RLIP76 Inhibition: A Promising Developmental Therapy for Neuroblastoma

Autor: Sanjay Awasthi, David Horne, Jyotsana Singhal, S. S. Singhal, Preeti Singhal, Sharad S. Singhal, Lokesh Dalasanur Nagaprashantha
Rok vydání: 2017
Předmět:
0301 basic medicine
Pharmaceutical Science
Context (language use)
Antineoplastic Agents
Apoptosis
Biology
medicine.disease_cause
Antibodies
03 medical and health sciences
Neuroblastoma
0302 clinical medicine
Cell Line
Tumor
medicine
Animals
Humans
Pharmacology (medical)
Molecular Targeted Therapy
Child
Sensitization
Pharmacology
Brain Neoplasms
Organic Chemistry
GTPase-Activating Proteins
Wnt signaling pathway
Biological Transport
Receptor-mediated endocytosis
medicine.disease
Glutathione
Protein ubiquitination
Clathrin
Endocytosis
Oxidative Stress
030104 developmental biology
medicine.anatomical_structure
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Immunology
Mutation
Cancer research
Molecular Medicine
ATP-Binding Cassette Transporters
Neoplasm Recurrence
Local
Tumor Suppressor Protein p53
Carcinogenesis
Biotechnology
Signal Transduction
Zdroj: Pharmaceutical research. 34(8)
ISSN: 1573-904X
Popis: Refractory and relapsed neuroblastoma (NB) present with significant challenges in clinical management. Though primary NBs largely with wild-type p53 respond well to interventions, dysfunctional signaling in the p53 pathways in a MYCN oncogene driven background is found in a number of children with NB. The p53-mutant NB is largely unresponsive to available therapies and p53-independent targeted therapeutics represents a vital need in pediatric oncology. We analyzed the findings on mercapturic acid pathway (MAP) transporter RLIP76, which has broad and critical effects on multiple pathways as essential for carcinogenesis, oxidative stress and drug-resistance, is over-expressed in NB. RLIP76 inhibition by antibodies or depletion by antisense causes apoptosis and sensitization to chemo-radiotherapy in many cancers. In addition, recent studies indicate that the interactions between p53, MYCN, and WNT regulate apoptosis resistance and protein ubiquitination. RLIP76 and p53 interact with each other and colocalize in NB cells. Targeted depletion/inhibition of RLIP76 causes apoptosis and tumor regression in NB irrespective of p53 status. In the present review, we discuss the mechanisms and the role of RLIP76 in oxidative stress, drug-resistance and clathrin-dependent endocytosis (CDE), and analyze the molecular basis for the role of RLIP76 targeted approaches in the context principal drivers of NB pathogenesis, progression and drug-resistance. The evidence from RLIP76 studies in other cancers, when taken in the context of our recent RLIP76 focused mechanistic studies in NB, provides strong basis for further characterization and development of RLIP76 targeted therapies for NB.
Databáze: OpenAIRE
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