Combination of TRAIL and actinomycin D liposomes enhances antitumor effect in non-small cell lung cancer

Abstract

Abstract:The intractability of non-small cell lung cancer (NSCLC) to multimodality treatments plays a large part in its extremely poor prognosis. Tumor necrosis factor-related apoptosisinducing ligand (TRAIL) is a promising cytokine for selective induction of apoptosis in cancer cells; however, many NSCLC cell lines are resistant to TRAIL-induced apoptosis. The therapeutic effect can be restored by treatments combining TRAIL with chemotherapeutic agents. Actinomycin D (ActD) can sensitize NSCLC cells to TRAIL-induced apoptosis by upregulation of death receptor 4 (DR4) or 5 (DR5). However, the use of ActD has significant drawbacks due to the side effects that result from its nonspecific biodistribution in vivo. In addition, the short half-life of TRAIL in serum also limits the antitumor effect of treatments combining TRAIL and ActD. In this study, we designed a combination treatment of long-circulating TRAIL liposomes and ActD liposomes with the aim of resolving these problems. The combination of TRAIL liposomes and ActD liposomes had a synergistic cytotoxic effect against A-549 cells. The mechanism behind this combination treatment includes both increased expression of DR5 and caspase activation. Moreover, systemic administration of the combination of TRAIL liposomes and ActD liposomes suppressed both tumor formation and growth of established subcutaneous NSCLC xenografts in nude mice, inducing apoptosis without causing significant general toxicity. These results provide preclinical proof-of-principle for a novel therapeutic strategy in which TRAIL liposomes are safely combined with ActD liposomes.

Onto better TRAILs for cancer treatment

“…To engineer the NP-core, different chemical compositions have been used such as human serum albumin, 153 , 167 , 168 poly (lactic-co-glycolic) acid (PLGA) microspheres, 151 , 152 , 169 a combination of PEGylated heparin and poly- l -lysine, 154 magnetic ferric oxide 170 or liposomes. 67 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 Among them, thanks to their versatility, liposomes have emerged as the most versatile of these platforms. Moreover, liposomes can be easily modified size- and composition-wise depending on the desired physicochemical properties.…”

“…Concerning the manner in which TRAIL is integrated with the NPs, there are two different strategies: (i) to encapsulate TRAIL inside the particles so that they are released from the particle in a constant and stable manner; 151 , 152 , 153 , 154 , 169 , 173 , 174 , 175 , 176 or (ii) to attach TRAIL to the surface of the nanoparticles so that TRAIL gets immobilized, resembling the physiological membrane-bound protein, increasing its bioactivity. 168 , 170 , 171 , 172 , 177 , 178 , 179 …”

N-Acetyl-Glucosamine Sensitizes Non-Small Cell Lung Cancer Cells to TRAIL-Induced Apoptosis by Activating Death Receptor 5

“…Although A549 lung cancer cells are resistant to TRAIL treatment, they become sensitized when TRAIL is combined with other agents [32]. In the present study, we examined the effects of GlcNAc in combination with TRAIL.…”

“…However, studies have shown that many types of cancers, including some NSCLCs, are resistant to the apoptotic effects of TRAIL [32, 37-39]. It has been reported that absence of DR expression and clustering may be a major cause of resistance to TRAIL-based cancer therapy [18].…”

Houttuynia cordata Thunb extract modulates G0/G1 arrest and Fas/CD95-mediated death receptor apoptotic cell death in human lung cancer A549 cells

“…The death receptor apoptotic pathway has previously been proposed as an anti-cancer drug target in human lung cancer [39,40]. Traditional Chinese medicine (TCM) that could stimulate the death receptor apoptotic pathway should have therapeutic potential in human lung cancer treatment [41-43].…”