Peninsula Medical School, Faculty of Health, University of Plymouth, Devon, United Kingdom
Corresponding author : C Oliver Hanemann
Abstract
External radiation therapy (RT) is often a primary treatment for inoperable meningiomas in the absence of established chemotherapy. Histone deacetylase 6 (HDAC6) overexpression, commonly found in cancer, is acknowledged as a driver of cellular growth, and inhibiting HDACs holds promise in improving radiotherapeutic efficacy. Downregulation of HDAC6 facilitates the degradation of β-catenin. This protein is a key element in the Wnt/β-catenin signalling pathway, contributing to the progression of meningiomas.
In order to elucidate the associations and therapeutic potential of HDAC6 inhibitors (HDAC6i) in conjunction with RT, we administered Cay10603, HDAC6i, to both immortalised and patient-derived meningioma cells prior to RT in this study.
Our findings reveal an increase in HDAC6 expression following exposure to RT, which is effectively mitigated with pre-treated Cay10603. The combination of Cay10603 with RT resulted in a synergistic augmentation of cytotoxic effects, as demonstrated through a range of functional assays conducted in both 2D as well as 3D settings; the latter containing syngeneic tumour microenvironment (TME). Radiation-induced DNA damage was augmented by pre-treatment with Cay10603, concomitant with the inhibition of β-catenin and minichromosome maintenance complex component 2 (MCM2) accumulation within the nucleus. This subsequently inhibited c-myc oncogene expression.
Our findings demonstrate the therapeutic potential of Cay10603 to improve the radiosensitisation and provide rationale for combining HDAC6i with RT for the treatment of meningioma.
This work was funded by Brain Tumour Research Centre of Excellence award to C Oliver Hanemann.
논문정보
형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-27)
연구진국외 연구진
분야
관련 인터뷰
학위를 하던 중 지도교수님께서 암을 죽이는 건 쉽다고 말씀하신 적이 있습니다. 플라스크에 깔려 있는 암세포에 에탄올, 아니 물만 처리한다 해도 세포는 자랄 수가 없으니까요. 하지만 그렇게 암환자를 치료한다면 좋은 세포 나쁜 세포 할 것 없이 모두 죽게 되겠죠. 때문에 어떻게 하면 암 주변에 있는 세포는 보호하면서 암세포만을 타겟하느냐가 현재까지도 중요한 숙제로 남아있습니다.