scholarly journals Synergistic Suppression Effect on Tumor Growth of Colorectal Cancer by Combining Radiotherapy With a TRAIL-Armed Oncolytic Adenovirus

2019 ◽  
Vol 18 ◽  
pp. 153303381985329 ◽  
Author(s):  
Hangxiang Gao ◽  
Xin Zhang ◽  
Ying Ding ◽  
Rong Qiu ◽  
Yupeng Hong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Necrosis Factor ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Tumor Necrosis ◽  
Xenograft Model ◽  
Oncolytic Adenovirus ◽  
Apoptotic Pathway ◽  
Colorectal Cancer Cells ◽  
Necrosis Factor

The combination of gene therapy and radiation is a promising new treatment for cancer. This study aimed to clarify the synergistic effect of targeted oncolytic adenovirus (radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand) and radiotherapy on colorectal cancer cells and elucidate the mechanisms of the underlying antitumor activity. Viability, cell cycle status, and apoptosis of treated colorectal cancer cells were determined via MTT and flow cytometric assays. The molecular mechanism underlying apoptotic pathway activation was elucidated through Western blot analysis of caspase-8, caspase-3, and PARP proteins. Combination treatment with radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand and radiotherapy displayed significantly greater antitumor activity than either of the monotherapies. The primary mechanism behind the antitumor activity in the SW480 and Lovo colorectal cancer cell lines was apoptosis induction through the caspase pathway and G1 phase arrest. In an SW480 xenograft model of colorectal cancer, the combination therapy achieved a significantly greater reduction in tumor volume than the monotherapies. Overall, in this study, we demonstrate that the oncolytic radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand construct can sensitize human colorectal cancer cells to radiation-induced apoptosis both in vitro and in vivo. Therefore, our findings point toward a novel synergistic approach to colorectal cancer treatment.

Kaempferol Improves TRAIL-Mediated Apoptosis in Leukemia MOLT-4 Cells by the Inhibition of Anti-apoptotic Proteins and Promotion of Death Receptors Expression

2019 ◽  
Vol 19 (15) ◽  
pp. 1835-1845
Author(s):  
Ali Hassanzadeh ◽  
Adel Naimi ◽  
Majid F. Hagh ◽  
Raedeh Saraei ◽  
Faroogh Marofi ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Tumor Necrosis ◽  
Lymphoblastic Leukemia ◽  
Annexin V ◽  
Death Receptors ◽  
Target Cells ◽  
Wide Range ◽  
Apoptotic Proteins ◽  
Necrosis Factor

Introduction: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily, which stimulates apoptosis in a wide range of cancer cells via binding to death receptors 4 and 5 (DR4/5). Nevertheless, TRAIL has noticeable anti-cancer abilities; some cancer cells acquire resistance to TRAIL, and consequently its potential for inducing apoptosis in target cells is strongly diminished. Acute lymphoblastic leukemia MOLT-4 cell line is one of the most resistant cells to TRAIL that developed resistance to TRAIL via different pathways. We used TRAIL plus kaempferol to eliminate resistance of the MOLT-4 cells to TRAIL. Material and Methods: First, IC50 for kaempferol (95 µM) was determined by using the MTT assay. Second, the viability of the MOLT-4 cells was assayed by FACS after Annexin V/PI staining, following treatment with TRAIL (50 and 100 nM) and kaempferol (95 µM) alone and together. Finally, the expression levels of the candidate genes involved in resistance to TRAIL were assayed by real-time PCR technique. Results: Kaempferol plus TRAIL induced apoptosis robustly in MOLT-4 cells at 12, 24 and 48 hours after treatment. Additionally, we found that kaempferol could inhibit expression of the c-FLIP, X-IAP, cIAP1/2, FGF-8 and VEGF-beta, and conversely augment expression of the DR4/5 in MOLT-4 cells. Conclusion: We suggest that co-treatment of MOLT-4 cells with TRAIL plus kaempferol is a practical and attractive approach to eliminate cancers’ resistance to TRAIL via inhibition of the intracellular anti-apoptotic proteins, upregulation of DR4/5 and also by suppression of the VEGF-beta (VEGFB) and FGF-8 expressions.

scholarly journals Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

2004 ◽  
Vol 15 (7) ◽  
pp. 3266-3284 ◽  
Author(s):  
Romaine Ingrid Fernando ◽  
Jay Wimalasena
Keyword(s):  
Breast Cancer ◽  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Dominant Negative ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

Estrogens such as 17-β estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-α, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-α-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.

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