scholarly journals Recent advances in the regulation of cholangiocarcinoma growth

2010 ◽  
Vol 299 (1) ◽  
pp. G1-G9 ◽  
Author(s):  
Heather Francis ◽  
Gianfranco Alpini ◽  
Sharon DeMorrow
Keyword(s):  
Neoplastic Transformation ◽  
Therapeutic Strategies ◽  
Chemotherapeutic Agents ◽  
Biliary Epithelium ◽  
Recent Advances ◽  
Relative Rarity ◽  
Deadly Disease ◽  
Novel Therapeutic Strategies ◽  
Molecular Pathophysiology ◽  
Novel Therapeutic

Cholangiocarcinomas arise after the neoplastic transformation of the cholangiocytes that line the intra- and extrahepatic biliary epithelium. Symptoms usually do not present until late in the course of the disease, at which time they are relatively resistant to chemotherapeutic agents and as such are difficult to treat and display a poor prognosis. Because of the relative rarity of this disease, the overall volume of research into the molecular pathophysiology associated with this disease is small compared with other more prevalent tumors. However, the incidence of this devastating cancer is on the rise and renewed efforts to understand the pathogenesis of cholangiocarcinoma is needed to design novel therapeutic strategies to combat this disease. This review summarizes the recent advances into our knowledge and understanding of cholangiocarcinoma and highlights potential novel therapeutic strategies that may prove useful to treat this deadly disease.

WT1 Interaction with the Chaperone Protein HSP90 Regulates Its Expression in Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1826-1826
Author(s):  
Sanjay Bansal ◽  
Hima Bansal ◽  
Emre Baris ◽  
Elizabeth Repasky ◽  
Asher Chanan-Khan ◽  
...  
Keyword(s):  
Heat Shock ◽  
Confocal Microscopy ◽  
Protein Expression ◽  
Therapeutic Strategies ◽  
Chemotherapeutic Agents ◽  
Leukemic Blast ◽  
Novel Therapeutic Strategies ◽  
Wt1 Protein ◽  
Novel Therapeutic ◽  
Interacting Domain

Abstract Introduction: Wilms tumor protein 1 (WT1) is a transcription factor that is universally expressed in AML, and clinical studies have demonstrated a significant correlation between WT1 expression and disease progression. Heat shock proteins (HSP) are ubiquitous molecular chaperones that are involved in the folding, activation and assembly of many proteins. HSP90 may facilitate the maintenance of altered oncogenic client proteins such as flt-3 and bcr-abl in myeloid malignancies. It has been also shown that WT1 is a client protein of Hsp70, and this interaction may be important for the function of WT1. Since HSP70 and HSP90 have similar functions and often complement each other in engaging with client cellular proteins we wanted to determine if WT1 was chaperoned by HSP90 and if so could this HSP90-WT1 interaction be modulated. Materials and methods: We first looked for a potential interaction between HSP90 and WT1 by confocal microscopy colocalization and then by immunoprecipitation (IP) in the myeloid cell line K562. For confocal studies, cells were grown on coverslips, fixed and permeabilized and stained with the rabbit anti-WT1 and anti- HSP90 antibodies. Samples were examined by using a laser confocal/Zeiss axiovert microscope imaging system. This interaction was further confirmed by co-IP/Western and then confirmed using a GST-pulldown assay. A glutathione S-transferase (GST)-WT1 fusion protein was expressed in E. coli strain BL21(DE3) and immobilized onto glutathione sepharose beads. The full length Hsp90 and different deletion mutant proteins were in vitro translated and [35S] methionine-labeled; the bound proteins were eluted and then separated by SDS-PAGE. The gels were fixed, dried and subjected to fluorography. Results: Confocal microscopy revealed colocalization of HSP90 and WT1 mainly in the nucleus. Immunoprecipitation of K562 lysates with either anti-WT1 or anti-HSP90 antibody followed by Western analysis for WT1 and HSP90 demonstrated that WT1 and HSP90 could be co-immunoprecipitated. The GST pull down assay confirmed this interaction. Additional mutants of HSP90 from the C to N terminus were prepared to localize the WT1 interacting domain. These studies localized the WT1 interacting domain to the HSP90 region close to the binding pocket of the HSP inhibitor geldanamycin. Treatment of K562 with the geldanamycin analog 17-allylamino-17-demethoxygeldanamycin (17-AAG) resulted in downregulation of WT1 protein expression with an IC50 of 3μM. Conclusions: Understanding the mechanisms that regulate WT1 expression thus may lead to novel therapeutic strategies to inhibit this expression and result directly in myeloid blast cell killing. We have shown elsewhere that downmodulating WT1 gene expression with interferon or shRNA potentiates myeloid leukemic blast killing by chemotherapeutic agents. We demonstrate here that the WT1 protein interacts with the co-chaperone heat shock protein HSP90. Taken together, our findings support the hypothesis that the regulation of WT1 occurs at the protein level through an interaction with WT1-protein-HSP chaperone levels, and that pharmacologically targeting this interaction with the HSP inhibitor 17AAG results in a significant reduction in WT1 protein expression. Ongoing studies in primary AML cells will confirm these findings and define novel therapeutic strategies to manipulate WT1 protein expression levels and modulate leukemic blast survival.

