BIBR1532 combined with radiotherapy induces ferroptosis in NSCLC cells and activates cGAS-STING pathway to promote anti-tumor immunity.

BACKGROUND: Telomerase, by safeguarding damaged telomeres and bolstering DNA damage repair, has the capacity to heighten the radioresistance of tumour cells. Thus, in turn, can compromise the efficacy of radiotherapy (RT) and radioimmunotherapy. Our previous studies have revealed that the highly selective telomerase inhibitor, BIBR1532, possesses the potential to enhance the radiosensitivity of Non-small cell lung cancer (NSCLC). In this study, we delve further into the impact of BIBR1532 on the immune activation induced by RT and elucidate the underlying mechanisms. METHODS: Biological information analyses, immunofluorescence assays, western blot assays, flow cytometry analysis were conducted to elucidate the functions of the combination of BIBR1532 with radiotherapy in NSCLC. Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Both in vitro and in vivo studies were conducted to examine the antitumor effects. RESULTS: Our findings indicate that the confluence of BIBR1532 with RT significantly augments the activation of the cGAS-STING pathway in both in vivo and in vitro settings, thereby fostering an effective anti-tumoral immune response. The effects can be ascribed to two key processes. Firstly, ionizing radiation, in precipitating DNA double-strand breaks (DSBs), prompts the release of tumour-derived double-stranded DNA (dsDNA) into the cytoplasm. Subsequently, BIBR1532 amplifies the activation of antigen-presenting cells by dsDNA post-RT and instigates the cGAS-STING pathway. Secondly, BIBR1532 enhances the ferroptosis response in NSCLC following RT, thereby promoting unrestrained lipid peroxidation and elevated levels of reactive oxygen species (ROS) within tumour cells. This ultimately leads to mitochondrial stress and the release of endogenous mitochondrial DNA (mtDNA) into the cytoplasm, thus facilitating the activation of the STING pathway and the induction of a type I interferon (IFN)-linked adaptive immune response. CONCLUSION: This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC.

Silencing PinX1 enhances radiosensitivity and antitumor-immunity of radiotherapy in non-small cell lung cancer.

BACKGROUND: We aimed to investigate the effects of PinX1 on non-small cell lung cancer(NSCLC) radiosensitivity and radiotherapy-associated tumor immune microenvironment and its mechanisms. METHODS: The effect of PinX1 silencing on radiosensitivity in NSCLC was assessed by colony formation and CCK8 assay, immunofluorescence detection of γ- H2AX and micronucleus assay. Western blot was used to assess the effect of PinX1 silencing on DNA damage repair pathway and cGAS-STING pathway. The nude mouse and Lewis lung cancer mouse model were used to assess the combined efficacy of PinX1 silencing and radiotherapy in vivo. Changes in the tumor immune microenvironment were assessed by flow cytometry for different treatment modalities in the Lewis luuse model. The interaction protein RBM10 was screened by immunoprecipitation-mass spectrometry. RESULTS: Silencing PinX1 enhanced radiosensitivity and activation of the cGAS-STING pathway while attenuating the DNA damage repair pathway. Silencing PinX1 further increases radiotherapy-stimulated CD8+ T cell infiltration and activation, enhances tumor control and improves survival in vivo; Moreover, PinX1 downregulation improves the anti-tumor efficacy of radioimmunotherapy, increases radioimmune-stimulated CD8+ T cell infiltration, and reprograms M2-type macrophages into M1-type macrophages in tumor tissues. The interaction of PinX1 and RBM10 may promote telomere maintenance by assisting telomerase localization to telomeres, thereby inhibiting the immunostimulatory effects of IR. CONCLUSIONS: In NSCLC, silencing PinX1 significantly contributed to the radiosensitivity and promoted the efficacy of radioimmunotherapy. Mechanistically, PinX1 may regulate the transport of telomerase to telomeres through interacting with RBM10, which promotes telomere maintenance and DNA stabilization. Our findings reveal that PinX1 is a potential target to enhance the efficacy of radioimmunotherapy in NSCLC patients.

