Zhang Die, Jia Tingting, Chen Xingxing, Jiang Haopeng, Guo Teng, Dong Junjun, Zeng Hairong, Wang Yixin, Yuan Yi
Department of Pharmacy, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
Heliyon. 2023 Feb 18;9(3):e13840. doi: 10.1016/j.heliyon.2023.e13840. eCollection 2023 Mar.
Docetaxel (DCT) is widely used in clinical practice, but the drug resistance of breast cancer patients has become an important reason to limit its clinical efficacy. Chan'su is a commonly used traditional Chinese medicine for the treatment of breast cancer. Bufalin (BUF) is a bioactive polyhydroxy steroid extracted from chan'su and has strong antitumor activity, but there are few studies on reversing drug resistance in breast cancer. The aim of this study is to determine whether BUF can reverse the drug resistance to DCT and restore efficacy in breast cancer.
The reversal index of BUF was detected by Cell Counting Kit-8 (CCK-8) assays. The effects of BUF on enhancing the apoptosis of DCT were detected by flow cytometry and Western Blot (WB), and the main differential expression levels of sensitive and resistant strains were detected by high-throughput sequencing. Rhodamine 123 assay, WB and ATP Binding Cassette Subfamily B Member 1 (ABCB1) ATPase activity experiments were used to detect the effect of BUF on ABCB1. The nude mouse orthotopic model was constructed to investigate the reversal effect of BUF on DCT resistance in .
With BUF intervention, the sensitivity of drug-resistant cell lines to DCT was increased. BUF can inhibit the expression of ABCB1 protein, increase the drug accumulation of DCT in drug-resistant strains, and reduce the ATPase activity of ABCB1. Animal experiments show that BUF can inhibit the growth of drug-resistant tumors in an orthotopic model of breast cancer and decrease the expression of ABCB1.
BUF can reverse ABCB1-mediated docetaxel resistance in breast cancer.
多西他赛（DCT）在临床实践中广泛应用，但乳腺癌患者的耐药性已成为限制其临床疗效的重要原因。蟾酥是治疗乳腺癌常用的传统中药。蟾毒灵（BUF）是从蟾酥中提取的一种具有生物活性的多羟基甾体，具有较强的抗肿瘤活性，但关于其逆转乳腺癌耐药性的研究较少。本研究旨在确定BUF是否能逆转乳腺癌对DCT的耐药性并恢复其疗效。
采用细胞计数试剂盒-8（CCK-8）检测BUF的逆转指数。通过流式细胞术和蛋白质免疫印迹法（WB）检测BUF对增强DCT诱导凋亡的作用，采用高通量测序检测敏感株和耐药株的主要差异表达水平。利用罗丹明123检测、WB和ATP结合盒转运蛋白B家族成员1（ABCB1）ATP酶活性实验检测BUF对ABCB1的影响。构建裸鼠原位模型，研究BUF对乳腺癌DCT耐药的逆转作用。
经BUF干预后，耐药细胞系对DCT的敏感性增加。BUF可抑制ABCB1蛋白的表达，增加DCT在耐药株中的药物蓄积，并降低ABCB1的ATP酶活性。动物实验表明，BUF可抑制乳腺癌原位模型中耐药肿瘤的生长，并降低ABCB1的表达。
BUF可逆转ABCB1介导的乳腺癌多西他赛耐药性。
