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The flavonoid morin from Moraceae induces apoptosis by modulation of Bcl-2 family members and Fas receptor in HCT 116 cells

It is evident based on literature that flavonoids from fruit can safely modulate cancer cell biology and induce apoptosis. Therefore, we investigated the anticancer activity of morin, a flavonoid which is plentiful in twigs of mulberry focusing on apoptosis, and its mechanisms. Morin upregulated the Fas receptor, and activates caspase-8, -9 and -3 in HCT-116 cells. Morin also activates Bid, and induced the loss of mitochondrial membrane potential (MMP, ∆Ψm) with Bax protein activation and cytochrome c release. In addition, morin induced ROS generation which was not blocked by N-acetylcysteine. Morin also suppressed Bcl-2 and cIAP-1, anti-apoptotic proteins, which may contribute to augmentation of morin-triggered apoptosis. As an upstream signaling pathway, suppressed Akt activity by morin was associated to apoptosis. This study suggests that morin induces caspase-dependent apoptosis through extrinsic pathway by upregulating Fas receptor as well as through the intrinsic pathway by modulating Bcl-2 and IAP family members, and ROS generation, and that Akt is the critical upstream signaling that regulates the apoptotic effect of morin in human colon cancer HCT-116 cells.

Prognostic impact of sarcopenia in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone

Sarcopenia is known to be related to an increased risk of chemotherapy toxicity and to a poor prognosis in patients with malignancy. We assessed the prognostic role of sarcopenia in patients with diffuse large B‐cell lymphoma (DLBCL).

Morin, a Flavonoid from Moraceae, Induces Apoptosis by Induction of BAD Protein in Human Leukemic Cells

Evidence suggests that phytochemicals can safely modulate cancer cell biology and induce apoptosis. Here, we investigated the anti-cancer activity of morin, a flavone originally isolated from members of the Moraceae family in human leukemic cells, focusing on apoptosis. An anti-cancer effect of morin was screened with several human leukemic cell lines. U937 cells were most sensitive to morin, where it induced caspase-dependent apoptosis in a dose-dependent manner. It also induced loss of MMP (ΔΨm) along with cytochrome c release, down-regulated Bcl-2 protein, and up-regulated BAX proteins. The apoptotic activity of morin was significantly attenuated by Bcl-2 augmentation. In conclusion, morin induced caspase-dependent apoptosis through an intrinsic pathway by upregulating BAD proteins. In addition, Bcl-2 protein expression is also important in morin-induced apoptosis of U937 cells. This study provides evidence that morin might have anticancer properties in human leukemic cells.

Clinical significance of the neutrophil–lymphocyte ratio in venous thromboembolism patients with lung cancer

BACKGROUND The neutrophil-lymphocyte ratio (NLR) has been identified as a potentially useful marker for predicting clinical outcome in patients with cardiovascular disease, diabetes, and various malignancies. The aim of this study was to determine whether NLR at the time of venous thromboembolism (VTE) diagnosis is a prognostic factor for the response to anticoagulation and survival in lung cancer patients treated with anticoagulation for VTE. PATIENTS AND METHODS We retrospectively analyzed the clinical characteristics, laboratory parameters, and NLR in 114 lung cancer patients newly diagnosed with VTE, among 991 patients pathologically confirmed for lung cancer between July 2008 and August 2013. RESULTS High NLR was significantly associated with high hematocrit (p=0.028), high C-reactive protein (p=0.002), and low albumin (p=0.001). Compared with the low NLR group, stage IV non-small cell lung cancer (NSCLC) at the time of VTE diagnosis (55.6 vs. 74.6%, p=0.055), central nervous system metastasis (5.8 vs. 25.8%, p=0.004), and cancer progression (14.3 vs. 38.8%, p=0.008) at the time of VTE diagnosis were also significant in the high NLR group. Moreover, the poor response to anticoagulation was statistically correlated with patients with NSCLC (p=0.037), high NLR (p=0.004), and low albumin (p=0.029). CONCLUSIONS The results demonstrate that the NLR at the time of VTE diagnosis could be a useful biomarker for predicting the response and prognosis following anticoagulation in patients with lung cancer and VTE.

