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Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
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Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule

Joshua J Souchek1, Amanda L Davis2, Tanner K Hill1

  • 1Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska.

Molecular Cancer Therapeutics
|June 16, 2017
PubMed

Insights

NanoOrl, a nanoparticle formulation of orlistat, overcomes taxane resistance in prostate cancer by inhibiting lipid synthesis and enhancing microtubule stability. This novel approach offers a promising strategy to improve patient survival in metastatic settings.

Area of Science:

  • Oncology
  • Nanomedicine
  • Drug Resistance

Background:

  • Taxane-based chemotherapy offers survival benefits for metastatic prostate cancer but is limited by resistance.
  • Chemoresistance, particularly taxane resistance, significantly reduces median survival in these patients.
  • Novel strategies are needed to overcome taxane resistance and improve treatment outcomes.

Purpose of the Study:

  • To investigate NanoOrl, a nanoparticle formulation of orlistat, for its efficacy against taxane-resistant prostate cancer.
  • To evaluate the synergistic potential of NanoOrl in combination with taxanes in resistant prostate cancer cell lines.
  • To elucidate the mechanisms underlying the synergy between NanoOrl and taxanes.

Main Methods:

  • Utilized two established taxane-resistant (TxR) prostate cancer cell lines (PC3-TxR and DU145-TxR).
  • Assessed cytotoxicity and apoptosis induction of NanoOrl and taxanes (paclitaxel, docetaxel, cabazitaxel) alone and in combination.
  • Investigated the role of P-glycoprotein efflux and microtubule stability via immunoblot and immunofluorescence staining.
  • Measured lipid synthesis using 14C-choline incorporation.

Main Results:

  • NanoOrl and orlistat synergistically inhibited cell viability with taxanes in TxR cells, showing additive effects in parental cells.
  • Combination therapy with NanoOrl and docetaxel induced synergistic apoptosis in TxR cells.
  • Synergy was independent of P-glycoprotein activity.
  • Enhanced microtubule stability was observed with NanoOrl and docetaxel combination.
  • NanoOrl abrogated increased lipid synthesis in TxR cells.

Conclusions:

  • NanoOrl demonstrates significant cytotoxic and synergistic effects against taxane-resistant prostate cancer.
  • The combination of NanoOrl with taxanes overcomes chemoresistance through mechanisms involving lipid synthesis inhibition and microtubule stabilization.
  • NanoOrl presents a promising therapeutic strategy to overcome taxane resistance in prostate cancer.

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