The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity in normal cells. However, most cancers, including glioblastoma multiforme (GBM), display TRAIL resistance, hindering its application in clinical practice. This entry is defined by some potential stratergies of applying TRAIL-based therapy via overriding resistance for GBM trearment.
To maximize the potential of TRAIL in treating GBM, most research has focused on developing methods to sensitize GBM to TRAIL treatment through two major directions: increasing TRAIL bioavailability via constructing efficient TRAIL delivery system and enhancing TRAIL tumoricidal activity through combining sensitizing drugs.
The clinical application of TRAIL is largely hindered by its short serum half-life and lack of efficient delivery approaches. In recent years, developing nanoparticles as carriers in gene therapy has been considered as an effective approach to increase TRAIL delivery to tumors as transfected cells will specifically secrete TRAIL into the tumor microenvironment. However, another huge obstacle for gene delivery to GBM in the brain is to cross the blood–brain barrier, and most delivery vehicles fail to generate high gene transfection efficiency in vivo
[1]
. By developing a targeted iron oxide nanoparticle coated with chitosan-polyethylene glycol-polyethyleneimine copolymer and chlorotoxin, one study has found that this delivery system successfully delivers TRAIL into human GBM cells and induces secretion of TRAIL in vitro and in vivo, resulting in near-zero tumor growth and induces apoptosis in tumor tissue
[2]
. This study suggests that nanoparticle-mediated TRAIL delivery can serve as a potential targeted therapeutic for more efficient TRAIL delivery to GBM. A similar concept has been applied to human adipose-derived stem cells (hADSCs), in which polymeric nanoparticles, as a drug-delivery vehicle, mediate the overexpression of TRAIL for targeting and eradicating GBM cells in vivo and prolong animal survival
[3]
. A recent study also reveals that TRAIL sensitivity in GBM cells can be enhanced by conjugation of TRAIL with silver nanoparticles, further supporting nanoparticle delivery to be a promising therapeutic approach to bypass consumption of TRAIL in circulation and effectively increase the TRAIL dose in tumor lesions for sensitizing TRAIL resistance
[4]
.
Most chemotherapeutic drugs kill cancer cells predominantly by triggering the apoptotic program. Increasing evidence has shown that several chemotherapeutic drugs treated in combination with TRAIL can result in the reversal of GBM resistance to TRAIL-mediated apoptosis. For example, combined TRAIL plus paclitaxel have cooperative anti-GBM efficacy in vivo, particularly with no discernable toxicity to normal tissue
[5]
. Analogically, co-delivery of the TRAIL gene also enhances the antitumor activity of paclitaxel against GBM cells in vitro and in vivo
[6]
. Except paclitaxel, a synergistic anti-GBM effect has been validated between TRAIL and cisplatin, as evidenced by cisplatin-enhanced sensitivity of GBM cells to adenovirus-delivered TRAIL
[7]
, and cisplatin-restored activation of the TRAIL apoptotic pathway in GBM-derived stem cells
[8]
. Moreover, doxorubicin and mitoxantrone were also identified as TRAIL-sensitizing agents for GBM
. Interestingly, L-asparaginase, a metabolic enzyme used in the treatment of acute lymphatic leukaemia by hydrolyzing asparagine, potently overcomes GBM cell resistance to TRAIL-induced extrinsic apoptosis
[11]
. Together, these preclinical observations suggest the therapeutic potential of combining TRAIL plus chemotherapeutic drugs in GBM treatment and encourage further preclinical and future clinical tests.
Compared with chemotherapeutic drugs, efficacious synergistic effects of non-chemotherapeutic agents and TRAIL may be uncommon. However, evidence has indicated that lovastatin, a lipid-reducing drug, enhances TRAIL-induced GBM cell apoptosis synergistically
[12]
. Another example is salinomycin, an antibiotic used in the poultry industries to eliminate coccidiosis, which potentiates the cytotoxic effects of TRAIL on GBM cell lines
[13]
. Moreover, quinacrine is a small molecule antimalarial agent that was recently recognized with anticancer potentials
[14]
, and it has been demonstrated that quinacrine is able to mediate the sensitization of GBM cells to TRAIL treatment
[15]
, suggesting a combination treatment for GBM therapy. Other non-chemotherapeutic drugs exhibiting TRAIL-sensitizing activity include nelfinavir
[16]
, troglitazone
[17]
, digitoxin
[18]
, melatonin
[19]
, and Lanatoside C
[20]
. One of the limitations of these studies is a shortage of clarity regarding the molecular mechanisms accounting for the synergistic effects of these non-chemotherapeutic drugs and TRAIL, which require further investigations.