Pachymic Acid Induces Apoptosis of EJ Bladder Cancer Cells by DR5 Up-Regulation, ROS Generation, Modulation of Bcl-2 and IAP Family Members

Pachymic acid (PA) is a lanostane‐type triterpenoid derived from Poria cocos mushroom that possess various biological effects such as anti‐cancer, antiinflammatory and anti‐metastasis effects. In this study, we investigated the anti‐cancer effects of PA in EJ bladder cancer cells. The results showed that PA significantly inhibited proliferation of EJ cells in a dose‐dependent manner. PA induced accumulation of sub‐G1 DNA content (apoptotic cell population), apoptotic bodies and chromatin condensation and DNA fragmentation in EJ cells in a dose‐dependent manner. PA also induces activation of caspase‐3, ‐8 and ‐9, and subsequent cleavage of poly (ADP‐ribose) polymerase, and significantly suppressed the inhibitor of apoptosis protein family proteins in a dose‐dependent manner. Furthermore, PA activates Bid and induced the loss of mitochondrial membrane potential (ΔΨm) with up‐regulated pro‐apoptotic proteins (Bax and Bad), down‐regulated anti‐apoptotic proteins (Bcl‐2 and Bcl‐xL) and cytochrome c release. In turn, PA increased the generation of reactive oxygen species (ROS); also, the ROS production was blocked by N‐acetyl‐L‐cysteine. The expressions of TNF‐related apoptosis inducing ligand and death receptor 5 were up‐regulated by PA in a dose‐dependent manner, suggesting extrinsic pathway also involved in PA‐induced apoptosis. This study provides evidence that PA might be useful in the treatment of human bladder cancer. Copyright

Clinical outcome and prognosis of patients with primary sinonasal tract diffuse large B-cell lymphoma treated with rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy: a study by the Consortium for Improving Survival of Lymphoma

Abstract We evaluated the clinical outcomes and relapse patterns of 80 patients with primary sinonasal tract diffuse large B-cell lymphoma (SN-DLBCL) treated with rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy at 22 institutions. A total of 59 (73.8%) patients received R-CHOP chemotherapy alone, whereas 21 (26.3%) were treated with R-CHOP followed by involved field radiotherapy (IFRT). In 73 patients with Ann Arbor stage I–II disease, no significant difference was found in the response rate or overall survival (OS) between R-CHOP alone (n = 52) and R-CHOP followed by IFRT (n = 21). Among 11 relapsed patients in this study, the most common pattern of relapse was local (n = 8, 11.8%), whereas central nervous system (CNS) relapse was observed in only one (1.9%) patient. These results suggest that patients with primary SN-DLBCL treated with R-CHOP have a relatively low CNS relapse rate and better OS compared to previous studies before the introduction of R.

p53 restoration can overcome cisplatin resistance through inhibition of Akt as well as induction of Bax

Cisplatin (CDDP) is a chemotherapeutic agent that is widely used to treat many cancers. However, initial resistance to CDDP is a serious problem in treating cancers. In this study, in order to develop an approach to overcome resistance to CDDP, we investigated the difference in apoptotic processes between CDDP-sensitive cells and CDDP-resistant cells. By screening with CDDP sensitivity tests, we chose SNU-16 cells which are relatively resistant to CDDP, and SNU-1 cells which are sensitive to CDDP. We compared the difference between the two cell lines focusing on apoptosis. CDDP-induced reactive oxygen species (ROS) generation significantly induced loss of mitochondrial membrane potential (MMP, ∆Ψm) in SNU-1 cells, but not in SNU-16 cells. In addition, the ratio of Bax to Bcl-2 was increased by CDDP treatment in SNU-1 cells, but not in SNU-16 cells. To augment the loss of MMP, ∆Ψm in SNU-16, we inhibited Akt activity of SNU-16 cells to suppress their anti-apoptotic activity. The inhibition of Akt activity led to suppression of the anti-apoptotic protein XIAP. Akt inhibition slightly enhanced CDDP-induced apoptosis in SNU-16 cells. In addition, we enhanced pro-apoptotic activity by transfecting the cells with the wild-type p53 gene. The induction of wild-type p53 can enhance CDDP-induced apoptosis not only by inducing Bax protein but also by suppressing anti-apoptotic proteins through inhibition of Akt. In conclusion, this study suggests that the primary contributor to resistance to CDDP in SNU-16 cells may well be a failure of induction of apoptosis due to a lack of induction of pro-apoptotic proteins rather than suppression of anti-apoptotic proteins, and that restoration of p53 function can overcome the resistance to CDDP not only by augmenting the pro-apoptotic drive through p53-mediated transcriptional activation but also by inhibiting the anti-apoptotic drive through inhibition of Akt activity.

