Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Environ Toxicol. 2018 May;33(5):587-593. doi: 10.1002/tox.22544. Epub 2018 Feb 13.
Colorectal cancer (CRC) is one of the most common cancers and causes of cancer-related death. There are several first-line chemotherapeutic drugs used to treat CRC. Oxaliplatin (OXA) is an alkylating cytotoxic agent that is usually combined with other chemotherapeutic drugs to treat stage II and stage III CRC. However, cancer cells commonly acquire multidrug resistance (MDR), which is a major obstruction to cancer treatment. Recent studies have shown that natural components from traditional Chinese medicine or foods that have many biological functions may be new adjuvant therapies in clinical trials. We challenged LoVo CRC cell lines with OXA in a dose-dependent manner to create an OXA-resistant model. The expression of ABCG2 was significantly higher, and levels of endoplasmic reticulum (ER) stress markers were lower than those Parental cells. However, Lupeol, which is found in fruits and vegetables, has been shown to have bioactive properties, including anti-tumor properties that are relevant to many diseases. In our study, Lupeol downregulated cell viability and activated cell apoptosis. Moreover, Lupeol decreased the expression of ABCG2 and activated ER stress to induce OXA-resistant cell death. Importantly, the anti-tumor effect of Lupeol in OXA-resistant cells was higher than that of LoVo Parental cells. In addition, we also confirmed our results with a xenograft animal model, and the tumor size significantly decreased after Lupeol injections. Our findings show that Lupeol served as a strong chemoresistant sensitizer and could be a new adjuvant therapy method for chemoresistant patients.
结直肠癌（CRC）是最常见的癌症之一，也是癌症相关死亡的主要原因之一。目前有几种一线化疗药物用于治疗 CRC。奥沙利铂（OXA）是一种烷化剂细胞毒性药物，通常与其他化疗药物联合用于治疗 II 期和 III 期 CRC。然而，癌细胞通常会获得多药耐药性（MDR），这是癌症治疗的主要障碍。最近的研究表明，来自中药或食物的天然成分具有许多生物功能，可能成为临床试验中的新辅助治疗方法。我们以剂量依赖性的方式用 OXA 挑战 LoVo CRC 细胞系，以建立 OXA 耐药模型。ABCG2 的表达明显更高，内质网（ER）应激标志物的水平低于亲本细胞。然而，在水果和蔬菜中发现的羽扇豆醇具有生物活性特性，包括与许多疾病相关的抗肿瘤特性。在我们的研究中，羽扇豆醇下调细胞活力并激活细胞凋亡。此外，羽扇豆醇降低了 ABCG2 的表达并激活了 ER 应激，以诱导 OXA 耐药细胞死亡。重要的是，羽扇豆醇在 OXA 耐药细胞中的抗肿瘤作用高于 LoVo 亲本细胞。此外，我们还通过异种移植动物模型证实了我们的结果，并且在羽扇豆醇注射后肿瘤大小显著减小。我们的研究结果表明，羽扇豆醇是一种强大的化疗耐药增敏剂，可能成为化疗耐药患者的新辅助治疗方法。