Aside from inhibitors of the Akt-mTOR-S6K1 pathway, KPNB1, and PIM kinases, a large growing body of studies have also shown that a variety of inhibitors that do not belong to therapeutic drugs but sensitize GBM to TRAIL-induced apoptosis. For instance, histone deacetylase inhibitors (HDACIs), such as MS275, suberoylanilide hydroxamic acid and valproic acid, sensitize GBM cells to TRAIL-induced apoptosis in vitro and in vivo through c-myc-downregulated c-FLIP
[21]
, suggesting the use of HDACIs in order to prime GBM for TRAIL-induced apoptosis by targeting c-FLIP. Since the anti-apoptotic Bcl-2 family members play a critical role in determining GBM sensitivity to TRAIL-induced apoptosis, inhibitors of this family members (BH3-mimetics), such as ABT-737
[22]
and ABT-199
[23]
, were found to cooperate with TRAIL to induce apoptosis in several GBM cell lines in a highly synergistic manner. These results outline the antagonism of surviving machinery as a highly potent intervention to sensitize GBM cells to TRAIL combination treatment. Protein synthesis inhibitors, such as cycloheximide, can reverse the resistance of some cancer cells to TRAIL
[24]
. Two studies have revealed that the proteasome inhibitor bortezomib primes GBM, including GBM stem cells, for TRAIL sensitization, which is dependent on increased tBid stability, mitochondrial apoptosis, and modulation of the NF-κB signaling pathway
. Consistent with these reports, pretreating GBM with bortezomib potentiates natural killer cell cytotoxicity to induce TRAIL-mediated apoptosis and prolongs animal survival
[27]
. Taken together, these findings provide compelling evidence that the combination of bortezomib and TRAIL presents a promising strategy to promote TRAIL sensitization and trigger apoptosis in GBM.
Owing to excusive the tumoricidal property revealed by a large amount of pre-clinical and clinical studies, it is believed that targeting the TRAIL/TRAIL-R1/R2 axis holds great promise to be harnessed in combinatorial therapies for treating cancers, including GBM, a deadly cancer without efficacious therapeutic options. However, employing either recombinant human TRAIL or agonist antibodies against TRAIL-R1/2 to reactive the extrinsic apoptosis pathway in cancer cells for cancer therapy has yielded undesirable outcomes in previous clinical trials, casting a shadow over the future clinical applications of this strategy. Currently, seeking methods to overcome TRAIL resistance for enhancing TRAIL efficacy is a research focus. As with many cancers, the majority of GBM tumors are generally resistant to TRAIL-induced apoptosis largely due to several aberrations in genetics that result in low or loss of expression of apoptotic genes and simultaneous overexpression of anti-apoptotic genes, which comprise the TRAIL-induced apoptotic signaling pathway. Attempts to understand the mechanisms of TRAIL-induced apoptotic signaling in GBM have unraveled novel regulators in promoting or inhibiting TRAIL resistance, mainly through modulating the levels or activation of TRAIL-R1/R2, c-FLIP, caspase-8, and DISC. These studies provide novel therapeutic targets that can potentially interfere the resistance mechanisms to overcome GBM resistance to TRAIL-based therapies. Another strategy to improve the therapeutic efficacy of TRAIL and sensitize TRAIL resistance in GBM is through developing more effective approaches of delivering a sufficient amount of TRAIL to tumor lesions in the brain. Recent studies have shown the advantages of nanoparticles in increasing the delivery efficiency of TRAIL to sensitize GBM to TRAIL treatment. In addition, sensitizing GBM to TRAIL-induced apoptosis has proven effective by multiple preclinical studies through the combinatorial treatment of TRAIL with other agents, such as some commonly used chemotherapeutic and non-chemotherapeutic drugs and synthetic inhibitors. According to these progresses in overcoming TRAIL resistance in GBM, we expect more clinical trials will participate to test the therapeutic potency and safety of TRAIL-based combination modalities in GBM treatment. Finally, however, despite the abovementioned advances, how GBM tumors acquire TRAIL resistance is still not fully understood, and the mechanisms underlying synergistic effect of TRAIL and chemotherapeutic or non-chemotherapeutic drugs remain largely unexploited. Addressing these challenges is needed to overcome TRAIL resistance for maximizing the therapeutic potential of TRAIL in treating GBM.