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

Overview

Journal Cancer Res

Specialty Oncology

Date 2017 Apr 22

PMID 28428276

Citations 31

Authors

Di Wen

Yang Peng

Feng Lin

Rakesh K Singh

Ram I Mahato

Affiliations

Soon will be listed here.

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 IC 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. .

Citing Articles

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References

Bissell M, Radisky D, Rizki A, Weaver V, Petersen O . The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation. 2002; 70(9-10):537-46. PMC: 2933198. DOI: 10.1046/j.1432-0436.2002.700907.x. View

Kopczynska E . Role of microRNAs in the resistance of prostate cancer to docetaxel and paclitaxel. Contemp Oncol (Pozn). 2016; 19(6):423-7. PMC: 4731449. DOI: 10.5114/wo.2015.56648. View

Agostini M, Tucci P, Killick R, Candi E, Sayan B, Rivetti di Val Cervo P . Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets. Proc Natl Acad Sci U S A. 2011; 108(52):21093-8. PMC: 3248477. DOI: 10.1073/pnas.1112061109. View

Chen W, Liu S, Chang Y, Yin J, Yeh H, Mouhieddine T . MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. Oncotarget. 2014; 6(1):441-57. PMC: 4381606. DOI: 10.18632/oncotarget.2690. View

Wang G, Liu G, Ye Y, Fu Y, Zhang X . Upregulation of miR-34a by diallyl disulfide suppresses invasion and induces apoptosis in SGC-7901 cells through inhibition of the PI3K/Akt signaling pathway. Oncol Lett. 2016; 11(4):2661-2667. PMC: 4812513. DOI: 10.3892/ol.2016.4266. View

Kojima K, Fujita Y, Nozawa Y, Deguchi T, Ito M . MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanisms. Prostate. 2010; 70(14):1501-12. DOI: 10.1002/pros.21185. View

Vo D, Staedel C, Zehnacker L, Benhida R, Darfeuille F, Duca M . Targeting the production of oncogenic microRNAs with multimodal synthetic small molecules. ACS Chem Biol. 2013; 9(3):711-21. DOI: 10.1021/cb400668h. View

Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H . The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011; 17(2):211-5. PMC: 3076220. DOI: 10.1038/nm.2284. View

Kojima K, Ohhashi R, Fujita Y, Hamada N, Akao Y, Nozawa Y . A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells. Biochem Biophys Res Commun. 2008; 373(3):423-8. DOI: 10.1016/j.bbrc.2008.06.045. View

10.

Wen D, Chitkara D, Wu H, Danquah M, Patil R, Miller D . LHRH-conjugated micelles for targeted delivery of antiandrogen to treat advanced prostate cancer. Pharm Res. 2014; 31(10):2784-95. DOI: 10.1007/s11095-014-1375-6. View

11.

Singh S, Chitkara D, Mehrazin R, Behrman S, Wake R, Mahato R . Chemoresistance in prostate cancer cells is regulated by miRNAs and Hedgehog pathway. PLoS One. 2012; 7(6):e40021. PMC: 3386918. DOI: 10.1371/journal.pone.0040021. View

12.

Li F, Danquah M, Mahato R . Synthesis and characterization of amphiphilic lipopolymers for micellar drug delivery. Biomacromolecules. 2010; 11(10):2610-20. DOI: 10.1021/bm100561v. View

13.

Lou P, Chen W, Lin C, Chen H, Wu J . Taxol reduces cytosolic E-cadherin and beta-catenin levels in nasopharyngeal carcinoma cell line TW-039: cross-talk between the microtubule- and actin-based cytoskeletons. J Cell Biochem. 2000; 79(4):542-56. View

14.

Liang J, Li Y, Daniels G, Sfanos K, De Marzo A, Wei J . LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a. Mol Cancer Res. 2015; 13(4):681-8. PMC: 4437214. DOI: 10.1158/1541-7786.MCR-14-0503. View

15.

Croce C . Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009; 10(10):704-14. PMC: 3467096. DOI: 10.1038/nrg2634. View

16.

Lee G, Kenny P, Lee E, Bissell M . Three-dimensional culture models of normal and malignant breast epithelial cells. Nat Methods. 2007; 4(4):359-65. PMC: 2933182. DOI: 10.1038/nmeth1015. View

17.

Okada N, Lin C, Ribeiro M, Biton A, Lai G, He X . A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes Dev. 2014; 28(5):438-50. PMC: 3950342. DOI: 10.1101/gad.233585.113. View

18.

Kashat M, Azzouz L, Sarkar S, Kong D, Li Y, Sarkar F . Inactivation of AR and Notch-1 signaling by miR-34a attenuates prostate cancer aggressiveness. Am J Transl Res. 2012; 4(4):432-42. PMC: 3493023. View

19.

Collins A, Berry P, Hyde C, Stower M, Maitland N . Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005; 65(23):10946-51. DOI: 10.1158/0008-5472.CAN-05-2018. View

20.

Wen D, Danquah M, Chaudhary A, Mahato R . Small molecules targeting microRNA for cancer therapy: Promises and obstacles. J Control Release. 2015; 219:237-247. PMC: 4749151. DOI: 10.1016/j.jconrel.2015.08.011. View