Selective activation of TNFR1 and NF-κB inhibition by a novel biyouyanagin analogue promotes apoptosis in acute leukemia cells

Background: Acquired resistance towards apoptosis is a hallmark of cancer. Elimination of cells bearing activated oncogenes or stimulation of tumor suppressor mediators may provide a selection pressure to overcome resistance. KC-53 is a novel biyouyanagin analogue known to elicit strong anti-inflammatory and anti-viral activity. The current study was designed to evaluate the anticancer efficacy and molecular mechanisms of KC-53 against human cancer cells. Methods: Using the MTT assay we examined initially how KC-53 affects the proliferation rates of thirteen representative human cancer cell lines in comparison to normal peripheral blood mononuclear cells (PBMCs) and immortalized cell lines. To decipher the key molecular events underlying its mode of action we selected the human promyelocytic leukemia HL-60 and the acute lymphocytic leukemia CCRF/CEM cell lines that were found to be the most sensitive to the antiproliferative effects of KC-53. Results: KC-53 promoted rapidly and irreversibly apoptosis in both leukemia cell lines at relatively low concentrations. Apoptosis was characterized by an increase in membrane-associated TNFR1, activation of Caspase-8 and proteolytic inactivation of the death domain kinase RIP1 indicating that KC-53 induced mainly the extrinsic/death receptor apoptotic pathway. Regardless, induction of the intrinsic/mitochondrial pathway was also achieved by Caspase-8 processing of Bid, activation of Caspase-9 and increased translocation of AIF to the nucleus. FADD protein knockdown restored HL-60 and CCRF/CEM cell viability and completely blocked KC-53-induced apoptosis. Furthermore, KC-53 administration dramatically inhibited TNFα-induced serine phosphorylation on TRAF2 and on IκBα hindering therefore p65/NF-κΒ translocation to nucleus. Reduced transcriptional expression of pro-inflammatory and pro-survival p65 target genes, confirmed that the agent functionally inhibited the transcriptional activity of p65. Conclusions: Our findings demonstrate, for the first time, the selective anticancer properties of KC-53 towards leukemic cell lines and provide a detailed understanding of the molecular events underlying its dual anti-proliferative and pro-apoptotic properties. These results provide new insights into the development of innovative and targeted therapies for the treatment of some forms of leukemia

Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis

Introduction Basal-like breast cancer (BLBC) is an aggressive subtype often characterized by distant metastasis, poor patient prognosis, and limited treatment options. Therefore, the discovery of alternative targets to restrain its metastatic potential is urgently needed. In this study, we aimed to identify novel genes that drive metastasis of BLBC and to elucidate the underlying mechanisms of action. Methods An unbiased approach using gene expression profiling of a BLBC progression model and in silicoleveraging of pre-existing tumor transcriptomes were used to uncover metastasis-promoting genes. Lentiviral-mediated knockdown of interleukin-13 receptor alpha 2 (IL13Ralpha2) coupled with whole-body in vivo bioluminescence imaging was performed to assess its role in regulating breast cancer tumor growth and lung metastasis. Gene expression microarray analysis was followed by in vitro validation and cell migration assays to elucidate the downstream molecular pathways involved in this process. Results We found that overexpression of the decoy receptor IL13Ralpha2 is significantly enriched in basal compared with luminal primary breast tumors as well as in a subset of metastatic basal-B breast cancer cells. Importantly, breast cancer patients with high-grade tumors and increased IL13Ralpha2 levels had significantly worse prognosis for metastasis-free survival compared with patients with low expression. Depletion of IL13Ralpha2 in metastatic breast cancer cells modestly delayed primary tumor growth but dramatically suppressed lung metastasis in vivo. Furthermore, IL13Ralpha2 silencing was associated with enhanced IL-13-mediated phosphorylation of signal transducer and activator of transcription 6 (STAT6) and impaired migratory ability of metastatic breast cancer cells. Interestingly, genome-wide transcriptional analysis revealed that IL13Ralpha2 knockdown and IL-13 treatment cooperatively upregulated the metastasis suppressor tumor protein 63 (TP63) in a STAT6-dependent manner. These observations are consistent with increased metastasis-free survival of breast cancer patients with high levels of TP63 and STAT6 expression and suggest that the STAT6-TP63 pathway could be involved in impairing metastatic dissemination of breast cancer cells to the lungs. Conclusion Our findings indicate that IL13Ralpha2 could be used as a promising biomarker to predict patient outcome and provide a rationale for assessing the efficacy of anti-IL13Ralpha2 therapies in a subset of highly aggressive basal-like breast tumors as a strategy to prevent metastatic disease

