Gold nanoparticles loaded with cullin-5 DNA increase sensitivity to 17-AAG in cullin-5 deficient breast cancer cells

Abstract

HSP90 inhibitors have the potential to treat many types of cancer due to the dependence of tumor cells on HSP90 for cell growth and proliferation. The Cullin-5 (Cul5) E3 ubiquitin ligase is required for HSP90 inhibitors to induce client protein degradation and subsequent cell death. Cul5 is expressed at low levels in breast cancer cells compared to patient matched controls. This observed low Cul5 expression may play a role in the reported decreased efficacy of 17-AAG and related HSP90 inhibitors as a monotherapy. We have developed a method for delivery of 17-AAG plus Cul5 DNA to cells via gold nanoparticles (AuNPs). Delivery of AuNPs containing Cul5 DNA increases the sensitivity of Cul5 deficient AU565 cells to 17-AAG. Characterization of AuNPs by UV-vis spectrum, TEM, gel electrophoresis assay and 1H NMR indicate attachment of both 17-AAG and DNA payload as well as AuNP stability. Studies in Cul5 deficient AU565 cells reveal that delivery of Cul5 and 17-AAG together increase cytotoxicity. Our results provide evidence that delivery of DNA with drug may serve as a method to sensitize drug resistant tumor cells.

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

“…In 1996, Alivisatos et al first developed AuNP–DNA conjugates by attaching several DNA strands of a defined length and sequence to the surface of individual AuNPs [ 154 ]. AuNP–DNA conjugates are generally formed by covalent binding, and there are many studies that have described alternative protocols for the preparation of them with discrete, well-defined, homogeneous, and soluble physicochemical properties [ 155 , 156 , 157 ]. The DNA sequences attached to the AuNPs guide the conjugates to targeted cells, where they combine with their complementary sequences following the Watson–Crick principle, thus achieving precise delivery.…”

Gold nanoparticle‑mediated delivery of paclitaxel and nucleic acids for cancer therapy (Review)

“…The conversion of amine-modified sirna duplexes into dithiocarbamate ligands followed by conjugation with aunPs increases sirna stability and enhances targeted release of sirna (47). additional potential advantages of aunP-based therapy have been demonstrated by the development of an intracellular self-assembly system of dna and aunPs (48). in a previous study (48), mrna of survivin, which is an apoptosis inhibitor, and aunPs in a complex with its complementary dna sequence were transfected into cancer cells separately and spontaneously formed cytoplasmic aggregates.…”

“…additional potential advantages of aunP-based therapy have been demonstrated by the development of an intracellular self-assembly system of dna and aunPs (48). in a previous study (48), mrna of survivin, which is an apoptosis inhibitor, and aunPs in a complex with its complementary dna sequence were transfected into cancer cells separately and spontaneously formed cytoplasmic aggregates. Survivin mrna and aunPs entered cells easily due to their small size, whereas the larger aggregates exhibited improved intracellular retention.…”

“…Survivin mrna and aunPs entered cells easily due to their small size, whereas the larger aggregates exhibited improved intracellular retention. This resulted in enhanced apoptosis and photothermal function, leading to cancer cell death rates of up to 93.3%, with minimal toxicity to normal cells (48).…”

Cullin-5 (CUL5) as a potential prognostic marker in a pan-cancer analysis of human tumors

“…Other research groups have suggested a functional association between the multifunctional CUL5 protein and the occurrence of ovarian [ 10 ], lung [ 11 , 12 ], and breast [ 13 , 14 ] cancers. The current evidence from animal and cell studies supports correlations between different cancer types and CUL5.…”