Role of NAT10-mediated ac4C-modified HSP90AA1 RNA acetylation in ER stress-mediated metastasis and lenvatinib resistance in hepatocellular carcinoma.

Emerging evidence showed that epigenetic regulation plays important role in the pathogenesis of HCC. N4-acetocytidine (ac4C) was an acetylation chemical modification of mRNA, and NAT10 is reported to regulate ac4C modification and enhance endoplasmic reticulum stress (ERS) in tumor metastasis. Here, we report a novel mechanism by which NAT10-mediated mRNA ac4C-modified HSP90AA1 regulates metastasis and tumor resistance in ERS of HCC. Immunohistochemical, bioinformatics analyses, and in vitro and in vivo experiments, e.g., acRIP-Seq, RNA-Seq, and double luciferase reporter experiment, were employed to investigate the effect of NAT10 on metastasis and drug resistance in HCC. The increased expression of NAT10 was associated with HCC risk and poor prognosis. Cell and animal experiments showed that NAT10 enhanced the metastasis ability and apoptosis resistance of HCC cells in ERS and ERS state. NAT10 could upregulate the modification level of HSP90AA1 mRNA ac4C, maintain the stability of HSP90AA1, and upregulate the expression of HSP90AA1, which further promotes the metastasis of ERS hepatoma cells and the resistance to apoptosis of Lenvatinib. This study proposes a novel mechanism by which NAT10-mediated mRNA ac4C modification regulates tumor metastasis. In addition, we demonstrated the regulatory effect of NAT10-HSP90AA1 on metastasis and drug resistance of ERS in HCC cells.

Anlotinib enhances the antitumor immunity of radiotherapy by activating cGAS/STING in non-small cell lung cancer.

Radiation resistance and unsatisfactory efficacy of radioimmunotherapy are important barriers to non-small cell lung cancer (NSCLC) treatment. The impacts of anlotinib on radiation and tumor immune microenvironment (TIME) in NSCLC remain to be resolved. Here, we find anlotinib enhances radiosensitivity, and further increases radiotherapy-stimulated CD8+ T cell infiltration and activation via triggering cGAS/STING pathway. Moreover, anlotinib shows significant effects on radioimmunotherapy (radiotherapy plus anti-PD-L1). The addition of anlotinib alleviates CD8+ T cell exhaustion, promotes the cytotoxicity and proliferation of CD8+ T cells, and boosts immune memory activation. Our work reveals the crucial role of anlotinib in antitumor immunity, and provides preclinical evidence for the application of anlotinib combined with radioimmunotherapy in NSCLC treatment.

Bacteria-Based Synergistic Therapy in the Backdrop of Synthetic Biology.

Although the synergistic effect of traditional therapies combined with tumor targeting or immunotherapy can significantly reduce mortality, cancer remains the leading cause of disease related death to date. Limited clinical response rate, drug resistance and off-target effects, to a large extent, impede the ceilings of clinical efficiency. To get out from the dilemmas mentioned, bacterial therapy with a history of more than 150 years regained great concern in recent years. The rise of biological engineering and chemical modification strategies are able to optimize tumor bacterial therapy in highest measure, and meanwhile avoid its inherent drawbacks toward clinical application such as bacteriotoxic effects, weak controllability, and low security. Here, we give an overview of recent studies with regard to bacteria-mediated therapies combined with chemotherapy, radiotherapy, and immunotherapy. And more than that, we review the bacterial detoxification and targeting strategies via biological reprogramming or chemical modification, their applications, and clinical transformation prospects.

Comparative Efficacy and Safety of Common Therapies in Keloids and Hypertrophic Scars: A Systematic Review and Meta-analysis.