Lattice QCD and Particle Physics

Contribution from the USQCD Collaboration to the Proceedings of the US Community Study on the Future of Particle Physics (Snowmass 2021).Comment: 27 pp. main text, 4 pp. appendices, 30 pp. reference

Lattice QCD and Particle Physics

Contribution from the USQCD Collaboration to the Proceedings of the US Community Study on the Future of Particle Physics (Snowmass 2021)

Drug Delivery Innovations for Enhancing the Anticancer Potential of Vitamin E Isoforms and Their Derivatives

Vitamin E isoforms have been extensively studied for their anticancer properties. Novel drug delivery systems (DDS) that include liposomes, nanoparticles, and micelles are actively being developed to improve Vitamin E delivery. Furthermore, several drug delivery systems that incorporate Vitamin E isoforms have been synthesized in order to increase the bioavailability of chemotherapeutic agents or to provide a synergistic effect. D-alpha-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) is a synthetic derivative of natural alpha-tocopherol which is gaining increasing interest in the development of drug delivery systems and has also shown promising anticancer effect as a single agent. This review provides a summary of the properties and anticancer effects of the most potent Vitamin E isoforms and an overview of the various formulations developed to improve their efficacy, with an emphasis on the use of TPGS in drug delivery approaches

Update on the Anti-Cancer Potency of Tocotrienols and α-Tocopheryl Polyethylene Glycol 1000 Succinate on Leukemic Cell Lines

The natural isoforms of vitamin E γ-tocotrienol (γ-ΤΤ) and δ-tocotrienol (δ-ΤΤ) and the synthetic derivative α-tocopheryl polyethylene glycol 1000 succinate (TPGS) have promising anticancer potency in a variety of cancer cell lines and animal models of cancer. Ongoing clinical trials are investigating the anti-tumor effectiveness of TTs in combination with chemotherapeutic agents in patients suffering from breast, colon, non-small cell lung and ovarian cancers. Despite extensive research on different types of cancer, the anticancer potency of TTs and TPGS has not been thoroughly investigated in leukemias. Given the fact that certain types of leukemias have very low survival rates and that patients suffer significantly from the toxic side effects of chemotherapeutic drugs, there is a need to develop novel treatments with increased specificity against cancer cells and reduced toxicity to the patients. The aim of this review is to report current evidence on the anticancer potency of TTs and TPGS on leukemic cells lines and to discuss future studies that could be carried out to investigate the role of these agents in the management of leukemias

Phenoxodiol, an anticancer isoflavene, induces immunomodulatory effects in vitro and in vivo

Phenoxodiol (PXD) is a synthetic analogue of the plant isoflavone genistein with improved anticancer efficacy. Various properties and mechanisms of action have been attributed to the drug, the most important being its ability to sensitize resistant tumour cells to chemotherapy, which led to its fast track FDA approval for phase II/III clinical trials. In this study, we examined the effects of PXD on human peripheral blood mononuclear cells (PBMC) and its potential role in regulating immune responses. We show that PXD, at concentrations ≥1 μg/ml (4 μM), inhibited proliferation and reduced the viability of healthy donor-derived PBMC. In contrast, lower PXD concentrations (0.05-0.5 μg/ml) augmented, upon 3-day incubation, PBMC cytotoxicity. Experiments with purified CD56 + lymphocytes revealed that PXD enhanced the lytic function of natural killer (NK) cells by directly stimulating this lymphocytic subpopulation. Furthermore, in an in vivo colon cancer model, Balb/C mice administered low-dose PXD, exhibited significantly reduced tumour growth rates and prolonged survival (in 40% of the animals). Ex vivo results showed that PXD stimulated both NK and tumour-specific cell lytic activity. We conclude that PXD, when administered at low concentrations, can act as an immunomodulator, enhancing impaired immune responses, often seen in cancer-bearing individuals. © 2009 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd