Wang Chih-Yang, Xuan Do Thi Minh, Ye Pei-Hsuan, Li Chung-Yen, Anuraga Gangga, Ta Hoang Dang Khoa, Lai Ming-Derg, Hsu Hui-Ping
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University Taipei 11031, Taiwan.
Am J Cancer Res. 2023 Oct 15;13(10):4661-4677. eCollection 2023.
Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to the limited targeted therapies available at present. Cancer cells preferentially use glycolysis as their primary source of energy, characterized by increased glucose uptake and lactate production. JTC-801, a nociception/orphanin FQ opioid peptide (NOP) receptor antagonist, was reported to suppress the opioid receptor-like1 (ORL1) receptor/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor (NF)-κB-mediated carbonic anhydrase 9 (CA9) signaling pathway. Sodium oxamate is an inhibitor of gluconeogenesis and a glycolysis inhibitor, as a competitive lactate dehydrogenase A (LDHA) inhibitor, which also produces tumor suppression due to loss of LDHA activity. However, the roles of opioid analgesic drugs (e.g., JTC-801) and glycolysis inhibitors (e.g., sodium oxamate) in TNBC have not fully been explored. Meanwhile, concurrent treatment with JTC-801 and sodium oxamate may cause synergistic anticancer effects in a TNBC model. In the present study, the combination of JTC-801 and sodium oxamate triggered cell death in the TNBC MDA MB-231 cell line. RNA-sequencing data revealed potential genes in the crosstalk between JTC-801 and sodium oxamate including , etc. The combination of JTC-801 and sodium oxamate provides a novel potential therapeutic strategy for TNBC patients via downregulating cell cycle- and amino acid metabolism-related pathways such as "Cell cycle-the metaphase checkpoint", "(L)-tryptophan pathways and transport", and "Glutamic acid pathway". Collectively, the present study demonstrated that the synergistic effect of co-treatment with JTC-801 and sodium oxamate significantly suppressed tumor growth and played a crucial role in tumor development, and in turn may serve as potential synergistic drugs for TNBC.
三阴性乳腺癌（TNBC）由于目前可用的靶向治疗有限，构成了重大的临床挑战。癌细胞优先利用糖酵解作为其主要能量来源，其特征是葡萄糖摄取增加和乳酸生成增加。JTC - 801是一种伤害感受/孤啡肽FQ阿片受体（NOP）拮抗剂，据报道可抑制阿片样受体1（ORL1）受体/磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）/核因子（NF）-κB介导的碳酸酐酶9（CA9）信号通路。草酸钠是糖异生的抑制剂和糖酵解抑制剂，作为竞争性乳酸脱氢酶A（LDHA）抑制剂，由于LDHA活性丧失也具有肿瘤抑制作用。然而，阿片类镇痛药（如JTC - 801）和糖酵解抑制剂（如草酸钠）在TNBC中的作用尚未得到充分探索。同时，JTC - 801和草酸钠联合治疗可能在TNBC模型中产生协同抗癌作用。在本研究中，JTC - 801和草酸钠的组合在TNBC MDA MB - 231细胞系中引发细胞死亡。RNA测序数据揭示了JTC - 801和草酸钠之间相互作用中的潜在基因，包括 等。JTC - 801和草酸钠的组合通过下调细胞周期和氨基酸代谢相关途径，如“细胞周期 - 中期检查点”、“（L）-色氨酸途径和转运”以及“谷氨酸途径”，为TNBC患者提供了一种新的潜在治疗策略。总体而言，本研究表明，JTC - 801和草酸钠联合治疗的协同作用显著抑制肿瘤生长，并在肿瘤发展中起关键作用，进而可能成为TNBC的潜在协同药物。
