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In vitro and in vivo pharmacologic evaluation of novel lysophospholipid analogs as anticancer agents

Hurh, Eunju
http://rave.ohiolink.edu/etdc/view?acc_num=osu1133187926

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Pharmacy.
Lysophospholipids are phospholipid growth factors that promote tumor cell proliferation, survival, and invasion by binding to a family of G protein-coupled receptors. Due to their involvement in cancer progression and overexpression of their receptors in cancer, novel agents that inhibit molecules in the lysophospholipid signal transduction pathways hold promise as potential chemotherapeutic agents. Prostate cancer presents a unique disease model to study the role of lysophospholipid growth factor signaling pathways. Different human prostate cancer cell lines represent a wide range of clinically relevant prostate tumor types demonstrating various stages of the disease, different sites of metastasis, and differences in androgen dependence for cell growth. Moreover, these cell lines demonstrate differential expression and activity profiles of the LPL receptors and downstream mediators including PTEN lipid phosphatase and AKT and MAPK. Three classes of lysophospholipid analogs were synthesized and tested in prostate cancer cell lines and a negative control cell line that lacks lysophospholipid receptors. Active serine amide derivatives showed potency similar to that of 5-fluorouracil, but they also affected growth of the negative control cell line. Thiazolidinone analogs were equipotent to serine amides with improved selectivity. Thiazolidine analogs were the most potent and selective of all three groups of lysophospholipid analogs examined. Further, thiazolidine analogs almost completely inhibited AKT phosphorylation, consequently inducing apoptosis. However, these analogs failed to interact directly with lysophosphatidic acid receptors as proven by absence of inhibitory action on lysophosphatidic acid-driven calcium mobilization. Two thiazolidine analogs were chosen for assessment of in vivo anticancer activity. Daily intraperitoneal doses of these analogs significantly delayed PC-3 xenograft tumor growth, validating the importance of LPL receptor and/or downstream signal transduction pathways in growth and progression of prostate tumors. Thiazolidine analogs also enhanced bicalutamide activity in vitro by 2- to 30-fold in both androgen-dependent and androgen-independent prostate cancer cell lines. In conclusion, lysophospholipid signal transduction pathways can be exploited to provide a novel modality for prostate cancer treatment. Identification of target proteins and improvement of intrinsic activity, selectivity profile, and pharmacokinetic properties will hopefully lead to an increase in the in vivo efficacy of this series of lysophospholipid analogs.
James Dalton (Advisor)
Health Sciences, Pharmacy
Mean SD

Recommended Citations

Citations

  • Hurh, E. (2005). In vitro and in vivo pharmacologic evaluation of novel lysophospholipid analogs as anticancer agents [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1133187926

    APA Style (7th edition)

  • Hurh, Eunju. In vitro and in vivo pharmacologic evaluation of novel lysophospholipid analogs as anticancer agents. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1133187926.

    MLA Style (8th edition)

  • Hurh, Eunju. "In vitro and in vivo pharmacologic evaluation of novel lysophospholipid analogs as anticancer agents." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1133187926

    Chicago Manual of Style (17th edition)

osu1133187926
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.