The long-term objectives of this application are to acquire a thorough understanding of the mechanisms of action and of resistance to Taxol, an antitumor agent that is known to be efficacious in the treatment of human cancer. Knowledge gained from the studies described in this application will improve the ability to design Taxol analogs with a better therapeutic index and to develop strategies to reverse or overcome drug resistance. The understanding of Taxol will be applied to other natural products such as the epothilones, whose mechanisms of action and resistance may be similar to that of Taxol. The specific objectives of this application are to: 1). Define the binding site for Taxol in the microtubule. Taxol analogs with radiolabeled photoreactive substituents at defined positions around the taxane nucleus and in the A-ring sidechain will be used to define the pocket in the microtubule in which Taxol fits. Each photoreactive substituent will provide another contact point between the drug and the microtubule. 2). Determine if modulating the levels of beta-tubulin isotypes in cells can alter sensitivity to Taxol. Two approaches will be used to analyze this problem; one involves inducible gene expression with the tetracycline and/or ecdysone regulated system and the other beta-tubulin antisense oligonucleotides. 3). Expand the applicant's studies on analyzing alterations in the levels of beta-tubulin isotypes in human ovarian tumors that acquire Taxol resistance. 4). Investigate endogenous molecules, such as p19, that regulate microtubule disassembly and may thereby antagonize the activity of Taxol and modulate low level resistance to the drug. 5). Perform structure activity relationships (SAR) studies on epothilone analogs to determine the structural requirements for biological activity. Examine the sensitivity of Taxol-resistant cells to epothilone and develop epothilone-resistant cells so that the two drugs can be carefully compared.
| Yang, Chia-Ping Huang; Wang, Changwei; Ojima, Iwao et al. (2018) Taxol Analogues Exhibit Differential Effects on Photoaffinity Labeling of ?-Tubulin and the Multidrug Resistance Associated P-Glycoprotein. J Nat Prod 81:600-606 |
| Mathew, Deepti; Wang, Yanhua; Van Arsdale, Anne et al. (2018) Expression of ?V-Tubulin in Secretory Cells of the Fallopian Tube Epithelium Marks Cellular Atypia. Int J Gynecol Cancer 28:363-370 |
| Nadaradjane, Celine; Yang, Chia-Ping Huang; Rodriguez-Gabin, Alicia et al. (2018) Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners. J Nat Prod 81:607-615 |
| Samaraweera, Leleesha; Adomako, Alfred; Rodriguez-Gabin, Alicia et al. (2017) A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC. Sci Rep 7:1900 |
| Prota, Andrea E; Bargsten, Katja; Redondo-Horcajo, Mariano et al. (2017) Structural Basis of Microtubule Stabilization by Discodermolide. Chembiochem 18:905-909 |
| Yang, Chia-Ping Huang; Horwitz, Susan Band (2017) Taxol®: The First Microtubule Stabilizing Agent. Int J Mol Sci 18: |
| Yang, Chia-Ping Huang; Yap, Eng-Hui; Xiao, Hui et al. (2016) 2-(m-Azidobenzoyl)taxol binds differentially to distinct ?-tubulin isotypes. Proc Natl Acad Sci U S A 113:11294-11299 |
| Frimer, Marina; Levano, Kelly S; Rodriguez-Gabin, Alicia et al. (2016) Germline mutations of the DNA repair pathways in uterine serous carcinoma. Gynecol Oncol 141:101-7 |
| Andreopoulou, Eleni; Schweber, Sarah J; Sparano, Joseph A et al. (2015) Therapies for triple negative breast cancer. Expert Opin Pharmacother 16:983-98 |
| Hou, June Y; McAndrew, Thomas C; Goldberg, Gary L et al. (2014) A clinical and pathologic comparison between stage-matched endometrial intraepithelial carcinoma and uterine serous carcinoma: is there a difference? Reprod Sci 21:532-7 |
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