1. Academic Validation
  2. Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer

Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer

  • Cancer Res. 2017 Jun 15;77(12):3244-3254. doi: 10.1158/0008-5472.CAN-16-2355.
Di Wen 1 Yang Peng 1 Feng Lin 1 Rakesh K Singh 2 Ram I Mahato 3
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska.
  • 2 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
  • 3 Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska. ram.mahato@unmc.edu.
Abstract

Treatment of prostate Cancer with paclitaxel often fails due to the development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that codelivery of paclitaxel and 2'-hydroxy-2,4,4',5,6'-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes paclitaxel-resistant prostate Cancer cells, killing both Cancer stem-like cells (CSC) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. Paclitaxel and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol; PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70% ± 0.10% and 5.34% ± 0.02% for paclitaxel and rubone, respectively, controlling a drug release of 60.20% ± 2.67% and 60.62% ± 4.35% release of paclitaxel and rubone at 24 hours. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing paclitaxel concentration. Coincubation with a miR-34a inhibitor diminished the effect of rubone. Paclitaxel IC50 in PC3 and PC3-TXR cells was 55.6 and 2,580 nmol/L, respectively, but decreased to 49.8 and 93.2 nmol/L when treated in combination with rubone, demonstrating a reversal of paclitaxel resistance by rubone. Systemic administration of micelles carrying paclitaxel and rubone inhibited orthotopic prostate tumor growth in nude mice, compared with monotherapy, by reversing the expression of miR-34a, SIRT1, cyclin D1, and E-cadherin. In summary, our results showed how rubone acts as an efficient small-molecule modulator of miR-34a to reverse chemoresistance and further enhance the therapeutic efficacy of paclitaxel in paclitaxel-resistant prostate Cancer. Cancer Res; 77(12); 3244-54. ©2017 AACR.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-119833
    99.1%, miR-34a调节剂