A small-molecule mimetic of Smac/Diablo that specifically counters the apoptosis-inhibiting activity of IAP proteins has been shown to enhance apoptosis induced by cell surface death receptors as well as chemotherapeutic drugs. Survey of a panel of 50 human non-small-cell lung cancer cell lines has revealed, surprisingly, that roughly one-quarter of these lines are sensitive to the treatment of Smac mimetic alone, suggesting that an apoptotic signal has been turned on in these cells and is held in check by IAP proteins. This signal has now been identified as the autocrine-secreted cytokine tumor necrosis factor alpha (TNFalpha). In response to autocrine TNFalpha signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis.

A poptosis in mammalian cells is executed by the proteolytic activities of caspases that are activated in response to apoptotic stimuli via two distinct signaling pathways 1 . These pathways have different initiator caspases that cleave and activate a common set of executioner caspases, including caspases 3, 6 and 7. The intrinsic (or mitochondrial) pathway of apoptosis is activated in response to DNA damage and other stress signals within the cell. Cytochrome c is consequently released from mitochondria into the cytosol and binds its adaptor protein, Apaf-1, to form the large 'apoptosome' complex, which recruits and activates caspase-9 (ref. 2). The extrinsic pathway is triggered from the exterior of the cell by members of the TNF superfamily, which bind and activate their corresponding death receptors [3][4][5] . For example, binding of TRAIL to the extracellular domain (ECD) of the death receptors DR4 (TRAIL-Receptor 1 (TRAIL-R1)) and DR5 (TRAIL-R2) promotes clustering of these receptors. The ligand-receptor complex in turn engages the adaptor protein Fas-associated death domain (FADD) via its cytoplasmic death domains. FADD then recruits the initiator caspase-8 through its N-terminal death-effector domain to form a death-inducing signaling complex (DISC) [6][7][8][9] .Caspase activation is tightly regulated by members of the inhibitor of apoptosis protein (IAP) family, such as XIAP, cIAP1 and cIAP2 (refs. 10-12). In response to death signals, a second mitochondriaderived activator of apoptosis (Smac; also called Diablo) is released from the mitochondria into the cytosol, where it binds the Bir domains of XIAP to relieve its inhibition of caspases and the Bir domains of cIAPs to induce their degradation. The four N-terminal residues (alanine, valine, proline and isoleucine) of Smac are sufficient for this interaction and have been mimicked using a peptidomimetic approach to generate cell-permeable small molecules that function similarly to the Smac protein [13][14][15] . Previously, we demonstrated that Smac mimetics not only effectively kill cancer cell lines with an autocrine TNFα signal but also substantially increase the cell-killing efficiency of TRAIL [13][14][15] .Selective activation of the apoptotic pathway provides tremendous therapeutic potential for cancer treatment 16 . Various strategies are currently under active clinical investigation, including the use of Bcl-2 inhibitors, Smac mimetics or IAP antagonists and deathreceptor agonists 17 . Among the death receptor-targeted agents, the therapeutic use of TNFα and agonistic CD95-specific antibodies has been hampered by their toxic side effects, particularly a severe inflammatory response through NF-κB activation 3,18 . However, mounting evidence from clinical trials has indicated that targeting DR4 and DR5 with agonist antibodies or recombinant TRAIL selectively eliminates tumor cells while sparing normal cells 19,20 . Although targeting TRAIL pathways may be promising as a safe anticancer therapy, the clinical use of TRAIL itself is limited by it...

