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

Abstract

Treatment of prostate cancer with paclitaxel (PTX) often fails due to development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that co-delivery of PTX and 2′-hydroxy-2,4,4′,5,6′-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes PTX-resistant prostate cancer cells, killing both cancer stem-like cells (CSCs) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. PTX 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 PTX and rubone, respectively, controlling a drug release of 60.20 ± 2.67% and 60.62 ± 4.35% release of PTX and rubone at 24 h. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing PTX concentration. Co-incubation with a miR-34a inhibitor diminished the effect of rubone. PTX IC50 in PC3 and PC3-TXR cells was 55.6 and 2580 nM, respectively, but decreased to 49.8 and 93.2 nM when treated in combination with rubone, demonstrating a reversal of PTX resistance by rubone. Systemic administration of micelles carrying PTX and rubone inhibited orthotopic prostate tumor growth in nude mice, compared to 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 PTX in PTX-resistant prostate cancer.

Retracted: Long noncoding RNA MALAT1 enhances the docetaxel resistance of prostate cancer cells via miR‐145‐5p‐mediated regulation of AKAP12

“…MiRNAs have been reported to play important roles in tumourigenesis, metastasis and multidrug resistance (including paclitaxel, DTX and enzalutamide) in prostate cancer. 2,[43][44][45] MiR-145 has been found to be sponged by lncRNA-ROR and therefore causes chemoresistance and EMT phenotypes of DTX-resistant lung adenocarcinoma cells. 46 Another study proposed that the inhibition of miR-145-5p…”

Concise Review: Prostate Cancer Stem Cells: Current Understanding

“…This, for example, includes miR-34a which directly regulates CD44 expression [170]; miR-141 which targets multiple genes involved in tumor development and metastatic dissemination [171]; miR128 which downregulates the stem cell factors NANOG, polycomb complex protein BMI-1 and Transforming Growth Factor Beta Receptor 1 (TGFBR1); miR-199a-3p which inhibits mitogenic signaling including epidermal growth factor receptor (EGFR), c-MYC, and cyclin D1 (CCND1) [48]; let-7 microRNA which acts as a tumor suppressor and PCSC inhibitor by targeting key oncogenes such as MYC, RAS and High Mobility Group A2 gene (HMGA2) [172] and miR-200b which inhibits PCa growth, EMT and metastases [105]. Collectively, these data provide a strong rationale for development of microRNA-based therapy against PCSCs, and ongoing studies are exploring the approaches for microRNA delivery in vivo [173].…”

miR-34a regulates adipogenesis in porcine intramuscular adipocytes by targeting ACSL4

“…MicroRNA-34a has attracted interest recently because of its ability to modulate a myriad of oncogenic functions in different cancers [21][22][23][24][25][26][27]. Not only does it play a role in cancer metastasis [28,29] and drug resistance [30], it is now being evaluated as a diagnostic as well as a prognostic biomarker [31][32][33].…”