Reversal of Rituximab-Resistant AIDS-B-NHL Clone to Chemotherapeutic Drug-Induced Apoptosis by Bortezomib and DHMEQ.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1516-1516
Author(s):  
Mario Vega ◽  
Ali Jazirehi ◽  
Benjamin Bonavida
Keyword(s):  
Tumor Cells ◽  
P38 Mapk ◽  
Selective Inhibition ◽  
Mapk Signaling ◽  
Drug Resistant ◽  
Chemotherapeutic Drug ◽  
Drug Induced ◽  
Cancer Review ◽  
Cd20 Expression ◽  
Induced Apoptosis

Abstract The mechanisms underlying the failure of B-NHL cancer patients to respond to treatment with rituximab, alone or in combination with chemotherapy, are not known. In efforts to address this issue, we have generated rituximab-resistant clones of the AIDS NHL cell line, (2F7RR). Recent findings have demonstrated that treatment of the wild type (wt) 2F7 with rituximab sensitized the tumor cells to various chemotherapeutic drug-induced apoptosis. Chemosensitization was the result of rituximab-mediated inhibition of the p38 MAPK signaling pathway and the selective inhibition of the anti-apoptotic Bcl-2 gene product (Vega et. al., Oncogene23:4993, 2004). Analysis of one clone, 2F7RR1, revealed that the cells have diminished surface CD20 expression and failed to respond to CDC and to apoptosis following cross-linking. In addition, the cells were resistant to rituximab-mediated chemosensitization. In contrast to wt2F7, molecular analysis of the 2F7RR1 clone revealed that rituximab failed to inhibit p-Lyn, p38-MAPK, BclXL, and Bcl-2. In addition, rituximab failed to inhibit the transcription factors NF-κB, YY1, SP-1, and STAT3. Noteworthy, 2F7RR1 exhibited higher resistance to drug-induced apoptosis compared to wt2F7 and showed overexpression of Bcl-2. Previous findings with the wt2F7 demonstrated that Bcl-2 was responsible for chemoresistance. Accordingly, we examined whether inhibition of Bcl-2 in 2F7RR1 can reverse chemoresistance. Since Bcl-2 is under the transcriptional regulation of NF-κB, we examined the effect of the NF-κB inhibitors Bortezomib and DHMEQ (DHMEQ was a kind gift from Dr.K. Umezawa Keio University, Japan) (Kikuchi, et al., Cancer Review, 2003, 63:107). The findings revealed that treatment of 2F7RR1 with these inhibitors resulted in the reversal of resistance to a number of chemotherapeutic drugs (examples: taxol, vincristine, ADR, CDDP, VP16, etc.). The chemo-sensitization by Bortezomib and DHMEQ was equivalent and the combination treatment of each of these inhibitors with the drug was synergistic. These studies present evidence that rituximab and drug-resistant tumor cells may be sensitized to chemotherapeutic drug-induced apoptosis via inhibition of NF-κB or Bcl-2. These findings also suggest that Bortezomib and DHMEQ may be clinically relevant in the treatment of rituximab and drug-resistant AIDS-B-NHL.

Human U3 protein 14a plays an anti-apoptotic role in cancer cells

2017 ◽  
Vol 398 (11) ◽  
pp. 1247-1257 ◽  
Author(s):  
Teng Ma ◽  
Chenxi Lu ◽  
Yafei Guo ◽  
Chunfeng Zhang ◽  
Xiaojuan Du
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Protein Level ◽  
Tumor Therapy ◽  
Caspase Inhibitor ◽  
Chemotherapeutic Drug ◽  
Intrinsic Pathway ◽  
Down Regulation ◽  
Drug Induced ◽  
Induced Apoptosis

AbstractHuman U three protein 14a (hUTP14a) binds p53 and promotes p53 degradation. Here, we report that hUTP14a plays an anti-apoptotic role in tumor cells through a p53-independent pathway. Knockdown of hUTP14a activated the intrinsic pathway of apoptosis and sensitized tumor cells to chemotherapeutic drug-induced apoptosis. In addition, the protein level of hUTP14a decreased upon chemotherapeutic drug- or irradiation-induced apoptosis. Importantly, the decrease of hUTP14a during induced apoptosis was not blocked by pan-caspase inhibitor z-VAD-FMK, indicating that the down-regulation of hUTP14a is an upstream event in apoptosis. Furthermore, ectopically expressed hUTP14a protected tumor cells from chemotherapeutic drug-induced apoptosis. In summary, our data showed that hUTP14a protected tumor cells from chemotherapeutic drug-induced apoptosis and thus might possess a potential as a target for anti-tumor therapy.

