LAUSR

Objectives: Docetaxel (Dtx) is the primary choice for the treatment of castrate-resistant prostate cancer (PrCa). Besides its therapeutic benefits, many men with castrate-resistant PCa fail to respond to treatment due to Dtx resistance. There are multiple signaling mechanisms that play pivotal role in the development of Dtx resistance. Seminal reports stated that Tau, highly soluble microtubule-associated protein play a crucial role in Dtx resistance development. Disruption Tau signaling affects its chemoresistance. To revert the drug-resistance and target specific pathway, development of novel and strategic therapies are much needed. In this line, we employed magnetic nanoparticle (MNP) loaded Dtx (MNP-Dtx) to revert the chemo resistance of Dtx in PrCa. Methods: Docetaxel loaded magnetic nanoparticle (MNP-Dtx) formulation is composed of an iron oxide core coated with cyclodextrin (for drug loading) and F127 polymer (for particle stability and chemosensitization). Dtx-resistant PrCa cell line models (PC-3R and DU145R) were developed in our laboratory by repeatedly treating cancer cells in a dose escalation manner for over 24 months. Intracellular drug levels of MNP-Dtx in wild type and drug resistant cancer cells was determined by flow cytometry, TEM and HPLC methods. The superior in vitro anti-cancer activity of MNP-Dtx was examined by MTS, proliferation kinetics, colony formation, immunoblotting and qPCR studies in both wild type and drug resistant PrCa cell lines. The interaction between tau and tubulin studies were assessed through immunoprecipitation studies. Results: MNP-Dtx formulation showed optimal particle size and zeta potential which can efficiently be internalized in PrCa/Dtx resistant PrCa cells. MNP-Dtx exhibited enhanced cellular uptake in drug resistant cell lines over wild type cells in a dose and time dependent manner, with 2 to 3 folds increase. Immunoblot and q PCR studies showed the expression of Tau, whole β tubulin, β tubulin III, β tubulin IV and MDR1 were found to be deregulated in both wild type and resistant cells. To delineate the mechanism of chemosensitization by MNP-Dtx on resistant cells, we performed immunoprecipitation studies, found the expression of Tau was significantly reduced during MNP-Dtx treatments w.r.t control and Dtx. HPLC studies have shown higher amounts of Dtx levels were detected in cells after MNP-Dtx treatments, annotating the sustain drug release ability of MNP nanoformulation. Further, these results were confirmed through tubulin polymerization studies. Conclusion: Overall, sustained drug release of Dtx aided in high intracellular levels of drug, thus facilitating high probability of Dtx-tubulin interaction instead of Tau-tubulin interactions resulting in tubulin fibers stabilization. This promotes Dtx induced apoptosis in wild type and Dtx resistant PrCa cells. This novel therapeutic modality might be effective to treat patients with Dtx resistant PrCa. Citation Format: Prashanth K. B. Nagesh, Pallabita Chowdhury, Elham Hatami, Vivek K. Kashyap, Bilal B. Hafeez, Sheema Khan, Subhash C. Chauhan, Meena Jaggi, Murali M. Yallapu. Docetaxel nanoformulation reverts drug resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4657.