Recent studies reveal that chemotherapy can enhance metastasis due to host responses, such as augmented expression of adhesion molecules in endothelial cells and increased populations of myeloid cells. However, it is still unclear how tumour cells contribute to this process. Here, we observed that paclitaxel and carboplatin accelerated lung metastasis in tumour-bearing mice, while doxorubicin and fluorouracil did not. Mechanistically, paclitaxel and carboplatin induced similar changes in cytokine and angiogenic factors. Increased levels of CXCR2, CXCR4, S1P/S1PR1, PlGF and PDGF-BB were identified in the serum or primary tumour tissues of tumour-bearing mice treated by paclitaxel. The serum levels of CXCL1 and PDGF-BB and the tissue level of CXCR4 were also elevated by carboplatin. On the other hand, doxorubicin and fluorouracil did not induce such changes. The chemotherapy-induced cytokine and angiogenic factor changes were also confirmed in gene expression datasets from human patients following chemotherapy treatment. These chemotherapy-enhanced cytokines and angiogenic factors further induced angiogenesis, destabilized vascular integrity, recruited BMDCs to metastatic organs and mediated the proliferation, migration and epithelial-to-mesenchymal transition of tumour cells. Interestingly, inhibitors of these factors counteracted chemotherapy-enhanced metastasis in both tumour-bearing mice and normal mice injected intravenously with B16F10-GFP cells. In particular, blockade of the SDF-1α-CXCR4 or S1P-S1PR1 axes not only compromised chemotherapy-induced metastasis but also prolonged the median survival time by 33.9% and 40.3%, respectively. The current study delineates the mechanism of chemotherapy-induced metastasis and provides novel therapeutic strategies to counterbalance pro-metastatic effects of chemo-drugs via combination treatment with anti-cytokine/anti-angiogenic therapy.

Background Standard chemotherapy with taxanes, such as paclitaxel (PTX), remains the mainstay of systemic treatment of triple-negative breast cancer. Nanotechnology-based formulations have gradually replaced PTX injection and are widely used in China. However, no studies have compared the colloidal stability, antitumor efficacy, and safety of commercial PTX nanoformulations. Additionally, the desire to evaluate preclinical antitumor efficacy in human-derived tumor cells led to the widespread application of immunodeficient mouse models that likely contributed to the neglect of nanomedicines-immune system interactions. The present study investigated the colloidal stability, antitumor efficacy and safety, and nanomedicines-host immune system interactions of PTX nanoformulations. A further comparative analysis was performed to evaluate the clinical potential. Results Compared with liposome, PTX emulsion and PTX nanoparticle exhibited favorable colloidal stability. PTX emulsion was superior in inducing apoptosis and had a more pronounced inhibitory effect on 4T1-tumor spheroids compared with PTX liposome and PTX nanoparticle. Although PTX emulsion exhibited superior in vitro antitumor effect, no significant differences in the in vivo antitumor efficacy were found among the three types of PTX nanoformulations in an immunocompetent orthotopic 4T1 murine triple-negative breast cancer model. All PTX nanoformulations at maximum tolerated dose (MTD) induced lymphopenia and immunosuppression, as evidenced by the reduction of T cell subpopulations and inhibition of the dendritic cells maturation. Conclusions The MTD PTX nanomedicines-induced lymphopenia and immunosuppression may weaken the lymphocyte-mediated antitumor cellular immune response and partly account for the lack of differences in the in vivo antitumor outcomes of PTX nanoformulations. Understanding of what impacts PTX nanomedicines has on the immune system may be critical to improve the design and conduct of translational research of PTX nanomedicines in monotherapy or combination therapy with immunotherapy. Graphic abstract

Background and methods: A Cu-doped composite scaffold of nano calcium-deficient hydroxyapatite (n-CDHA)/multi(amino acid) copolymer (MAC) was prepared. The structure, porosity, morphology and compressive strength of the scaffolds were characterized, the in vitro degradability in phosphate-buffered solution (PBS) and cell responses to the scaffolds were investigated, and in vivo stimulation of bone formation were analyzed. Results: The scaffolds showed the compressive strength of approximately 12 MPa and total porosity of about 81%. Weight loss of the composite scaffolds was 63% after 16-week immersion in PBS. Cu release in scaffolds showed a marked dependence on the initial amount in the scaffolds over time. Cu-doped n-CDHA/MAC scaffolds with the content of Cu 0.5% and 1% in mass ratio showed better cell responses to proliferation and differentiation of rat bone marrow stromal cells (rBMSCs) than that with no Cu. After 12-week implantation in rabbits, 1% Cu-doped n-CDHA/MAC showed better ability of angiogenesis and osteogenesis compared to 0% Cu-doped n-CDHA/MAC. Conclusion: The 1% Cu-doped n-CDHA/MAC composite scaffold showed good capacity of angiogenesis and osteogenesis, and the Cu showed positive effects on cell growth and osteogenesis. And it has potential to be used as bone regeneration scaffolds.