RESUMO
The prevalence of cardiac malignant neoplasms in the general population has been shown to be significant higher than what was previously estimated, yet their treatment has remained difficult and effective therapies are lacking. In the current study, we developed a novel thermotherapy in which PEG-functionalized carbon nanotubes were injected into the tumor regions to assist in the targeted delivery of infrared radiation energy with minimal hyperthermic damage to the surrounding normal tissues. In a mouse model of cardiac malignant neoplasms, the injected carbon nanotubes could rapidly induce coagulative necrosis of tumor tissues when exposed to infrared irradiation. In accordance, the treatment was also found to result in a restoration of heart functions and a concomitant increase of survival rate in mice. Taken together, our carbon nanotube-based thermotherapy successfully addressed the difficulty facing conventional laser ablation methods with regard to off-target thermal injury, and could pave the way for the development of more effective therapies against cardiac malignant neoplasms.
Assuntos
Neoplasias Cardíacas/terapia , Animais , Materiais Biocompatíveis/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Testes de Função Cardíaca , Neoplasias Cardíacas/fisiopatologia , Humanos , Hipertermia Induzida , Injeções , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanotubos de Carbono/química , Nanotubos de Carbono/ultraestrutura , Polietilenoglicóis/química , Análise de Sobrevida , Temperatura , Carga Tumoral/efeitos dos fármacosRESUMO
TET proteins, by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are hypothesized, but not directly shown, to protect promoter CpG islands (CGIs) against abnormal DNA methylation (DNAm) in cancer. We define such a protective role linked to DNA damage from oxidative stress (OS) known to induce this abnormality. TET2 removes aberrant DNAm during OS through interacting with DNA methyltransferases (DNMTs) in a "Yin-Yang" complex targeted to chromatin and enhanced by p300 mediated TET2 acetylation. Abnormal gains of DNAm and 5hmC occur simultaneously in OS, and knocking down TET2 dynamically alters this balance by enhancing 5mC and reducing 5hmC. TET2 reduction results in hypermethylation of promoter CGIs and enhancers in loci largely overlapping with those induced by OS. Thus, TET2 indeed may protect against abnormal, cancer DNAm in a manner linked to DNA damage.