Differential susceptibility to TRAIL of normal versus malignant human urothelial cells

Steele, Lynette P.; Georgopoulos, Nikolaos T.; Southgate, Jennifer; Selby, Peter J.; Trejdosiewicz, Ludwik K.

doi:10.1038/sj.cdd.4401846

Cited by 33 publications

(30 citation statements)

References 42 publications

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“…In addition, the HT1376 cell line appears to have a lower level of apoptotic proteins. Also post gemcitabine sensitization, TRAIL can induce a rapid negative-feedback loop that could downregulate TRAIL receptor expression thus allowing tumour cells to escape TRAIL mediated effect (28). In addition, we observed in this and other studies (unpublished data), that TRAIL can trigger the intrinsic pathway via Bid and that this pathway may be hampered or impaired in TRAIL-resistant UC cells.…”

Section: Discussionsupporting

confidence: 69%

“…In some experiments we observed that UC cell lines that are less responsive to TRAIL express DR4 and DR5 receptors at levels comparable to the TRAIL-sensitive ones (data not shown). That is, the apoptotic sensitivity of the UC cells did not appear to be related to the DR expression patterns alone (27)(28)(29). Thus, our current observation that TRAIL induced apoptosis in a caspase- dependent fashion may suggest that resistance to TRAIL may depend more on the level of intracellular signalling molecules rather than differences in receptor expression.…”

Section: Discussionmentioning

confidence: 68%

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Urothelial cancer cell response to combination therapy of gemcitabine and TRAIL

Moibi

Mak²,

Sun³

et al. 2011

Int J Oncol

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Abstract. High-risk superficial urothelial carcinoma of the bladder (UCB) is commonly treated with intravesical bacillus Calmette-Guerin (BCG), but with significant side effects. We recently showed that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibited high therapeutic potential against UCB cells and with only limited toxic effects in normal cells. However, many cancer cells are refractory to TRAIL during monotherapy. Therefore, our experimental aim was to develop combinatorial approaches with other proapoptotic agents to reactivate apoptosis in resistant phenotypes. We demonstrate that UCB cells varied in their response to TRAIL, and the effect was caspase-dependent (reduced or abrogated by pre-incubation of cells with caspase-inhibitor peptides). In contrast wortmannin, a PI3K/Akt inhibitor, enhanced the TRAIL effect. Furthermore, combination therapy of TRAIL with low dose gemcitabine markedly enhanced UCB cell response (except in the TRAIL-resistant HT1376 cell line). The enhanced response was both time-and concentrationdependent and asymptotic at gemcitabine concentration >1 µmol/l. To define the mechanisms underlying gemcitabine-augmented TRAIL action, we evaluated the expression of several proteins regulating the apoptotic pathway. Gemcitabine-augmented TRAIL effect was associated with inhibition of the Bcl-2 protein (intrinsic signalling) along with activation of the caspase (extrinsic) cascade. The combined maximal stimulation of both the intrinsic and extrinsic signalling pathways also appeared to overcome the survival (PI3K/Akt) pathway as evident by the lack of response to wortmannin. Our semisolid multicellular-spheroid model showed that TRAIL and gemcitabine selectively caused UCB cells to undergo apoptosis without affecting normal cells, and both appeared to penetrate deeply enough to allow for combination intravesical therapy.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 68%

Urothelial cancer cell response to combination therapy of gemcitabine and TRAIL

Moibi

Mak²,

Sun³

et al. 2011

Int J Oncol

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“…T2 (T cell) and K562 (CML) cell lines were grown in RPMI 1640 (Life Technologies), 10% FCS (Harlan Sera-Labs), and 1% glutamine (Life Technologies). Bladder tumor cell lines EJ, RT112, and 253J cells were grown in a 50:50 ratio of RPMI 1640:DMEM (Life Technologies), 5% FCS and 1% glutamine; SW480 cells (colorectal tumor cells) were grown in DMEM, 10% FCS, and 1% glutamine; parental RT112 and SW480 cell lines were transduced to express CD40 using a retroviral vector (16,17). Human foreskin fibroblast (HFF) and normal human urothelial (NHU) cells were grown as previously described (16).…”

Section: Cd14mentioning

confidence: 99%

OK432-Activated Human Dendritic Cells Kill Tumor Cells via CD40/CD40 Ligand Interactions

