Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in conjunction with microtubule-targeting agents may be a promising novel anticancer treatment strategy. In vitro studies have suggested that relatively low concentrations of TRAIL enhance the lethality of paclitaxel (Taxol) against human cancer cells. The increased efficacy may be due to the triggering of caspase activation, resulting in mitotic checkpoint abrogation and catastrophe. We show here that wild-type p53 protects cells from caspase-dependent death induced by this therapeutic combination in vitro. We have now also developed an imaging-based model system to test the in vivo efficacy of combined TRAIL and Taxol, in which tumor growth and treatment response can be monitored noninvasively and in real-time. We further utilize bioluminescence, F 18 -fluorodeoxyglucose-positron emission tomography, and microscale computed tomography imaging to confirm the effects of combined treatment on tumors. These studies together provide the first in vivo confirmation that combined TRAIL plus paclitaxel results in better tumor control compared with either TRAIL or paclitaxel alone, and with no discernable increased normal tissue toxicity in the mouse. Interestingly, the in vivo antitumor response elicited by combined treatment was not affected by the p53 status of the tumor cells. These preclinical observations together suggest the therapeutic potential of combining TRAIL plus paclitaxel in cancer treatment, and support further preclinical and future clinical testing. [Mol Cancer Ther 2009;8(12):3285-95]

Pathophysiological mechanisms regulated by cytokines in gliomas

“…Very recently, gingerol was also shown to induce TRAIL-associated apoptosis, by up-regulating TRAIL receptors (DR4, DR5) on one hand and down-regulating Bcl-2 and survivin on the other hand [44]. The concept of increasing TRAIL receptors is further enhanced by the synergistic use of TRAIL and the well known drugs salinomycin [45] and paclitaxel [46] which appeared to stimulate DR4, DR5 expression, thus increasing responsiveness of gliomas to TRAIL. In a similar way TIC 10 via FOXO3A also triggers the expression of both TRAIL and its receptor [47].…”

Immunological effects of Taxol and Adryamicin in breast cancer patients

“…1a) showed a significative augment only in CA patients (from 16.47 ± 0.82 lM in controls to 21.21 ± 1.78 lM in CA group, P = 0.0453), without alteration in the other groups (18.30 ± 1.96 lM in DOX (Table 2) showed significative leucopenia in DOX-treated group (7,714 ± 453.5 cells/mm 3 in CA patients to 7,063 ± 485.5 cells/mm 3 in DOX group, P = 0.0328), nevertheless counting was within the interval considered normal to healthy human blood (4,000-10,000 cells/mm 3 Spearman's test did not show any significative correlation between tested parameters (Fig. 2).…”

“…Although systemic chemotherapy has been known as immunosuppressive to most of patients, evidences have demonstrated that antineoplastic drugs present an important immunogenic role during their tumoricidal effect [1], as tumor apoptosis enhancement [2], higher expression of signaling molecules [3][4][5][6], as well as increment in effector cells number [7] and killing potential [8]. Further, these immunological interactions have been recently evidenced as critical points for response to chemotherapy and patients' clinical outcome [9].…”

Correlation between TRAIL and caspase-8 expression and their relationship with cell proliferation and apoptosis in human osteosarcoma

“…Basic research has revealed that TRAIL targets five receptors, one of which is the death receptor expressed in tumor cells, and it can induce apoptosis by binding with that receptor. In contrast, when TRIAL binds to the decoy receptor that is mainly expressed in normal cells, apoptosis may not occur (Dorsey et al, 2009;Na et al, 2010;Piras et al, 2011). Because its effect on cells depends on the distribution of the receptors, TRAIL has a unique antitumor function (Chen et al, 2010).…”