Department of Radiation Oncology, Hacettepe University School of Medicine, Sihhiye, Ankara, Turkey.
Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, Ankara, Turkey.
Clin Oncol (R Coll Radiol). 2023 Nov;35(11):744-755. doi: 10.1016/j.clon.2023.08.007. Epub 2023 Sep 3.
The role of metformin on the radiosensitising effect of cisplatin is not clear. Here we investigated the radiosensitising effect of metformin alone and combined with cisplatin in HeLa cells, as well as the implications of the adenosine monophosphate-activated protein kinase (AMPK) pathway on the radiosensitising effect.
HeLa cells were treated with ionising radiation, metformin, cisplatin, A769662 (AMPK activator) and dorsomorphin (AMPK inhibitor) or in combination. A cell proliferation assay, Western blot and flow cytometry were carried out.
Metformin potentiated cisplatin cytotoxicity when administered 4 h before ionising radiation. Although the radiosensitising effects of metformin and cisplatin alone were observed, which is more apparent at high ionising radiation doses, the metformin-cisplatin combination did not increase the radiosensitivity of cisplatin at any ionising radiation dose. Dorsomorphin alone significantly decreased cell proliferation and potentiated the radiosensitising effects of cisplatin with ionising radiation. Administration of A769662 24 h prior to cisplatin treatment resulted in an increased AMPK level that yielded resistance to cisplatin, but this effect was not observed in HeLa cells concomitantly treated with A769662 and cisplatin.
Modulation of AMPK may have a role in cervical cancer treatment. Increased AMPK levels result in higher sensitivity to ionising radiation but causes resistance to cisplatin. Dorsomorphin is proven to be a potent radiosensitising agent. The use of metformin alone may be an option as a radiosensitiser during high-dose ionising radiation (e.g. intracavitary brachytherapy).
二甲双胍对顺铂放射增敏作用的作用尚不清楚。本研究旨在探讨二甲双胍单独及联合顺铂对 HeLa 细胞的放射增敏作用，以及腺苷单磷酸激活蛋白激酶（AMPK）通路对放射增敏作用的影响。
用电离辐射、二甲双胍、顺铂、A769662（AMPK 激活剂）和 dorsomorphin（AMPK 抑制剂）或联合处理 HeLa 细胞。进行细胞增殖测定、Western blot 和流式细胞术。
二甲双胍在电离辐射前 4 小时给药可增强顺铂的细胞毒性。虽然单独使用二甲双胍和顺铂具有放射增敏作用，在高电离辐射剂量下更为明显，但二甲双胍-顺铂联合用药并不能增加顺铂在任何电离辐射剂量下的放射敏感性。单独使用 dorsomorphin 可显著降低细胞增殖并增强顺铂联合电离辐射的放射增敏作用。在顺铂处理前 24 小时给予 A769662 可导致 AMPK 水平升高，从而对顺铂产生耐药性，但在同时给予 A769662 和顺铂的 HeLa 细胞中未观察到这种作用。
AMPK 的调节可能在宫颈癌的治疗中发挥作用。AMPK 水平的升高导致对电离辐射的敏感性增加，但对顺铂产生耐药性。dorsomorphin 被证明是一种有效的放射增敏剂。单独使用二甲双胍可能是一种选择，可作为高剂量电离辐射（如腔内近距离放射治疗）期间的放射增敏剂。
