Analysis of the EF24-modulated signaling pathways for thedevelopment of novel cancer combination therapies 公开

Abstract

Abstract

Analysis of the EF24-modulated signaling pathways for the development of novel cancer combination therapies

By Shala L. Thomas This dissertation seeks to uncover the cellular mechanisms of the curcumin analog EF24 that are responsible for its anticancer activity and differ from the parent compound. Additionally, this study highlights signaling pathways induced by EF24 that ultimately interferes with its therapeutic effect. We suggest that identifying these major pathways and inhibiting survival signaling will enhance the anticancer activity of EF24. We provide evidence that inhibiting p38 with pyrinidyl imidazole compounds potentiates EF24-mediated inhibition of cancer cell proliferation and induction of apoptosis. Additional studies suggest that one way in which EF24-induced p38 activation promotes survival is through the specific transcriptional up-regulation of Hsp70, a heat shock protein strongly up-regulated in response to stress. Moreover, we show that EF24 treatment results in microtubule polymerization, leading to the inhibition microtubule-dependent pathways like HIF. p38 inhibition further enhanced microtubule polymerization, suggesting this anti-tubulin activity is involved in the synergistic nature of the EF24 and p38 inhibitor combination. The collective findings presented herein provide insight into the mechanisms by which EF24 promotes cancer cell death, the cellular response to EF24, and potential strategies in the form of combination therapies to exploit of these cellular activities.

Table of Contents

Table of Contents Page

I. Introduction 1 a. Curcumin 3 i. Historical uses 4 ii. Chemical properties 5 iii. Biological activity 7 iv. Inhibition of nuclear factor kappa-B (NF-B) 14 v. Curcumin-based clinical trials 20 vi. Development of curcumin conjugates and analogs 21 b. p38 Mitogen-activated protein kinase (MAPK) pathway 25 i. Identification and isoforms of p38 27 ii. Regulation of p38 activity 28 iii. Functional role of p38 30 iv. Involvement in heat shock protein 70 (Hsp70) 33 v. Small molecule p38 inhibitors 36 c. Microtubule 41 i. Structure and dynamics 41 ii. Regulation of microtubules 44 iii. Microtubule function 47 iv. Targeting microtubules for cancer therapy 50 v. Downstream hypoxia inducible factor-1 (HIF-1) pathway 56 II. Materials and Methods 64 III. Enhancing the anticancer activity of EF24 and p38 MAPK inhibitors 73

a. Rational 74 b. Results 76 c. Conclusions 105

IV. Induction of Hsp70 by EF24-mediated p38 signaling confers cancer 110 survival advantage a. Rational 111 b. Results 113 c. Conclusions 127 V. EF24 disrupts the microtubule cytoskeleton and inhibits HIF-1 130 a. Rational 131 b. Results 132 c. Conclusions 157 VI. Dicussion 163 VII. References

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Pharmacology Health Sciences, Oncology
关键词	curcumin analog cancer combination therapy signal transduction natural products
Committee Chair / Thesis Advisor	Fu, Haian, Emory University
Committee Members	Liotta, Dennis C, Emory University Sun, Shi-Yong, Emory University Yang, Lily, Emory University

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