Department of Gynecology, Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China.
Department of Orthopedics, Shenzhen Hospital of Southern Medical University, Shenzhen 518100, China.
Curr Oncol. 2022 Apr 16;29(4):2808-2822. doi: 10.3390/curroncol29040229.
Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related death. The high mortality and morbidity associated with EOC are mostly due to late diagnosis and chemotherapy drug resistance. Currently, the standard first-line chemotherapy regimen is systemic administration of platinum-based chemotherapy combined with a taxane. A major problem besides cisplatin resistance (occurring in nearly one-third of patients) is the greater toxicity of the drug combinations. A synergistic treatment with drug supporting activity could maximize the cytotoxic effects of chemotherapeutic agents on tumor cells while decreasing the dosage of each drug to potentially reduce toxicity. The ALDH-blocking agent Disulfiram (DSF), a clinically approved drug used for alcoholism treatment, has displayed promising anti-cancer activity. We previously described that blocking ALDH activity enhances the induction of apoptosis, especially in ovarian cancer stem cells treated with chemotherapeutic agents. In this study, we further investigated the synergistic effect of DSF in combination with cytotoxic chemotherapeutic drugs. The concentration of each chemotherapeutic agent could be significantly reduced with sustained efficacy on tumor cell apoptosis in cell lines in vitro (Dose-Reduction Index at IC from 1 to 50). Moreover, the potential chemo-sensitizing effects of DSF on ALDH-associated cisplatin-resistant ovarian cancer stem cells were also investigated and shown that in contrast to its high resistance to cisplatin, the cisplatin-resistant cells remain very sensitive to DSF-induced cytotoxicity (apoptosis and necrosis: cisplatin-resistant cells vs. parental cells: 60.4% vs. 20.5%). In combination with DSF and cisplatin, relatively more apoptosis and necrosis were induced in cisplatin-resistant cells than in their parental cells (apoptosis and necrosis: cisplatin-resistant cells vs. parental cells: 81.5% vs. 50.1%). A transcriptome analysis identified that ALDH was mainly enriched in the cancer-associated fibroblasts and showed that ALDH plays roles in responding to oxidative stress, metabolisms, and energy transition in the ALDH-associated cisplatin-resistant ovarian cancer stem cells. In conclusion, our data demonstrate a key role of ALDH-associated cisplatin-resistant cancer stem cells and identifies DSF as a potential adjuvant for a rational protocol design by computational quantitative assessment in vitro on ovarian cancer cell lines. Our work contributes to resolving the ALDH-associated cisplatin resistance and provides a resource for the development of novel chemotherapeutic regimens.
上皮性卵巢癌 (EOC) 是妇科癌症相关死亡的主要原因。EOC 相关的高死亡率和发病率主要归因于晚期诊断和化疗药物耐药性。目前，标准的一线化疗方案是铂类化疗联合紫杉烷的全身给药。除顺铂耐药（发生在近三分之一的患者中）之外，一个主要问题是药物联合的毒性更大。药物支持活性的协同治疗可以最大限度地提高化疗药物对肿瘤细胞的细胞毒性作用，同时降低每种药物的剂量，从而有可能降低毒性。醛脱氢酶阻断剂双硫仑 (DSF) 是一种用于治疗酒精中毒的临床批准药物，已显示出有希望的抗癌活性。我们之前描述过，阻断 ALDH 活性可增强化疗药物诱导的细胞凋亡，特别是在卵巢癌干细胞中。在这项研究中，我们进一步研究了 DSF 与细胞毒性化疗药物联合使用的协同作用。在体外细胞系中，每种化疗药物的浓度可以显著降低，而肿瘤细胞凋亡的疗效持续（IC 处的剂量减少指数为 1 至 50）。此外，还研究了 DSF 对 ALDH 相关顺铂耐药卵巢癌干细胞的潜在化疗增敏作用，并表明与顺铂的高耐药性相比，顺铂耐药细胞对 DSF 诱导的细胞毒性仍非常敏感（细胞凋亡和坏死：顺铂耐药细胞与亲本细胞相比：60.4%对 20.5%）。与顺铂和 DSF 联合使用时，顺铂耐药细胞比亲本细胞诱导更多的细胞凋亡和坏死（细胞凋亡和坏死：顺铂耐药细胞与亲本细胞相比：81.5%对 50.1%）。转录组分析表明 ALDH 主要富集在癌相关成纤维细胞中，并表明 ALDH 在 ALDH 相关顺铂耐药卵巢癌干细胞中对氧化应激、代谢和能量转换的反应中起作用。总之，我们的数据表明 ALDH 相关顺铂耐药癌干细胞的关键作用，并确定 DSF 作为通过体外卵巢癌细胞系的计算定量评估进行合理方案设计的潜在辅助药物。我们的工作有助于解决与 ALDH 相关的顺铂耐药性问题，并为开发新的化疗方案提供了资源。