Hill

Errington

Steele

et al. 2008

The Journal of Immunology

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In vivo, dendritic cells (DC) are programmed to orchestrate innate and adaptive immunity in response to pathogen-derived “danger” signals. Under particular circumstances, DC can also be directly cytotoxic against tumor cells, potentially allowing them to release tumor associated Ags from dying cells and then prime antitumor immunity against them. In this study, we describe the innate characteristics of DC (OK-DC) generated in vitro after exposure of immature human myeloid-derived DC to OK432, a penicillin-inactivated and lyophilized preparation of Streptococcus pyrogenes. OK-DC produced proinflammatory cytokines, stimulated autologous T cell proliferation and IFN-γ secretion, expressed CCR7, and migrated in response to MIP-3β. Moreover, OK-DC displayed strong, specific cytotoxicity toward tumor cell targets. This cytotoxicity was associated with novel, OK432-induced up-regulation of CD40L on the cell surface of OK-DC, and was absolutely dependent on expression of CD40 on the tumor targets. These data demonstrate that maturation of human DC with OK432, an adjuvant suitable for clinical use, induces direct tumor cell killing by DC, and describes a novel CD40/CD40L-mediated mechanism for specific DC antitumor cytotoxicity.

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“…In several types of cancers, increased c-FLIP expression is correlated with resistance to TRAIL-, Fas-, or TNF-induced apoptosis (17)(18)(19)41,42). Post-translational modification and degradation of c-FLIP as well as increased mRNA levels have been suggested to be involved in increasing c-FLIP expression (43).…”

Section: Discussionmentioning

confidence: 99%

“…Both c-FLIP S and c-FLIP L are recruited to the DISC where c-FLIP L is cleaved into a p43 intermediate form, which, together with c-FLIP S , remains in the DISC where they inhibit caspase-8 cleavage (16). c-FLIP is expressed in various cancers and its expression is associated with enhanced tumorigenicity and poor clinical outcome in many types of cancers because of chemotherapeutic drug and TRAIL resistance (17)(18)(19).…”

mentioning

confidence: 99%

The sesquiterpene lactone eupatolide sensitizes breast cancer cells to TRAIL through down-regulation of c-FLIP expression

Lee

Hwangbo²,

Lee³

et al. 2009

Oncol Rep

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Abstract. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. However, sensitivity of cancer cells for induction of apoptosis by TRAIL varies considerably. Therefore, it is important to develop agents that overcome this resistance. We show, for the first time, that eupatolide, the sesquiterpene lactone isolated from the medicinal plant Inula britannica, sensitizes human breast cancer cells to TRAIL-induced apoptosis. Treatment with TRAIL in combination with subtoxic concentrations of eupatolide enhanced the TRAILinduced cytotoxicity in MCF-7, MDA-MB-231 and MDA-MB-453 breast cancer cells, whereas each reagent alone slightly induced cell death. The combination induced sub-G 1 phase DNA content and annexin V-staining in MCF-7 cells, which are major features of apoptosis. Apoptotic characteristics induced by the combined treatment were significantly inhibited by a pan-caspase inhibitor. The sensitization to TRAIL-induced apoptosis was accompanied by the activation of caspase-8 and was concomitant with Bid and poly(ADP-ribose) polymerase (PARP) cleavage. Treatment of eupatolide alone significantly down-regulated the expression of cellular FLICE inhibitory protein (c-FLIP) in MCF-7 cells. Furthermore, enforced expression of c-FLIP significantly attenuated the apoptosis induced by this combination in MCF-7 cells, suggesting a key role for c-FLIP down-regulation in these events. We also observed that euaptolide inhibited AKT phosphorylation in a dose-and time-dependent manner. Moreover, inhibition of Akt by LY294002, a specific PI3K inhibitor, down-regulated c-FLIP expression in MCF-7 cells. Taken together, these results indicate that eupatolide could augment TRAIL-induced apoptosis in human breast cancer cells by down-regulating c-FLIP expression through the inhibition of AKT phosphorylation and be a valuable compound to overcome TRAIL resistance in breast cancer cells.

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Differential susceptibility to TRAIL of normal versus malignant human urothelial cells

Cited by 33 publications

References 42 publications

Urothelial cancer cell response to combination therapy of gemcitabine and TRAIL

Urothelial cancer cell response to combination therapy of gemcitabine and TRAIL

OK432-Activated Human Dendritic Cells Kill Tumor Cells via CD40/CD40 Ligand Interactions

The sesquiterpene lactone eupatolide sensitizes breast cancer cells to TRAIL through down-regulation of c-FLIP expression

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