scholarly journals Involvement of FKHR-Dependent TRADD Expression in Chemotherapeutic Drug-Induced Apoptosis

2002 ◽  
Vol 22 (24) ◽  
pp. 8695-8708 ◽  
Author(s):  
Susumu Rokudai ◽  
Naoya Fujita ◽  
Osamu Kitahara ◽  
Yusuke Nakamura ◽  
Takashi Tsuruo
Keyword(s):  
Drug Treatment ◽  
Tumor Cells ◽  
Tumor Necrosis Factor Receptor ◽  
Chemotherapeutic Drugs ◽  
Death Domain ◽  
Chemotherapeutic Drug ◽  
Caspase Activation ◽  
Drug Induced ◽  
Responsive Element ◽  
Induced Apoptosis

ABSTRACT Chemotherapeutic drugs exhibit their cytotoxic effect by inducing apoptosis in tumor cells. Because the serine/threonine kinase Akt is involved in apoptosis suppression, we investigated the relationship between Akt activity and drug sensitivity. We discovered that certain chemotherapeutic drugs induced apoptosis with caspase activation only when Akt was inactivated after drug treatment, while inactivation of Akt was not observed when tumor cells showed resistance to the drug-induced caspase activation. So, turn-off of the Akt-mediated survival signal is correlated with the sensitivity of the cells to chemotherapy. With a cDNA microarray, we revealed that tumor necrosis factor receptor-associated death domain (tradd) gene expression was elevated in response to Akt inactivation. Reportedly, Forkhead family transcription factors are phosphorylated by Akt, which results in their nuclear exit and inactivation. Analysis of the tradd promoter revealed that it contains at least one potential Forkhead family transcription factor-responsive element, and we confirmed that this element was involved in chemotherapeutic drug-induced TRADD expression. Overexpression of mutant TRADD proteins to block its apoptosis-inducing capability attenuated chemotherapeutic drug-induced apoptosis. Thus, chemotherapeutic drugs exhibited their cytotoxic effects in part by down-regulating Akt signaling following TRADD expression. These results indicate that Akt kinase activity after drug treatment is a hallmark of sensitivity of the cells to chemotherapeutic drugs.

Sensitization of Rituximab-Resistant Ramos RR1 and Daudi RR1 Clones to Various Chemotherapeutic Drugs by a Novel Nuclear Factor-κB Activation Inhibitor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 83-83 ◽  
Author(s):  
Ali R. Jazirehi ◽  
Kazeo Umezawa ◽  
Benjamin Bonavida
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Nuclear Translocation ◽  
Response To Treatment ◽  
Continuous Exposure ◽  
Drug Resistant ◽  
Chemotherapeutic Drug ◽  
Drug Induced ◽  
Induced Apoptosis

Abstract Rituximab (chimeric anti-CD20 mAb) has been recently shown to signal NHL B-cell lines (e.g., Ramos and Daudi) and inhibits the constitutively activated NF-κB signaling pathway. This results in the selective downregulation of the anti-apoptotic Bcl-xL expression and sensitization to various chemotherapeutic drug-induced apoptosis (Jazirehi et al., 2004. Submitted). The novel NF-κB factor inhibitor, dehydroxymethyl derivative of epoxyquinomicin (DHMEQ), inhibits NF-κB activity via inhibition of nuclear (translocation) accumulation of p65 (Ariga et al., JBC 277:24625, 2002). This study examined the similarities and differences observed in wild type (wt) parental and rituximab-resistant Ramos and Daudi cells following treatment with either rituximab (20 mg/ml) or DHMEQ (10 mg/ml). In the wt cells, both agents inhibited NF-κB DNA-binding activity, down-regulated Bcl-xL expression and sensitized the cells to drug-induced apoptosis. Rituximab inhibited both the NIK—IκB-α—IKK—NF-κB and the Raf-1—MEK1/2—ERK1/2—AP-1 signaling pathways, while DHMEQ specifically inhibited NF-κB activity. We have generated rituximab-resistant Ramos and Daudi clones by continuous exposure of the cells to step-wise increasing concentrations of rituximab for several weeks and clones isolated by limiting dilution. The CD20+ expressing Ramos RR1 and Daudi RR1 clones were analyzed for their response to treatment with rituximab or DHMEQ. Compared to the wt cells, the resistant clones exhibited hyper-activation of the NF-κB pathway, increased expression of Bcl-xL, and higher resistance to structurally and functionally distinct drugs; their treatment with DHMEQ (15 mg/ml), but not with rituximab, inhibited the activity of the hyper-activated NF-κB, reduced the over-expressed Bcl-xL and sensitized the highly drug-resistant Ramos RR1 and Daudi RR1 clones to various chemotherapeutic drug (CDDP, ADR, VP-16, Taxol, etc.)-induced apoptosis. These findings demonstrate that DHMEQ can reverse the acquired drug-resistance phenotype in both parental and rituximab/drug-resistant NHL B-cell lines when used in combination with subtoxic concentrations of drugs. In vivo, DHMEQ inhibits subcutaneously transplanted prostate cancer xenografts in nude mice (Kikuchi et al., Cancer Res. 63:107, 2003). Consequently, the present findings suggest the potential therapeutic application of DHMEQ in combination with drugs, in the treatment of rituximab/drug resistant B-NHL.

