Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion

Abstract

DNA Methyltransferase 1 (DNMT1) promotes DNA methylation to maintain cancer drug resistance. The epigenetic drug, decitabine (DAC) is a potent hypomethylating agent, but its effect is transient because of its instability. We tested the efficacy of DAC-loaded nanogels in doxorubicin-resistant breast cancer cells, DAC-resistant melanoma cells, and leukemia cells. DAC in nanogel sustained DNMT1 depletion, prolonged cell arrest in the G2/M cell-cycle phase, and significantly enhanced antiproliferative effect of DAC. The efficacy of DAC-loaded nanogels was more significant in resistant than sensitive cells. Our data suggest that effective delivery of DAC and prolonged DNMT1 depletion are critical to overcoming drug resistance.

Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth

“…Importantly, as with demethylating treatment (Figure 7C), we observed that ectopic miR-150 expression also corresponded to a large antiproliferative effect that attenuated MYB expression in these crizotinib-resitant NPM-ALK(+) cells ( Figure 7, C and F). The same results were obtained in KARPAS-299-CR6 cells when STAT3 activity was blocked by the small-molecule inhibitor Stattic, or when siRNAs directed against STAT3 mRNA were used in com- cell arrest in the G2/M cell cycle phase and significantly enhanced the antiproliferative effect of decitabine (57). They also showed that the efficacy of decitabine was more significant in resistant cells than in sensitive cells.…”

“…They also showed that the efficacy of decitabine was more significant in resistant cells than in sensitive cells. These data suggest that effective delivery of decitabine and prolonged DNMT1 depletion are critical to overcome drug resistance (57).…”

Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia

“…This level of drug loading was compared to that of previous studies, in which nanostructured lipid carriers were developed. Drug loading ranged from 6% to 7% w/w for decitabine-loaded nanogels 7 and was 8.54%±2.65% in lipid-based nanocarriers developed by Neupane et al 10 The size obtained in our formulation was less than that of previously developed formulations, ranging from 80 to 200 nm. 9,10,30,31 Paillard et al have demonstrated that the number of LNCs internalized into cells is inversely proportional to their size, 32 suggesting that the size obtained for the THP-T80-LNC formulation could favor internalization.…”

“…For example, Vijayaraghavalu and Labhasetwar have tested decitabine-loaded nanogels for their ability to protect decitabine from degradation and enhance its intracellular uptake. 7 Cui et al have developed decitabine conjugates incorporated into micelles to enhance the activity of an associated drug, temozolomide, against glioblastoma cells, 8 Neupane et al 9,10 have developed lipid-decitabine conjugate nanoparticles for oral administration. All these studies used organic solvents for chemical modification of the drug or the process of nanoparticle formulation.…”

Epigenetic changes in gastroenteropancreatic neuroendocrine tumours

“…64 The antiproliferative effect of decitabine has been tested in different tumour histotypes with encouraging results. [65][66][67][68][69][70][71] However, its anticancer activity in patients with refractory and metastatic solid tumours led to only limited responses because of difficulty to calibrate steady-state blood concentration and a narrow therapeutic index, resulting in dose-limiting haematologic toxicities. [72][73][74] Therefore, considering that the therapeutic potential of decitabine is hampered by its systemic instability, further studies are required to improve drug stability in solution and efficacy of delivery, in order to minimise toxicities, and to prolong epigenetic outcomes.…”