D-Dimer Can Serve as a Prognostic and Predictive Biomarker for Metastatic Gastric Cancer Treated by Chemotherapy

Abstract Systemic activation of hemostasis and thrombosis has been implicated in tumor progression and metastasis. D-dimer has been used as an indicator for the thrombosis. Here, we investigated the role of the activation of coagulation in patients with metastatic gastric cancer by measuring D-dimer level. We conducted an observation study of 46 metastatic gastric cancer patients who received palliative chemotherapy (CTx). D-dimer levels were assessed before CTx and at the first response evaluation after CTx. The overall survival (OS) of patients with pretreatment D-dimer levels <1.5 &mgr;g/mL was significantly longer than that of patients with D-dimer levels ≥1.5 &mgr;g/mL (22.0 vs 7.9 months, P = 0.019). At the first response evaluation, the mean level of D-dimer was significantly decreased by 2.11 &mgr;g/mL in patients either with partial response or stable disease (P = 0.011) whereas the mean level of D-dimer, although the difference did not reach statistical significance, was increased by 2.46 &mgr;g/mL in patients with progressive disease. In addition, the OS of patients with D-dimer levels <1.0 &mgr;g/mL at the first response evaluation was significantly longer than that of patients with D-dimer levels ≥1.0 &mgr;g/mL (22.0 vs 7.0 months, P = 0.009). The lower D-dimer levels (<1.0 &mgr;g/mL) at the first response evaluation after CTx was independent predictive factor for better survival in multivariate analysis (P = 0.037). This study suggests that D-dimer levels may serve as a biomarker for response to CTx and OS in patients with metastatic gastric cancer.

Clinical significance of the preoperative platelet count and platelet-to-lymphocyte ratio (PLT-PLR) in patients with surgically resected non-small cell lung cancer

Background The aim of this study was to assess the prognostic significance of the preoperative platelet count (PLT) and platelet-to-lymphocyte ratio (PLR) in patients with surgically resected non-small-cell lung cancer (NSCLC). Patients and Methods We retrospectively reviewed 202 patients treated for NSCLC between January 2002 and December 2007. Preoperative PLT and PLR scores were calculated using data obtained at the time of admission. Patients were assigned a PLT-PLR score of 0, 1, or 2 based upon the presence of thrombocytosis, an elevated PLR, or both. Results Patients with a PLT-PLR score of 2 had a significantly lower median overall survival (OS) [12.715 mo; 95% confidence interval (CI) 1.215-24.215] when compared with patients with PLT-PLR scores of 1 (52.238 mo; 95% CI 17.062-87.414, p = 0.002) or 0 (not reached, p < 0.001). Relapse-free survival (RFS) was also significantly decreased in patients with a PLT-PLR score of 2 (10.107 mo; 95% CI 3.388-16.826) relative to patients with a PLT-PLR score of 1 (27.214 mo; 95% CI 0-56.253, p = 0.002) or 0 (58.893 mo; 95% CI 32.938-84.848, p < 0.001). In multivariate analysis, a PLT-PLR score of 2 was an independent prognostic factor for poor OS (hazard ratio (HR) 3.473; 95% CI 1.765-6.835, p < 0.001) and RFS (HR 2.286; 95% CI 1.243-4.206, p = 0.008) compared with a PLT-PLR score of 0. Conclusions Preoperative PLT-PLR scores can be useful for predicting disease prognosis in patients with surgically resected NSCLC. Further large prospective studies will be necessary to validate our findings.

Cyclosporine A treatment for relapsed subcutaneous panniculitis-like T-cell lymphoma: a case with long-term follow-up.

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a distinctive lymphoma characterized by an infiltration of subcutaneous tissue by neoplastic cytotoxic T cells. There was no distinction between TCR alpha/beta phenotype and TCR gamma/delta phenotype, and anthracycline-based chemotherapy was usually used for both. Here, we report a patient with recurrent SPTL who achieved a second long-term complete remission by repeated cyclosporine A (CsA) treatment. From 2000 to 2001, the patient received anthracycline-based combination chemotherapy. However, the treatment did not induce long-term remission. In 2002, he received cyclosporine treatment for about 6 months. This resulted in a 5-year remission that ended in relapse in 2008. He received CsA treatment once again and attained a second long-term remission. This case suggests that re-treatment with CsA can be a good option for relapsed SPTL cases and can result in long-term remission.