LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2α-ATF4-CHOP axis.

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1-25 µM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 µM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK-eIF2α-ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

LW-213, a newly synthesized flavonoid, induces G2/M phase arrest and apoptosis in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell neoplasm characterized by an uncontrolled proliferation of moderately and well differentiated cells of the granulocytic lineage. LW-213, a newly synthesized flavonoid compound, was found to exert antitumor effects against breast cancer through inducing G2/M phase arrest. We investigated whether LW-213 exerted anti-CML effects and the underlying mechanisms. We showed that LW-213 inhibited the growth of human CML cell lines K562 and imatinid-resistant K562 (K562r) in dose- and time-dependent manners with IC50 values at the low µmol/L levels. LW-213 (5, 10, 15 µM) caused G2/M phase arrest of K562 and K562r cells via reducing the activity of G2/M phase transition-related proteins Cyclin B1/CDC2 complex. LW-213 treatment induced apoptosis of K562 and K562r cells via inhibiting the expression of CDK9 through lysosome degradation, thus leading to the suppression of RNAPII phosphorylation, down-regulation of a short-lived anti-apoptic protein MCL-1. The lysosome inhibitor, NH4Cl, could reverse the anti-CML effects of LW-213 including CDK9 degradation and apoptosis. LW-213 treatment also degraded the downstream proteins of BCR-ABL1, such as oncoproteins AKT, STAT3/5 in CML cells, which was blocked by NH4Cl. In primary CML cells and CD34+ stem cells, LW-213 maintained its pro-apoptotic activity. In a K562 cells-bearing mice model, administration of LW-213 (2.5, 5.0 mg/kg, ip, every other day for 4 weeks) dose-dependently prolonged the survival duration, and significantly suppressed huCD45+ cell infiltration and expression of MCL-1 in spleens. Taken together, our results demonstrate that LW-213 may be an efficient agent for CML treatment.

Risk of gastrointestinal complications in breast cancer patients treated with neratinib: a meta-analysis.

BACKGROUNDS: Neratinib is a potent EGFR/HER2 kinase inhibitor. Gastrointestinal complications (i.e. diarrhea, vomiting and nausea) are the most common adverse events. In this study, we aimed to investigate (1) the overall incidence and relative risk (RR) of diarrhea, vomiting and nausea and (2) whether combination neratinib therapy increased the incidence of gastrointestinal complications versus neratinib alone. METHODS: Relevant studies were identified from the PubMed database, from abstracts presented at the American Society of Clinical Oncology annual conference and from the Web of Science database. Incidences, RRs, and 95% confidence intervals (CIs) were calculated. RESULTS: The incidences of all-grade diarrhea, vomiting and nausea in the neratinib groups were 89% (95% CI = 77-95%), 31% (95% CI = 25-37%) and 44% (95% CI = 33-55%), respectively. The neratinib arms significantly increased the risk of diarrhea and vomiting in comparison with the control groups (diarrhea: all-grade, RR = 2.06, 95% CI = 1.38-3.08, P = 0.0004; grade 3/4, RR = 8.77, 95% CI = 2.91-26.40, P = 0.0001; vomiting: all-grade, RR = 2.02, 95% CI = 1.10-3.71, P = 0.02; grade 3/4, RR = 7.10, 95% CI = 3.33-15.15, P < 0.00001). CONCLUSIONS: Our meta-analysis demonstrates that the neratinib arms are associated with a significantly increased risk of diarrhea and vomiting.

Does the addition of drugs targeting the vascular endothelial growth factor pathway to first-line chemotherapy increase complete response? A meta-analysis of randomized clinical trials.

Drugs targeting the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling (anti-VEGF/VEGFR drugs) are the most validated anti-angiogenic strategies for cancer treatment. Complete response (CR) is a rare event in cancer patients receiving chemotherapy. A meta-analysis was conducted to determine whether adding anti-VEGF/VEGFR drugs to chemotherapy can further increase the chance of CR in the first-line therapy. Relevant databases were systematically searched for the period 2000-2015. Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The incidence, relative risk (RR), and 95 % confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 12,453 patients from 28 randomized controlled trials were included. The overall incidence of CR in patients treated with anti-VEGF/VEGFR drugs plus chemotherapy was 1.5 % (95 % CI, 1.0-2.0 %) compared to 1.1 % (95 % CI, 0.7-1.4 %) in the chemotherapy-alone arm. Adding anti-VEGF/VEGFR drugs was associated with significant improvement of CR (RR, 1.52, 95 % CI, 1.18-1.95, P = 0.001). When stratified by drug type, adding VEGFR tyrosin kinase inhibitors (TKIs) did not increase the chance of CR (RR, 0.87, 95 % CI, 0.51-1.49; P = 0.614). The addition of bevacizumab with 7.5 mg/kg every 3 weeks, but not 15 mg/kg every 3 weeks, significantly improves the CR (7.5 mg, RR, 2.43, 95 % CI, 1.64-3.60, P = 0.000; 15 mg, RR, 1.07, 95 % CI, 0.63-1.81, P = 0.799). In subgroup analysis, a significant improvement of CR by the addition of anti-VEGF/VEGFR drugs was observed in patients with colorectal cancer (RR, 2.10, 95 % CI 1.21-3.63, P = 0.008), ovarian cancer (RR, 3.07; 95 % CI, 1.68-5.62, P = 0.000), and patients who are treated with platinum-based regimens (RR, 1.78, 95 % CI, 1.23-2.59, P = 0.002). Low-dose bevacizumab, rather than VEGFR TKIs or high-dose bevacizumab, can increase the chance of CR in patients receiving chemotherapy.