Accumulation of circulating myeloid-derived suppressor cell subsets: predicting poor clinical efficacy and prognosis through T cell suppression in non-Hodgkin's lymphoma.

Myeloid-derived suppressor cells (MDSCs) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's lymphoma (NHL) have not been systematically investigated. So, we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared with healthy donors. Notably, MDSCs, monocytic MDSCs, and CD14 + CD66b + MDSCs significantly increased in NHL patients compared with those with lymphadenitis donors. polymorphonuclear MDSCs (PMN-MDSCs), early-stage MDSCs (e-MDSCs), and the International Prognostic Index were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSCs emerged as an independent prognostic factor for PFS. PMN-MDSCs, e-MDSCs, and the International Prognostic Index were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSCs, PMN-MDSCs, e-MDSCs, and CD14 + CD66b + MDSCs experienced a shorter overall survival compared with those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSCs via involving arginase-1 and interleukin-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subset expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.

Specific inhibitory effects of guanosine on breast cancer cell proliferation.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Drug therapy for breast cancer is currently selected based on the subtype classification; however, many anticancer drugs are highly cytotoxic. Since intracellular levels of GTP are elevated in many cancer cells that undergo a specific cell proliferation cycle, GTP has potential as a target for cancer therapy. The present study focused on nucleosides and nucleotides and examined intracellular GTP-dependent changes in cell proliferation rates in normal (MCF-12A) and cancer (MCF-7) breast cell lines. Decreased cell proliferation due to a reduction in intracellular GTP levels by mycophenolic acid (MPA), an inosine monophosphate dehydrogenase inhibitor, was observed in both cell lines. The inhibitory effects of MPA on cell proliferation were suppressed when it was applied in combination with Guanosine (Guo), a substrate for GTP salvage synthesis, while the single exposure to Guo suppressed the proliferation of MCF-7 cells only. Although the underlying mechanisms remain unclear, since the inhibitory effects of Guo on cell proliferation did not correlate with GTP or ATP intracellular levels or the GTP/ATP ratio, there may be another cause besides GTP metabolism. Guo inhibited the proliferation of MCF-7, a human breast cancer cell line, but not MCF-12A, a human normal breast cell line. Further studies are needed to investigate the potential of applying Guo as a target for the development of a novel cancer treatment system.

Evodiamine induces apoptosis of leukemia cell line K562 VIA modulation of TRIB2/AKT pathway / 中国药理学通报

Aim To investigate the effects of Evodiamine (EVO) on proliferation and apoptosis of human leukemia cell line K562 and its potential mechanisms. Methods K562 cells were treated with EVO at different concentrations (0, 1, 2, 4, 8, 16, 32, 64 jxmol • L

Ligand-based discovery of small molecules suppressing cancer cell proliferation via autophagic flux inhibition.

Autophagy is a conserved self-degradation system closely related to cancer progression. Small molecule inhibitors of autophagy have proven to be efficient tools in cancer therapy and are in high demand. Here we report the discovery of two compounds (LZ02/01) capable of suppressing cancer cell proliferation via inhibiting autophagy flux and promoting apoptosis. Potential autophagy inhibitors were selected based on the pharmacophore model derived from the structures of known autophagy inhibitors. LZ02/01-mediated autophagy flux disruption and apoptosis promotion in breast and hepatocellular carcinoma cells (MCF-7 and Hep3B) were examined using a combination of molecular methods in vitro and in vivo. The synergistic tumor-suppressing effects of LZ02 and chloroquine were validated by adopting a xenograft mice model of human breast cancer. Two potential inhibitors (LZ02/01) targeting an autophagy pathway were discovered from the Enamine database. In both MCF-7 and Hep3B cells, LZ02 and LZ01 had the effect of causing the co-occurrence of autophagic flux inhibition and apoptosis induction, robustly suppressing the growth, proliferation, and cell cycle progression. Further tests revealed that FoxO3a and its downstream target genes regulating autophagy, apoptosis, and cell cycle progression were activated and overexpressed, suggesting such effects of LZ02/01 on autophagy and apoptosis were associated with the activation and overexpression of FoxO3a. In addition, LZ02/01-mediated apoptosis is not independent; it was verified to be promoted by autophagic flux inhibition. Meanwhile, synergistic effects on tumor growth reduction were detected in the xenograft mice model of human breast cancer simultaneously treated with LZ02 and chloroquine. Our findings suggest that LZ01 and LZ02 are potent in suppressing cancer cell proliferation and tumor growth through autophagic flux inhibition and apoptosis promotion. The synergistic anti-cancer effects of LZ02 with chloroquine may provide a rational basis for prospective cancer therapy. KEY MESSAGES: A ligand-based pharmacophore model of high quality is constructed to query hits and two novel scaffold lead compounds LZ01/02 were identified by high-throughput virtual screening. LZ01/02 works to inhibit autophagic flux by attenuating lysosome function. LZ01/02 induces apoptosis through autophagic flux inhibition and apoptosis is the main mechanism to inhibit MCF-7 and Hep3B cancer cell proliferation. The synergistic antitumor growth effects of LZ02 and chloroquine are verified in human xenograft model.

Phenotype properties and status of corticosteroid resistance among patients with uncontrolled asthma.

BACKGROUND: Control cannot be achieved in some asthmatics although optimal monitoring and treatment is administered. Glucocorticoid (GC) resistance is one of the reasons of poor asthma control. We aimed to investigate GC resistance by lymphocyte proliferation suppression test (LPST) in uncontrolled asthmatics. METHODS: After assessing asthma control level of 77 asthmatics their treatment was adjusted upon GINA guidelines. They were followed-up for three to six months and the patients who remained uncontrolled were accepted as uncontrolled patients. Steroid resistance test (SRT) was applied to them (7-14 days oral prednisolone) and the patients who were still uncontrolled and/or had a FEV1 increase <15% after SRT were assessed as the "case group" while the remaining composed the "control group". Optimal treatment was adjusted and at the end of a follow-up period LPST was performed to both groups. RESULTS: Fourteen of the case (n=22) and four (n=8) of the control groups could be evaluated by LPST. Proliferated lymphocytes were observed to be significantly suppressed in all dexamethasone concentrations in the control group (p=0.001). However, in the case group LPST was positive only at 10(-6) and 10(-4) concentrations although statistically not significant (p=0.147). There was no significant relationship between clinically GC resistance and LPST positivity (p=0.405). CONCLUSION: We determined that in vitro responses to the GCs were significantly declined in the uncontrolled asthma cases. An SRT alone does not seem to be very sensitive for evaluating GC sensitivity, LPST may be performed for demonstrating GC responsiveness in asthmatic patients in addition to SRT.