방사선의학 웹진

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Abstract
Background: Despite available treatment approaches, including surgical resection along with chemotherapy and radiotherapy, glioblastoma (GBM), the most prevalent primary brain tumor, remains associated with a grim prognosis. Although radiotherapy is central to GBM treatment, its combination with bioenergetics regulators has not been validated in clinical practice. Here, we hypothesized that bioenergetics regulators can enhance the radio-sensitivity of GBM tumorspheres (TSs).

Methods: Gene expression profiles of GBM patient-derived TSs were obtained through microarray and RNA-seq. In vitro treatment efficacy was assessed using clonogenic assay, 3D invasion assay, neurosphere formation assay, and flow cytometry. Protein expression was measured via western blot, and γH2AX foci were detected via immunofluorescence. In vivo efficacy was confirmed in an orthotopic xenograft model.

Results: Based on radiation response-associated gene expression, GBM TSs were classified into high- or low-radioresistant groups. Among the five bioenergetics regulators, the pentose phosphate pathway inhibitor DHEA and the glycolysis inhibitor 2-DG notably enhanced the efficacy of ionizing radiation (IR) efficacy in vitro, reducing the survival fraction, stemness, and invasiveness in high- and low-radioresistant TSs. Combination with 2-DG further stimulated IR-induced DNA damage response and apoptosis in low-radioresistant GBM TSs. RNA-seq analysis revealed a downregulation of bioenergetics- and cell cycle-associated genes, whereas extracellular matrix- and cell adhesion-associated genes were enhanced by combined IR and 2-DG treatment. This therapeutic regimen extended survival and diminished tumor size in mouse xenograft models.

Conclusions: Our data suggest that combination with bioenergetics regulator 2-DG enhances the radio-sensitivity of GBM TSs, highlighting the clinical potential of this combined regimen.

방사선 치료는 교모세포종 종양구의 DNA 손상을 유발하며, 여기에 생체에너지 조절제(DHEA 또는 2-DG)를 병행하면 종양 세포의 생존 능력이 약화되어 세포 사멸과 성장 억제가 더욱 효과적으로 촉진됩니다. 따라서, 이러한 병용치료가 방사선 저항성을 낮추고 종양 억제 효과를 극대화할 수 있음을 보여주며, 생체에너지 조절을 활용한 병용 치료가 효과적인 치료 접근법이 될 가능성을 시사합니다.

Affiliations

Seo Jin Kim 1, Junseong Park 2, Jin-Kyoung Shim 1, Ran Joo Choi 1, Ju Hyung Moon 3, Eui Hyun Kim 3, Wan-Yee Teo 4, Jong Hee Chang 3, Seok-Gu Kang 5
1Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, South Korea.
2Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea; Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
3Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
4Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
5Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, South Korea; Department of Medical Science, Yonsei University Graduate School, Seoul, South Korea. Electronic address: seokgu9@gmail.com.