms, including down-regulation of DR expression and pro-apoptotic proteins, and up-regulation of anti-apoptotic proteins, make cancer cells TRAIL-resistant. Therefore, many researchers have investigated strategies to overcome TRAIL resistance. In this review, we focus on protein regulation in relation to extrinsic apoptotic signaling pathways via ubiquitination. The ubiquitin proteasome system (UPS) is an important process in control of protein degradation and stabilization, and regulates proliferation and apoptosis in cancer cells. The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and deubiquitinases (DUBs), which determine protein stability. Regulation of the UPS may be an attractive target for enhancement of TRAIL-induced apoptosis. Our review provides insight to increasing sensitivity to TRAIL-mediated apoptosis through control of post-translational protein expression.

• 생명과학회지
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• 제19권9호
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• pp.1209-1217
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• 2009

많은 암세포에 선택적 세포독성을 나타내는 TNF-related apoptosis-inducing ligand (TRAIL)는 유효한 항암제로서 사용될 수 있지만, TRAIL에 내성을 나타내는 암세포에는 TRAIL-sensitization의 방법이 필요하다. 사람 대장암 세포인 KMl2 세포도 TRAIL에 내성을 나타낸다. 본 연구에서는 KMl2세포의 TRAIL 내성에 대한 새로운 표적 분자의 발굴과 이를 토대로 한 새로운 내성극복 방법을 연구하였다. 새로운 TRAIL sensitizer로서 quercetin을 발굴하고, 이를 KMl2세포에 TRAIL과 병용 처리하여 TRAIL의 효과증강을 시도하였다. KMl2세포에서 quercetin은 c-FLTP의 발현을 감소시키고, DNA-PK/Akt 신호전달경로를 억제하므로서, death receptors (DR4/DR5) 발현을 증강시켰다. 또한 caspases (caspase 3, -8 및 -9)활성 증강과 PARP cleavage, 이에 따른 Bax의 발현을 증강시키는 기전으로 TRAIL에 의한 apoptosis를 증대시키는 활성이 있음을 밝혔다. 즉 quercetin이 KMl2세포의 TRAIL-sensitization에 사용될 수 있음을 제시하였다. 이러한 연구 결과는 대장암의 치료 시 TRAIL과 quercetin병용하므로서 치료 효과를 높일 수 있는 새로운 약제 병용 방법을 제시하였고, 다른 TRAIL 내성 종양에 응용 될 수 있음을 시사하였다.

• Journal of Acupuncture Research
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• 제30권1호
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• pp.43-55
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• 2013

I investigated whether snake venom toxin(SVT) from Vipera lebetina turanica enhances the apoptosis ability of tumor necrosis factor(TNF)-related apoptosis-inducing ligand(TRAIL) in cancer cells. TRAIL inhibited HCT116 cell growth in a dose-dependent manner. Consistent with cell growth inhibition, the expression of TRAIL receptors; DR4 and DR5 was significantly increased as well as apoptosis related proteins such as cleaved caspase-3, 8, 9 and Bax. However, the expression of survival proteins(eg, cFLIP, survivin, XIAP and Bcl2) was suppressed by the combination treatment of SVT and TRAIL. Pretreatment with the reactive oxygen species(ROS) scavenger N-acetylcysteine reduced the SVT and TRAIL-induced upregulation of DR4 and DR5 expression and expression of the apoptosis related protein such as caspase-3 and-9 as well as cell growth inhibitory effects. The collective results suggest that SVT facilitates TRAIL-induced apoptosis in human colorectal cancer HCT116 cells through up-regulation of the TRAIL receptors; DR4 and DR5 via ROS pathway signals.