Department of Pharmacy, University of Chieti-Pescara "G. d'Annunzio", Via dei Vestini, 31, 66100 Chieti, Italy.
Department of Health Sciences, University of Catanzaro "Magna Graecia", Viale Europa, University Campus "S. Venuta", I-88100 Germaneto - Catanzaro, Italy.
Anticancer Agents Med Chem. 2019;19(12):1513-1522. doi: 10.2174/1871520619666190626114641.
Glutathione (GSH), which is the predominant low molecular weight intracellular thiol in mammals, has multiple functions, such as those of protecting against oxidative stress and detoxifying endogenous and exogenous electrophiles. High GSH levels, which have been observed in various types of tumors, have been thought to contribute to the resistance of neoplastic cells to apoptotic stimuli triggered by pro-oxidant therapy. Although L-(S,R)-Buthionine Sulfoximine (BSO), a selective irreversible inhibitor of glutamate cysteine ligase, depletes GSH and in and sensitizes tumor cells to radiation and some cancer chemotherapeutics, its toxicity and short half-life have limited its application to combination anticancer therapies.
To demonstrate that a folate-targeted PEGylated BSO conjugate can sensitize cancer cells to a Reactive Oxygen Species (ROS)-generating anticancer agent by depleting GSH.
A novel folate-targeted PEGylated-BSO conjugate was synthesized and tested in combination with gemcitabine in human cell lines that over-express (HeLa) or do not express (A549) the folate receptor.
The prepared folate-PEG-GFLG-BSO conjugate proved to be efficacious in reducing GSH levels and, when used in combination with the pro-oxidant drug gemcitabine, it enhanced drug activity in the cell line overexpressing the folate receptor.
The folate-PEG-GFLG-BSO conjugate studied was found to be effective in sensitizing folatereceptor positive cancer cells to the ROS-generating drug gemcitabine.
谷胱甘肽（GSH）是哺乳动物中主要的低分子量细胞内巯基，具有多种功能，如保护细胞免受氧化应激、解毒内源性和外源性亲电体等。在各种类型的肿瘤中观察到高 GSH 水平，人们认为这有助于肿瘤细胞抵抗由促氧化剂治疗引发的凋亡刺激。虽然 L-（S，R）-丁硫氨酸亚砜（BSO）是谷氨酸半胱氨酸连接酶的选择性不可逆抑制剂，可耗尽 GSH 并使肿瘤细胞对辐射和一些癌症化疗药物敏感，但它的毒性和短半衰期限制了其在联合抗癌治疗中的应用。
证明叶酸靶向聚乙二醇化 BSO 缀合物通过耗尽 GSH 使癌细胞对产生活性氧物质（ROS）的抗癌剂敏感。
合成了一种新型的叶酸靶向聚乙二醇化 BSO 缀合物，并在过度表达（HeLa）或不表达（A549）叶酸受体的人细胞系中与吉西他滨联合测试。
所制备的叶酸-PEG-GFLG-BSO 缀合物被证明在降低 GSH 水平方面有效，并且当与促氧化剂药物吉西他滨联合使用时，它增强了在表达叶酸受体的细胞系中的药物活性。
研究发现，叶酸-PEG-GFLG-BSO 缀合物能够有效使叶酸受体阳性癌细胞对产生 ROS 的药物吉西他滨敏感。
