Doxorubicin sensitizes human tumor cells to NK cell‐ and T‐cell‐mediated killing by augmented TRAIL receptor signaling

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat different types of malignancy. In this study, it was studied whether DOX could be used to render tumor cells susceptible to apoptosis by NK and T cells. Pretreatment with subapoptotic doses of DOX sensitized tumor cell lines of various histotypes to both NK and T cells resulting in a 3.7 to 32.7% increase in lysis (2.5 mean fold increase, p < 0.0001) and a 2.9 to 14.2% increase in lysis (3.0 mean-fold increase, p < 0.05), respectively. The sensitizing effect of the drug was primarily dependent on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptor signaling, but not on Fas-ligand, perforin, NKG2D or DNAM-1. The central role of the TRAIL signaling pathway was further supported by an increased expression of TRAIL-R2 on DOX-treated tumor cells and by downregulation of cellular FLICE inhibitory protein, the inhibitors of death receptor-mediated apoptosis. Compared to untreated cells, pretreatment of tumor cells with DOX showed increased processing and activation of caspase-8 on coculture with NK or T cells. The significance of this treatment strategy was confirmed using a xenogeneic tumor-bearing mouse model. Tumor progression was delayed in mice that received either NK cells (p < 0.05) or T cells (p < 0.0001) following DOX treatment compared to mice receiving either cell type alone. Moreover, combined infusion of both NK and T cells following DOX treatment not only delayed tumor progression but also significantly improved the long-term survival (p < 0.01). Based on these findings, it was proposed that DOX can be used to improve the efficacy of adoptive cell therapy in patients with cancer.Several studies have demonstrated that intratumoral infiltration of T cells and NK cells correlates with favorable prognosis in patients with cancer.

Pre-activated human mesenchymal stromal cells in combination with doxorubicin synergistically enhance tumor-suppressive activity in mice

“…Such effect was achieved by increasing the sensitivity of TRAIL by up-regulation of TRAIL death receptors and down-regulation of TRAIL decoy receptors. Although previous studies showed that doxorubicin sensitizes cancer cells by activating TRAIL receptors or caspase cascade [11,30,31], the combination treatment further increased expression of TRAIL receptors compared with doxorubicin alone treatment ( Figure 3D). In addition to the upregulation of TRAIL-related apoptosis pathway, we also observed that the combination therapy also upregulated additional cell death pathway, Fas.…”

Bringing natural killer cells to the clinic: ex vivo manipulation

“…Further, recent advances in our ability to expand NK cells ex vivo have fueled translational research investigating a variety of novel methods to bolster immunity against cancer through the use of adoptive NK cell infusions. [12][13][14][15][16] Until recently, the therapeutic potential of NK cell-based immunotherapy remained largely unexplored because the small number of NK cells isolated after a typical apheresis procedure and the inability to reliably expand large numbers of NK cells ex vivo precluded investigators from pursuing phase 1 trials evaluating for an NK cell dose-response relationship. At present, it is not at all clear what threshold of NK cell numbers is needed to achieve an antitumor effect after adoptive NK cell transfer.…”

Equol-induces apoptosis in chemoresistant ovarian cancer cells via external pathway

“…The extrinsic pathway can strengthen apoptosis initiated by the cytotoxic drugs. However, there are reports that other anti-cancer drugs stimulate expression of TRAIL (Barbetti et al, 2013, Wennerberg et al, 2013. Actually, equol is one of the most potent anti-oxidant among isoflavones (Arora et al, 1998).…”