化疗耐药癌细胞经常表现出一种持续激活的内质网（ER）应激状态。与ER应激相互作用，未折叠蛋白反应（UPR）是一种由未折叠蛋白积累引发的适应性反应。蛋白质二硫化异构酶（PDI）是一种分子伴侣，已知在通过替莫唑胺（TMZ）获得耐药性的恶性胶质母细胞瘤中高度表达。我们研究了靶向PDI的治疗是否提供了克服化疗耐药的理论依据。使用小分子抑制剂CCF642抑制胶质母细胞瘤细胞中的PDI活性。采用单一或联合治疗TMZ。我们制备了CCF642的纳米制剂，以白蛋白为药物载体用于正位移植肿瘤模型。抑制PDI显著增强了TMZ对胶质母细胞瘤细胞的细胞毒作用。更重要的是，抑制PDI能够使最初对TMZ治疗耐药的胶质母细胞瘤细胞敏感化。CCF642纳米制剂耐受性良好并能有效地抑制肿瘤生长。它通过下调PERK信号诱导细胞死亡触发UPR，超过修复并引起ER扰动。与任一单独模式相比，TMZ与CCF642的联合治疗显著减少了肿瘤生长。我们的研究表明，通过靶向PDI调节ER应激是克服化疗耐药的有前途的治疗理论依据。©2023年作者，独家授权给施普林格自然有限公司。

Chemoresistant cancer cells frequently exhibit a state of chronically activated endoplasmic reticulum (ER) stress. Engaged with ER stress, the unfolded protein response (UPR) is an adaptive reaction initiated by the accumulation of misfolded proteins. Protein disulfide isomerase (PDI) is a molecular chaperone known to be highly expressed in glioblastomas with acquired resistance to temozolomide (TMZ). We investigate whether therapeutic targeting of PDI provides a rationale to overcome chemoresistance.The activity of PDI was suppressed in glioblastoma cells using a small molecule inhibitor CCF642. Either single or combination treatment with TMZ was used. We prepared nanoformulation of CCF642 loaded in albumin as a drug carrier for orthotopic tumour model.Inhibition of PDI significantly enhances the cytotoxic effect of TMZ on glioblastoma cells. More importantly, inhibition of PDI is able to sensitise glioblastoma cells that are initially resistant to TMZ treatment. Nanoformulation of CCF642 is well-tolerated and effective in suppressing tumour growth. It activates cell death-triggering UPR beyond repair and induces ER perturbations through the downregulation of PERK signalling. Combination treatment of TMZ with CCF642 significantly reduces tumour growth compared with either modality alone.Our study demonstrates modulation of ER stress by targeting PDI as a promising therapeutic rationale to overcome chemoresistance.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.