The present data showed that sunitinib potentiated the in vitro and in vivo anticancer capabilities of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand. Interactions between sunitinib and TRAIL were examined in colon cancer SW620 cells and lung cancer 95-D cells. The average combination index (CI) values of the anti-proliferation abilities on each cancer cell line were less than 1.0, demonstrating the synergism of the combination of sunitinib and TRAIL. Western blot experiments indicated that TRAIL and sunitinib synergistically enhanced apoptosis by simultaneously activating the extrinsic and intrinsic pathways. The decrease in the expression levels of anti-apoptotic proteins cFLIP, XIAP and Mcl-1 were probably involved in this apoptosis enhancement. Furthermore, treatment of colon cancer SW620-bearing nude mice with sunitinib plus TRAIL resulted in more significant tumor growth inhibition (52.8%), comparing with the moderate inhibition in TRAIL-treated (35.3%) or sunitinib-treated groups (26.7%) (p < 0.05). These results indicate that the combination of TRAIL with sunitinib seems highly encouraging and warrants further investigation in a clinical setting. 相似文献
Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptors (DR) 4 and 5 have attracted significant attention in recent years due to their ability to selectively induce apoptosis in malignant cells while demonstrating little cytotoxicity in normal cells. Although these candidates are promising in cancer therapy, a number of tumor cells are resistant to TRAIL-mediated apoptosis. We describe the use of a cationic amphipathic lytic peptide, KLA (single letter sequence HHHHHKLAKLAKKLAKLAKC), for the chemosensitization of TRAIL-resistant LNCaP and PC3-PSMA human prostate cancer cells to DR agonistic antibodies. ‘Single-agent’ treatment with DR agonistic antibodies did not result in loss of viability of these cells confirming the resistance of these cells. However, the combination treatment of KLA followed by DR agonists resulted in greater cell death compared to the individual treatments acting alone, indicating synergistic action between the two components of the combination treatment. The combination of lytic peptide and DR agonists resulted in a significant increase in activated caspase-3 cleavage and cytochrome-C protein levels in cells, indicating a role for the caspase-mediated apoptotic pathway. In addition, KLA treatment also resulted in increased localization of DR5 and lipid rafts in LNCaP cells. Our results demonstrate, for the first time, that lytic peptides can be employed for sensitizing TRAIL-resistant prostate cancer cells to DR-mediated apoptosis resulting in novel combination treatments for the ablation of advanced cancer cells. 相似文献
Research over the years has progressively shown substantial broadening of the tumor necrosis factor alpharelated apoptosis-inducing ligand (TRAIL)-mediated signaling landscape. Increasingly it is being realized that pancreatic cancer is a multifaceted and genomically complex disease. Suppression of tumor suppressors, overexpression of oncogenes, epigenetic silencing, and loss of apoptosis are some of the extensively studied underlying mechanisms. Rapidly accumulating in vitro and in vivo evidence has started to shed light on the resistance mechanisms in pancreatic cancer cells. More interestingly a recent research has opened new horizons of miRNA regulation by DR5 in pancreatic cancer cells. It has been shown that DR5 interacts with the core microprocessor components Drosha and DGCR8, thus impairing processing of primary let-7. Xenografting DR5 silenced pancreatic cancer cells in SCID-mice indicated that there was notable suppression of tumor growth. There is a paradigm shift in our current understanding of TRAIL mediated signaling in pancreatic cancer cellsthat is now adding new layers of concepts into the existing scientific evidence. In this review we have attempted to provide an overview of recent advances in TRAIL mediated signaling in pancreatic cancer as evidenced byfindings of in vitro and in vivo analyses. Furthermore, we discuss nanotechnological advances with emphasis on PEG-TRAIL and four-arm PEG cross-linked hyaluronic acid (HA) hydrogels to improve availability of TRAIL at target sites. 相似文献
The aim of this study was to investigate induction of apoptosis by the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and gemcitabine in the pancreatic cancer cell line SW1990. The sensitivity of SW1990 cells to TRAIL and/or gemcitabine-induced apoptosis and the rate of apoptosis were assessed by MTT assay and flow cytometry, respectively. We used Hoechst 33342 staining to observe apoptotic morphology and expression levels of proteins were analyzed by Western blottin. Growth inhibition and apoptosis rates on treatment with the combination of TRAIL and gemcitabine were significantly higher than with each drug alone (p<0.05). Pancreatic cancer cells exhibited a typical apoptosis morphology after treatment with TRAIL or gemcitabine. The levels of cellular apoptosis-associated proteins such as Smac/DIABLO, Cyto C, and the activated fragment of caspase-3 (P17) increased, but the expression of XIAP was significantly decreased after 24 h (p<0.05). SW1990 cells responded to TRAIL and/or gemcitabine-induction of apoptosis in a time and concentration-dependent manner. The mechanism of the apoptosis-sensitization effect appeared associated with significant up-regulation of Smac/DIABLO and cytochrome C, down-regulation of XIAP, and activation of caspase-3. 相似文献
Purpose: To explore the synergistic effect of a seleno-organic compound Ebselen (Ebs) and/or γ-radiation to exert antitumor effects on human breast cancer (MCF-7) cell line in vitro.
Materials and methods: Ebs cytotoxicity at various concentrations (10, 25, 50 and 75 μg), cell proliferation and clonogenic assay of Ebs and/or γ-radiation (at 1, 3 and 6?Gy), expression of p-IκBα and NF-κB, inflammatory cytokines levels (TNF-α, IL-2, INF-γ, IL-10 and TGF-β), apoptotic factors (Caspase-3, Granzyme-B and TRAIL) and angiogenic factor (VEGF) were investigated.
Results: The results showed that the effective dosage of this combination was observed at 25 μg/ml of Ebs with γ-radiation at 6?Gy. Data displayed a significant reduction in NF-κB mRNA along with an elevation in granzyme-B mRNA and TRAIL mRNA expression. Furthermore, protein expression of caspase-3 was elevated, whereas p-IκBα and p-NF-κB(p65) protein expression was reduced significantly. Also, a significant decline in TNF-α, IL-2, INF-γ, TGF-β with a significant increase in IL-10 levels were revealed. Meanwhile, a significant decrease in VEGF level and proliferation capacity were observed.
Conclusions: We conclude that a combination of Ebs with radiotherapy has a major antitumor efficiency in inducing apoptosis and inhibiting cancer cell progression, due to the synergistic effect in regulating gene and protein expression, and in a modulating response of pro-and anti-inflammatory cytokines. 相似文献