title: Aerosol delivery of beclin1 enhanced the anti-tumor effect of radiation in the lungs of K-rasLA1 mice.
abstract: Radiotherapy alone has several limitations for treating lung cancer. Inhalation, a non-invasive approach for direct delivery of therapeutic agents to the lung, may help to enhance the therapeutic efficacy of radiation. Up-regulating beclin1, known as a tumor suppressor gene that plays a major role in autophagy, may sensitize tumors and lead to tumor regression in lungs of K-ras(LA1) lung cancer model mice. To minimize the side-effects of radiotherapy, fractionated exposures (five times, 24-h interval) with low dose (2 Gy) of radiation to the restricted area (thorax, 2 cm) were conducted. After sensitizing the lungs with radiation, beclin1, complexed with a nano-sized biodegradable poly(ester amine), was prepared and delivered into the murine lung via aerosol three times/week for four weeks. In a histopathological analysis, animals treated with beclin1 and radiation showed highly significant tumor regression and low progression to adenocarcinoma. An increase in the number of autophagic vacuoles and secondary lysosomes was detected. Dissociation of beclin1-bcl2 stimulated autophagy activation and showed a synergistic anti-tumor effect by inhibiting the Akt-mTOR pathway, cell proliferation and angiogenesis. The combination of radiation with non-invasive aerosol delivery of beclin1 may provide a prospect for developing novel therapy regimens applicable in clinics.
authors: Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
authors: Ji-Young
authors: JY
authors: Shin
authors: Hwang-Tae
authors: HT
authors: Lim
authors: Arash
authors: A
authors: Minai-Tehrani
authors: Mi-Suk
authors: MS
authors: Noh
authors: Ji-Eun
authors: JE
authors: Kim
authors: Ji-Hye
authors: JH
authors: Kim
authors: Hu-Lin
authors: HL
authors: Jiang
authors: Rohidas
authors: R
authors: Arote
authors: Doo-Yeol
authors: DY
authors: Kim
authors: Chanhee
authors: C
authors: Chae
authors: Kee-Ho
authors: KH
authors: Lee
authors: Mi-Sook
authors: MS
authors: Kim
authors: Myung-Haing
authors: MH
authors: Cho
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics*; D001343:Autophagy; D000071186:Beclin-1; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D011905:Genes, ras; D015316:Genetic Therapy / Q000379:methods; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D011401:Promoter Regions, Genetic; D011878:Radiotherapy / Q000379:methods; D019098:Telomerase / Q000235:genetics
chemical_list: D000336:Aerosols; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D019098:Telomerase; C509187:Tert protein, mouse