OBJECTIVES: At present, there are many therapies for treating keloids and hypertrophic scars, but there is still a lack of treatments that are relatively balanced in efficacy and safety. The study aims to evaluate comprehensively efficacy and safety of common therapies in keloids and hypertrophic scars. METHODS: The literature search was conducted up to May 2019. The traditional meta-analysis was performed on 17 therapies. Bayesian network meta-analysis was conducted on the four most common treatments. The outcome indicators were the numbers of patients with good-to-excellent effect, Vancouver Scar Scale (VSS) and adverse events. RESULTS: There was no significant difference in the efficacy of triamcinolone acetonide (TAC) compared with other monotherapies except for silicone gel sheet and neodymium-yttrium-aluminum-garnet in primary indicator. The combination therapies were superior to TAC, and the results were consistent after the pooled analysis (RR = 0.522, 95% CI 0.332-0.823). The level of VSS in TAC group was higher than that in 5-flurouracil (5-FU) and TAC + 5-FU group, but lower than that in verapamil (VER) group. And the patients treated with TAC were less safe than those treated with verapamil (P = 0.013). Surface under cumulative ranking ranked verapamil and TAC + 5-FU as the favorable efficacy therapies in terms of primary indicator and ranked TAC + 5-FU as the best therapy for VSS, while VER was ranked as the worst. CONCLUSION: This meta-analysis showed that TAC + 5-FU may be the most effective therapy, while verapamil may be a better therapeutic strategy for safety. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Inhibitory effects of octreotide on the progression of hepatic fibrosis via the regulation of Bcl-2/Bax and PI3K/AKT signaling pathways.

In a previous study, we showed that octreotide alleviate hepatic fibrosis. However, its underlying molecular mechanisms are still poorly understood. In the current study, rats with CCl4-induced liver injury and Hepatic Stellate Cells (HSCs) were employed for in vitro and in vivo studies to observe the effects of octreotide on progression of liver fibrosis. The results in rats indicated that octreotide remarkably alleviated hepatic injury. The treated rats showed improved pathological manifestations and reduced liver indicators, e.g., liver weight, liver index and liver hydroxyproline (Hyp) content. Additionally, activities of serum total bilirubin (TBIL), aspartate transaminase (AST) and alanine transaminase (ALT), and serum levels of hyaluronic acid (HA), laminin (LN), type IV collagen (IV-C) and procollagen III peptide (PIIIP) also decreased. Furthermore, releasing inflammatory factors and proliferation of activated HSCs under different treatments were detected in which levels of IL-1ß, IL-6, TNF-α decreased and hepatocytes proliferative capacity reduced through Bcl-2/Bax-dependent apoptosis. Finally, our results demonstrated that octreotide was able to exert an inhibitory effect on the activation of HSCs regulating the PI3K/AKT signaling pathway. In summary, our study corroborated that octreotide could prevent liver fibrosis probably via modulating Bcl-2/Bax and PI3K/AKT signaling pathway.

Octreotide attenuates hepatic fibrosis and hepatic stellate cells proliferation and activation by inhibiting Wnt/ß-catenin signaling pathway, c-Myc and cyclin D1.

Fibrosis is the common results from an excessive wound-healing response to chronic liver injury. Otreotide (OCT), an analogue of somatostatin, was reported to have an anti-hepatic fibrosis effect. However, its anti-fibrosis mechanisms have not been well characterized to date. The present study aimed to investigate the protective effects of OCT on carbon tetrachloride (CCl4)-induced rat liver fibrosis and activation and proliferation of transforming growth factor-ß1 (TGF-ß1)-treated hepatic stellate cells (HSCs) and explore its anti-hepatofibrotic mechanisms. Our results indicated that treatment with OCT markedly down-regulated the protein and mRNA expression of liver fibrosis markers including α-smooth muscle actin (α-SMA) and collagen I in CCl4-induced rat model of liver fibrosis, accompanied by decreasing aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin (TBIL) activities and increasing the serum level of albumin (ALB). In addition, in vitro results revealed that OCT inhibited the activation and proliferation of TGF-ß1-treated LX-2 cells in a concentration-dependent manner and decreased in parallel the expression of Wnt1, ß-catenin, c-Myc and cyclin D1, indicating that OCT might attenuate liver fibrosis, at least in part, by inhibiting Wnt/ß-catenin signaling pathway. Overall, these results provide a novel anti-fibrotic mechanism of OCT, which might be associated with its ability to repress Wnt/ß-catenin signaling pathway.