Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand and Chemotherapy Cooperate to Induce Apoptosis in Mesothelioma Cell Lines

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in certain tumor cells. In addition, TRAIL and chemotherapy can act cooperatively, possibly as a result of chemotherapy-induced increases in expression of a TRAIL receptor, DR5. We used cell lines derived from a highly chemoresistant tumor, malignant mesothelioma, to learn whether TRAIL was effective alone or together with chemotherapy and whether cooperativity depended on increases in DR5 expression. TRAIL (codons 95-285) was expressed in a bacterial expression vector and purified by nickel affinity chromatography. TRAIL alone (25 to 500 ng/ml) had little effect on mesothelioma cells. TRAIL plus chemotherapy (doxorubicin, cis-platinum, etoposide, or gemcitabine) acted cooperatively to induce apoptosis in mesothelioma cells (M28, REN, VAMT, and MS-1). For example, in M28 cells treated for 18 h, apoptosis from TRAIL (100 ng/ml) plus doxorubicin (0.6 microg/ml; 71 +/- 11%) greatly exceeded that from TRAIL alone (21 +/- 8%) or from doxorubicin alone (6 +/- 2%) (means +/- standard deviation; P < 0.03). Mesothelioma cells treated with chemotherapy showed no change in DR5 protein by Western analysis or by immunocytochemistry. TRAIL plus chemotherapy was associated with an increase in mitochondrial cytochrome c release and mitochondrial depolarization. We conclude that TRAIL and chemotherapy act cooperatively to kill mesothelioma cell lines, not by increases in DR5 receptor but in association with mitochondrial amplification of apoptotic signals.

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

“…The importance of activation of both types of signalling in sensitisation of cancer cells to TRAIL has been recently shown for prostate cancer cells (Ray and Almasan, 2003). Our findings are in accord to those of Liu et al, 2001, reporting that sensitisation of MM cells toward TRAIL by chemotherapeutic is dependent on the mitochondrial pathway, in a c-Jun N-terminal kinase (JNK)-dependent manner (Vivo et al, 2003). Thus, a-TOS, although also acting via the JNK pathway (Yu et al, 2001) signalling downstream through Bax (Lei et al, 2002), promotes the receptor-dependent pathway, thereby maximizing the apoptotic potential of the cell.…”

Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL

“…The results shown are from a single experiment performed in triplicate. 35 In contrast, lower concentrations of doxorubicin, which were sufficient to sensitize cells to TRAIL, did not result in elevation of TRAIL receptor expression 29,36 or changes in receptor mRNA levels that correlated with sensitivity. 13 Therefore, changes in TRAIL receptor status following doxorubicin treatment may vary with the concentration or cell type studied.…”

“…Although most of the toxicity was attributed to doxorubicin, two other studies using breast and mesothelial cells have demonstrated lack of selectivity for malignant cells when doxorubicin was combined with TRAIL. 13,29 It is important to note that the recombinant TRAIL used in this study contains a histidinetag, which has been shown to have different biochemical and toxicological properties than TRAIL /Apo2L.0. 10 However, in the prostate cancer cell lines, we have tested noncross -linked TRAIL lacking a tag ( PeproTech ) with results comparable to those achieved with the histidine -tagged TRAIL purchased from R&D systems (Voelkel -Johnson, unpublished observations ).…”

“…Alternatively, doxorubicin may sensitize cells to TRAIL by affecting the intrinsic, mitochondrial pathway of apoptosis. 29 At least five of the prostate cancer cell lines we examined harbor p53 mutations ( Du145, JCA -1, PC -3, PPC -1, TsuPr1). 37 Only LNCaP and PrEC have confirmed wildtype p53.…”

Cell cycle checkpoint status in human malignant mesothelioma cell lines: response to gamma radiation

“…In the same vein, recent reports show significant augmentation of proapoptotic gene therapy by pharmacological downregulation of survival signals in MM cells Mohiuddin et al, 2001). Furthermore, both tumour necrosis factor-related apoptosis-inducing ligand and chemotherapy cooperate to induce apoptosis in HMCLs (Liu et al, 2001). In conclusion, HMCLs exhibited different responses to gradiation exposure.…”