scholarly journals Acute Myeloid Leukemia: Focus on novel Therapeutic Strategies

2012 ◽  
Vol 6 ◽  
pp. CMO.S7244 ◽  
Author(s):  
Tara L. Lin ◽  
M. Yair Levy
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Risk Groups ◽  
The Elderly ◽  
Therapeutic Strategies ◽  
Recent Advances ◽  
Novel Therapeutic Strategies ◽  
Acute Myeloid ◽  
Novel Therapeutic

Acute myeloid leukemia (AML) is a heterogeneous disease with variable clinical outcomes. Cytogenetic analysis reveals which patients may have favorable risk disease, but 5-year survival in this category is only approximately 60%, with intermediate and poor risk groups faring far worse. Advances in our understanding of the biology of leukemia pathogenesis and prognosis have not been matched with clinical improvements. Unsatisfactory outcomes persist for the majority of patients with AML, particularly the elderly. Novel agents and treatment approaches are needed in the induction, post-remission and relapsed settings. The additions of clofarabine for relapsed or refractory disease and the hypomethylating agents represent recent advances. Clinical trials of FLT3 inhibitors have yielded disappointing results to date, with ongoing collaborations attempting to identify the optimal role for these agents. Potential leukemia stem cell targeted therapies and treatments in the setting of minimal residual disease are also under investigation. In this review, we will discuss recent advances in AML treatment and novel therapeutic strategies.

scholarly journals Long Non-Coding RNAs in Multidrug Resistance of Glioblastoma

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 455
Author(s):  
Parvaneh Mahinfar ◽  
Behzad Baradaran ◽  
Sadaf Davoudian ◽  
Fatemeh Vahidian ◽  
William Chi-Shing Cho ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Multidrug Resistance ◽  
Therapeutic Strategies ◽  
Chemotherapeutic Agents ◽  
The Other ◽  
The Common ◽  
Non Coding Rnas ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Glioblastoma, also known as glioblastoma multiforme, is the most aggressive brain tumor in adults. Despite the huge advance in developing novel therapeutic strategies for patients with glioblastoma, the appearance of multidrug resistance (MDR) against the common chemotherapeutic agents, including temozolomide, is considered as one of the important causes for the failure of glioblastoma treatment. On the other hand, recent studies have demonstrated the critical roles of long non-coding RNAs (lncRNAs), particularly in the development of MDR in glioblastoma. Therefore, this article aimed to review lncRNA’s contribution to the regulation of MDR and elucidate the underlying mechanisms in glioblastoma, which will open up new lines of inquiry in the treatment of glioblastoma.

PCSK9 Inhibitors: Novel Therapeutic Strategies for Lowering LDLCholesterol

2018 ◽  
Vol 19 (2) ◽  
pp. 165-176 ◽  
Author(s):  
Yan Wang ◽  
Zhao-Peng Liu
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Maximum Tolerated Dose ◽  
Therapeutic Strategies ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Cvd Risk ◽  
Safety Issues ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-offunction mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues.

scholarly journals The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 485
Author(s):  
Lorenzo Cuollo ◽  
Fabrizio Antonangeli ◽  
Angela Santoni ◽  
Alessandra Soriani
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Senescent Cell ◽  
Pharmacological Intervention ◽  
Tissue Microenvironment ◽  
Age Related ◽  
Secretory Phenotype ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

scholarly journals Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management

2021 ◽  
Vol 139 ◽  
pp. 111708
Author(s):  
Pushkar Singh Rawat ◽  
Aiswarya Jaiswal ◽  
Amit Khurana ◽  
Jasvinder Singh Bhatti ◽  
Umashanker Navik
Keyword(s):  
Molecular Mechanism ◽  
Therapeutic Strategies ◽  
Effective Management ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic
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