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Study on MDZ-03 an Indolocarbazoles, on Anticancer Effects and Mechanisms and Development of Screening Model for PKC Inhibitor

Author: QinZhiZhen
Tutor: LiJing
School: Ocean University of China
Course: Pharmacognosy
Keywords: Protein kinase C Tumor Inhibitor Mechanism
CLC: R730.5
Type: Master's thesis
Year: 2011
Downloads: 74
Quote: 0
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Abstract


Protein Kinase C (PKC) belongs to a family of serine/threonine kinases which consists of at least 11 such kinases with distinct and in some cases opposing roles in cell proliferation, differentiation, apoptosis and angiogenesis.The subsequent classification of the isoforms is based on structural and activational characteristics. PKC can be classified into 3 groups: classical or conventional PKCs (cPKCs; PKCα, PKCβI, PKCβΙΙand PKCγ), which are calcium- dependent and activated by both phosphotidylserine (PS) and diacylgylcerol (DAG); novel PKCs (nPKCs; PKCδ, PKCε, PKCηand PKCθ), which are calcium- independent and regulated by DAG and PS; and atypical PKCs (aPKCs; PKCζand PKCι/λ), which are calcium-independent and do not require DAG for activation, although PS can regulate their activity;and PKCμconsidered to be the 11th member of PKC family.Early observations that PKC isozymes are activated by tumor promoting phorbol esters suggested a key role for PKC in tumor promotion and progression lead to PKC being considered as a target for cancer therapy. Several PKC inhibitors are in the clinical trial now. However, many difficulties arise in designing effective and specific PKC inhibitors because of the individual PKC isozymes and their different cellular functions. Improvement of isozyme specificity is the key point in PKC inhibitor research.MDZ-03 is a lead compound which porforms a good inhibition effect on PKCβⅡphosphorylation?discovered in the provious works in our lab. This paper aims at the study of effects and mechanism of MDZ-03 as potential anti-tumor drug, and to establish a stable molecular screening model for PKCαand PKCβⅡinhibitor based on the luminescent assay.1.?Study of MDZ-03 on anticancer effects and its mechanismsWe evaluated the activities of MDZ-03 against multiple cell lines including tumor cells and normal cells. MDZ-03 showed selective inhibition on A549, 435, K562 and P388 cell lines. MDZ-03 led to vacuoles in cytoplasm of A549 and arrested the cell cycle at G0/G1 stage. Furthermore, tumor growth was obviously abrogated by MDZ-03 in vivo xenografy model. MDZ-03 specifically inhibits phorbol ester induced activation of PKC isoforms, such as PKCβⅡ、PKCδ、PKCθ, as well as phosphorylation of downstream signaling molecules. In addition, we demonstrated that MDZ-03 induced A549 death through the autophagy pathway instead of apoptosis。2. Establishment of the molecular screening models for protein kinase C inhibitorWe established the molecular screening model for protein kinase C inhibitor using luminescent assay technology, and verified the screening model with the PKC inhibitor staurosporine as positive drug, and then screened the compounds. The results showed that we successfully established stable screening models for protein kinase Cαand protein kinase CβⅡinhibitor and obtained several compounds which significantly inhibited PKCαand PKCβⅡ?enzyme activity.

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CLC: > Medicine, health > Oncology > General issues > Tumor Therapy
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