Department of Reproductive Medicine, the First Affiliated Hospital of the Medical College, Xi'an Jiaotong University Medical School, 76 West Yanta Road, Xi'an, 710061, China.
Division of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Medical School, Xi'an, 710061, China.
BMC Cancer. 2022 May 9;22(1):521. doi: 10.1186/s12885-022-09574-5.
Tumor resistance is a global challenge for tumor treatment. Cancer stem cells (CSCs) are the main population of tumor cells for drug resistance. We have reported that high aldehyde dehydrogenase (ALDH) activity represents a functional marker for cervical CSCs. Here, we aimed at disulfiram (DSF), an ALDH inhibitor, that has the potential to be used for cervical cancer treatment.
MTT assay, western blot, vector construction and transfection, cell sorting and in vivo anti-tumor assays were performed using cervical cancer cell lines SiHa and HeLa. Cell cycle distribution and cell apoptosis were carried out by flow cytometry. The cytotoxicity of DSF was detected by MTT assay and cervical cancer xenograft models.
DSF was cytotoxic to cervical cancer cell lines in a copper (Cu)-dependent manner. Disulfiram/copper (DSF/Cu) complex induced deregulation of S-phase and inhibited the expression of stemness markers in cervical cancer cells. Furthermore, DSF/Cu could also reduce the cancer stem cell-like LGR5 cells which lead to cisplatin resistance in cervical cancer cells. DSF/Cu complex had the greater antitumor efficacy on cervical cancer than cisplatin in vitro and in vivo.
Our findings indicate that the cytotoxicity of DSF/Cu complex may be superior to cisplatin because of targeting LGR5-positive cervical cancer stem-like cells in cervical cancer. Thus, the DSF/Cu complex may represent a potential therapeutic strategy for cervical cancer patients.
肿瘤耐药是肿瘤治疗的全球性挑战。癌症干细胞（CSCs）是肿瘤细胞耐药的主要群体。我们已经报道，高醛脱氢酶（ALDH）活性代表宫颈 CSCs 的功能标志物。在这里，我们旨在研究一种名为双硫仑（DSF）的 ALDH 抑制剂，它有可能用于宫颈癌的治疗。
使用宫颈癌细胞系 SiHa 和 HeLa 进行 MTT 测定、western blot、载体构建和转染、细胞分选和体内抗肿瘤测定。通过流式细胞术检测细胞周期分布和细胞凋亡。通过 MTT 测定和宫颈癌异种移植模型检测 DSF 的细胞毒性。
DSF 以铜（Cu）依赖性方式对宫颈癌细胞系具有细胞毒性。双硫仑/铜（DSF/Cu）复合物诱导 S 期失调并抑制宫颈癌细胞中干性标志物的表达。此外，DSF/Cu 还可以减少导致宫颈癌细胞顺铂耐药的 LGR5 阳性癌症干细胞样细胞。DSF/Cu 复合物在体外和体内对宫颈癌的抗肿瘤疗效优于顺铂。
我们的研究结果表明，DSF/Cu 复合物的细胞毒性可能优于顺铂，因为它可以靶向宫颈癌中 LGR5 阳性的癌症干细胞样细胞。因此，DSF/Cu 复合物可能代表了宫颈癌患者的一种潜在治疗策略。
