한빛사 논문
Jong Cheol Lee a,1, Gui Chul Kim b,1, Na Kyeong Lee c, Seong Who Kim d, Young Seok Cho e, Seung Woo Chung c,f,g, Yoon Se Lee b, Hyo Won Chang b, Youngro Byun c,e,*, Sang Yoon Kim b,*
a Department of Otorhinolaryngology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung-si, Gangwon-do 25440, Republic of Korea b Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea c Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea d Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea e Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea f Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States g Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States
* Corresponding author.
1 These authors equally contributed as a first author to this work.
Abstract
Therapy-induced senescence (TIS), a common outcome of current cancer therapy, is a known cause of late recurrence and metastasis and thus its eradication is crucial for therapy success. In this study, we introduced a conceptually novel strategy combining radiation-induced apoptosis-targeted chemotherapy (RIATC) with an effective glycolysis inhibitor, 2-deoxy-d-glucose (2DG) to target TIS. RIATC releases cytotoxic payload by amplification, continually increasing TIS, and this can be targeted by 2DG that stimulates an intrinsic apoptotic pathway in senescent cells, the senolysis; the senolytic 2DG also sensitizes cancer cells to chemo/radiation treatment. Anti-tumor efficacy of RIATC was investigated in numerous tumor models, and various cancer types were screened for TIS. Furthermore, in vitro evaluations of molecular markers of senescence, such as senescence-associated β-galactosidase (SA-β-Gal) assay, were performed to confirm that TIS was induced by RIATC therapy in MCF-7 cells. The combination therapy with 2DG proved to be effective in MCF-7 tumor-bearing mice that demonstrated feedback amplification of senolysis and successful inhibition of tumor growth. Our findings suggest that RIATC, when given together with 2DG, can overcome therapy-induced senescence and this combination is a promising strategy that enhances the therapeutic benefit of anti-cancer cytotoxic therapy.
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