Rubone

Dual responsive micelles capable of modulating miRNA-34a to combat taxane resistance in prostate cancer.[Pubmed:30447399]

Biomaterials. 2019 Feb;192:95-108.

There is a direct correlation between increase in the number of cancer stem cells CSCs and chemoresistance that impedes successful chemotherapy. Synergistic therapy by targeting both bulk tumor cells and CSCs has shown promise in reversing chemoresistance and treating resistant prostate cancer. Herein, we demonstrated the fabrication of a pH and glutathione (GSH) sensitive nanocarrier for co-delivery of docetaxel (DTX) and Rubone (RUB), a miR-34 activator for targeting CSCs, for the treatment of taxane resistant (TXR) prostate cancer. DTX loaded P-RUB (DTX/P-RUB) micelles were prepared by encapsulating DTX into pH responsive diisopropylaminoethanol (DIPAE) and GSH responsive RUB prodrug conjugated polycarbonate based micelles. The self-assembled DTX/P-RUB micelles displayed good stability in vitro and could efficiently target to tumors by enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the micelles underwent expansion and disassembly due to the protonation of DIPAE and GSH induced cleavage of disulfide bond in acidic endocytic vesicles, resulting in fast release of DTX and RUB. The released RUB then upregulated the intracellular miR-34a, which then affected the expression of proteins involved in chemoresistance, thus sensitizing the tumor cells towards DTX and further leading to significant inhibition of TXR tumor progression. Thus, DTX/P-RUB micelles have the potential to treat TXR prostate cancer. By taking advantage of this dual responsive strategy, the successful delivery of many other hydrophobic drugs can be achieved for cancer treatment.

Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer.[Pubmed:28428276]

Cancer Res. 2017 Jun 15;77(12):3244-3254.

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(50) 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. (c)2017 AACR.

Carboxymethyl Dextran-Stabilized Polyethylenimine-Poly(epsilon-caprolactone) Nanoparticles-Mediated Modulation of MicroRNA-34a Expression via Small-Molecule Modulator for Hepatocellular Carcinoma Therapy.[Pubmed:27300477]

ACS Appl Mater Interfaces. 2016 Jul 13;8(27):17068-79.

MicroRNA-34a (miR-34a) modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC). 2'-Hydroxy-2,4,4',5,6'-pentamethoxychalcone, termed Rubone, has been shown to specifically upregulate miR-34a expression in HCC cells and considered as novel anticancer agent. However, the extremely low aqueous solubility of Rubone hampers its use in cancer treatment. In the present study, surface-stabilized nanoparticles-based delivery strategy was engaged to overcome this impediment. In our preparation, Rubone was encapsulated in the micelles composed of polyethylenimine-poly(epsilon-caprolactone) (PEI-PCL) through hydrophobic interactions, which were subsequently stabilized with anionic carboxymethyl dextran CMD via electronic interaction. We found that Rubone-encapsulating nanoparticles are dispersed well in aqueous solution. The results further demonstrated that Rubone could be efficiently delivered in HCC cells by nanoparticles and upregulate miR-34a expression, which in turn led to inhibition of proliferation, migration, and increased apoptosis of HCC cells. In vivo experiments showed that Rubone can be preferentially delivered into tumor tissues by CMD-stabilized PEI-PCL nanoparticles after intravenous administration and significantly inhibited tumor growth. Furthermore, low cytotoxicity of the nanoparticles was observed in vitro and in vivo analyses, indicating a good compatibility of generated nanoparticles. The obtained results suggest that CMD-stabilized PEI-PCL nanoparticles may serve as a novel approach for small-molecule-modulator-mediated miR-34a restoration for HCC therapy.

Small molecule targeting miR-34a for cancer therapy.[Pubmed:27308410]

Mol Cell Oncol. 2015 Feb 24;2(1):e977160.

miR-34a functions as a tumor suppressor in many cancers. In a recent issue of Cancer Research, we describe a small molecule, Rubone, with strong anticancer activity. Rubone selectively restored miR-34a expression in hepatocellular carcinoma cells in which miR-34a was silenced. Restoration of miR-34a by Rubone represents a promising therapeutic approach against cancer.

A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma.[Pubmed:25217526]

Cancer Res. 2014 Nov 1;74(21):6236-47.

Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wild-type or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function.

Rubone (CAS 73694-15-2) is a natural product offered by BioCrick for research applications. Customers can buy or order Rubone from BioCrick, a supplier and manufacturer of research chemicals, with product specifications, purity, packaging, and pricing information available upon request.