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Molecular Pharmacology and Preclinical Studies of Novel Small-molecule Targeted Agents for The Treatment of Hepatocellular Carcinoma

Omar, Hany Ahmed Mostafa Mohamed
http://rave.ohiolink.edu/etdc/view?acc_num=osu1290565602

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and Africa, which is lethal in about 75% of cases. In the United States, there are 6,000-9,000 new cases of HCC per year. HCC is one of the highly chemo-resistant cancers, for which systemic treatments have been unsuccessful. The available therapies are surgical (10-20% of cases), locoregional or recently, chemical using Sorafenib, a multi-kinase inhibitor which has been shown in clinical trial to add two months to the lifespan of late stage HCC patients. To combat HCC with its assortment of genomic and cellular aberrations that occur during the progression of the disease, we have developed OSU-A9 and OSU-2S, novel small-molecule targeted agents for HCC therapy, using indole-3-carbinol (I3C) and fingolimod (FTY720) respectively, as scaffolds. In this study, we used pharmacological and molecular genetic approaches to investigate the mechanisms of action of the lead compounds of these classes (OSU-A9 and OSU-2S) and assess both the efficacy and safety in a series of preclinical studies carried out both in vitro and in vivo. OSU-A9 exhibits up to 100-fold greater in vitro efficacy relative to I3C in HCC cells and provides a considerable therapeutic advantage over I3C with respect to chemical stability. Mechanistic evidence indicates that OSU-A9 antitumor effect is mediated by blocking the Akt-NF-kB signaling network, leading to the inhibition of signaling pathways governing cell cycle progression, survival, and metastasis. Equally important , oral administration of OSU-A9 suppressed HCC xenograft tumor growth in mice without causing overt signs of toxicity. In addition, sub-toxic doses of OSU-A9 combined with the tumor necrosis factor-related apoptosis inducing ligand (TRAIL) effectively inhibited the resistance of HCC to TRAIL-induced apoptosis. The synergistic apoptotic effect is mediated by the ability of OSU-A9 to antagonize TRAIL-activated NF-κB cell survival pathway and to upregulate death receptor (DR) 5 expression in HCC cells. The ability of OSU-A9-TRAIL combination to selectively target HCC cells regardless of p53 status could shed the light on a promising combination therapy for HCC. Based on our finding that FTY720 mediates apoptosis in HCC cells by activating the reactive oxygen species (ROS)-protein kinase (PK)C delta signaling independent of S1P1 receptor, we developed OSU-2S, a novel PKCdelta-targeted non-immunosuppressive antitumor agent, by abrogating the S1P1 receptor activity of FTY720. Several lines of pharmacological evidence indicate that OSU-2S exhibits higher potency than FTY720 in suppressing HCC due to the metabolic inactivation of FTY720 through phosphorylation in the context of antitumor activity. As a single agent, OSU-2S exhibits high in vivo potency in suppressing xenograft tumor growth without overt toxicity, which supports its clinical promise as a component of therapeutic strategies for advanced HCC. Moreover, PKCdelta is a major downstream effector of DNA damage-induced apoptosis, so the activation of PKCdelta by OSU-2S is noteworthy, since it provides a rationale to combine OSU-2S with other genotoxic agents in HCC therapy.
Ching-Shih Chen, PhD (Advisor)
Robert W. Brueggemeier, PhD (Committee Member)
Matthew D. Ringel, MD (Committee Member)
Tushar Patel, MD (Committee Member)
148 p.
Biochemistry; Molecular Biology; Pharmacology
hepatocellular carcinoma; OSU-A9; Akt; NF-kB; indole-3-carbinol; TRAIL; FTY720; OSU-2S; sphingosine 1-phosphate receptor; protein kinase C delta,

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Citations

  • Omar, H. A. M. M. (2010). Molecular Pharmacology and Preclinical Studies of Novel Small-molecule Targeted Agents for The Treatment of Hepatocellular Carcinoma [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1290565602

    APA Style (7th edition)

  • Omar, Hany. Molecular Pharmacology and Preclinical Studies of Novel Small-molecule Targeted Agents for The Treatment of Hepatocellular Carcinoma. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1290565602.

    MLA Style (8th edition)

  • Omar, Hany. "Molecular Pharmacology and Preclinical Studies of Novel Small-molecule Targeted Agents for The Treatment of Hepatocellular Carcinoma." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1290565602

    Chicago Manual of Style (17th edition)

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© 2010, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.