Inhibiting (pro)renin receptor-mediated p38 MAPK signaling decreases hypoxia/reoxygenation-induced apoptosis in H9c2 cells

2015 ◽  
Vol 403 (1-2) ◽  
pp. 267-276 ◽  
Author(s):  
Yan Liu ◽  
Shenglin Zhang ◽  
Dechun Su ◽  
Jinqiu Liu ◽  
Yunpeng Cheng ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Signaling ◽  
H9c2 Cells ◽  
Induced Apoptosis ◽  
Hypoxia Reoxygenation

scholarly journals Chinese medicine Di-Huang-Yi-Zhi protects PC12 cells from H2O2-induced apoptosis by regulating ROS-ASK1-JNK/p38 MAPK signaling

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Li-Min Zhang ◽  
Rong-Rong Zhen ◽  
Chao Gu ◽  
Tian-Li Zhang ◽  
Yue Li ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Pc12 Cells ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Induced Apoptosis

scholarly journals Cross-Resistance of CD95- and Drug-Induced Apoptosis as a Consequence of Deficient Activation of Caspases (ICE/Ced-3 Proteases)

Blood ◽  
1997 ◽  
Vol 90 (8) ◽  
pp. 3118-3129 ◽  
Author(s):  
Marek Los ◽  
Ingrid Herr ◽  
Claudia Friesen ◽  
Simone Fulda ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Cell Death ◽  
Drug Treatment ◽  
Tumor Cells ◽  
Anticancer Drugs ◽  
Ex Vivo ◽  
Resistant Cell ◽  
Cross Resistance ◽  
Strong Increase ◽  
Drug Induced ◽  
Induced Apoptosis

Abstract The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-induced by anticancer drugs. Apoptosis induced in tumor cells by cytarabine, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system. After drug treatment, a strong increase of caspase activity was found that preceded cell death. Drug-induced activation of caspases was also found in ex vivo-derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin. The peptide inhibitor was effective even if added several hours after drug treatment, indicating a direct involvement of caspases in the execution and not in the trigger phase of drug action. Drug-induced apoptosis was also strongly inhibited by antisense approaches targeting caspase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspases upon CD95 triggering were cross-resistant to drug-mediated apoptosis. Our data strongly support the concept that sensitivity for drug-induced cell death depends on intact apoptosis pathways leading to activation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor cells.

scholarly journals Metformin Alleviated Aβ-Induced Apoptosis via the Suppression of JNK MAPK Signaling Pathway in Cultured Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Bin Chen ◽  
Ying Teng ◽  
Xingguang Zhang ◽  
Xiaofeng Lv ◽  
Yanling Yin
Keyword(s):  
P38 Mapk ◽  
Hippocampal Neurons ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ldh Assay ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Positive Effect

Both diabetes and hyperinsulinemia are confirmed risk factors for Alzheimer’s disease. Some researchers proposed that antidiabetic drugs may be used as disease-modifying therapies, such as metformin and thiazolidinediones, although more evidence was poorly supported. The aim of the current study is to investigate the role of metformin in Aβ-induced cytotoxicity and explore the underlying mechanisms. First, the experimental results show that metformin salvaged the neurons exposed to Aβin a concentration-dependent manner with MTT and LDH assay. Further, the phosphorylation levels of JNK, ERK1/2, and p38 MAPK were measured with western blot analysis. It was investigated that Aβincreased phospho-JNK significantly but had no effect on phospho-p38 MAPK and phospho-ERK1/2. Metformin decreased hyperphosphorylated JNK induced by Aβ; however, the protection of metformin against Aβwas blocked when anisomycin, the activator of JNK, was added to the medium, indicating that metformin performed its protection against Aβin a JNK-dependent way. In addition, it was observed that metformin protected the neurons via the suppression of apoptosis. Taken together, our findings demonstrate that metformin may have a positive effect on Aβ-induced cytotoxicity, which provides a preclinical strategy against AD for elders with diabetes.

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