Syrosingopine is a dual MCT1 and MCT4 inhibitor, with IC50 values of 2.5µM and 0.04µM, respectively[1]. Syrosingopine enhances the 20S proteasome and promotes the degradation of fluorogenic substrates and α-synuclein[2]. Syrosingopine has been widely used in cancer cell models to inhibit cell proliferation and to develop novel combination therapies to inhibit tumor growth[3].
In vitro, Syrosingopine treatment for 4 days effectively suppressed the viability of HL60 cells, with an IC50 value of 10µM [4]. Treatment with 10µM Syrosingopine for 72 hours resulted in a significant decrease in glucose consumption and lactate secretion and induced apoptosis in MDA-MB-231 cells[5]. Treatment of leukemic cells with 10µM Syrosingopine for 48 hours inhibited glycolysis, resulting in increased intracellular lactate levels and induced autophagy[6].
In vivo, Syrosingopine treatment via intraperitoneal injection at a dose of 7.5mg/kg every other day for 5 weeks reduced the body weight of mice with liver fibrosis and increased collagen deposition in liver tissues[7]. The combination of Syrosingopine (7.5mg/kg/day) and UK-5099 (3mg/kg/day) administered intraperitoneally for 14 consecutive days significantly inhibited tumor growth in a PC-9 cell xenograft tumor mouse model[8].
References:
[1] Benjamin D, Robay D, Hindupur S K, et al. Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD+ depletion in cancer cells[J]. Cell reports, 2018, 25(11): 3047-3058. e4.
[2] Sadahiro Y, Nishimura S, Hitora Y, et al. Syrosingopine enhances 20S proteasome activity and degradation of α-synuclein[J]. Journal of Natural Products, 2023, 87(3): 554-559.
[3] Benjamin D, Colombi M, Hindupur S K, et al. Syrosingopine sensitizes cancer cells to killing by metformin[J]. Science advances, 2016, 2(12): e1601756.
[4] Benjamin D, Hall M N. Combining metformin with lactate transport inhibitors as a treatment modality for cancer-recommendation proposal[J]. Frontiers in Oncology, 2022, 12: 1034397.
[5] Buyse C, Joudiou N, Warscotte A, et al. Evaluation of syrosingopine, an MCT inhibitor, as potential modulator of tumor metabolism and extracellular acidification[J]. Metabolites, 2022, 12(6): 557.
[6] Saulle E, Spinello I, Quaranta M T, et al. Targeting lactate metabolism by inhibiting MCT1 or MCT4 impairs leukemic cell proliferation, induces two different related death-pathways and increases chemotherapeutic sensitivity of acute myeloid leukemia cells[J]. Frontiers in oncology, 2021, 10: 621458.
[7] Guo M, Gou Y, Dong X, et al. Syrosingopine, an anti-hypertensive drug and lactate transporter (MCT1/4) inhibitor, activates hepatic stellate cells and exacerbates liver fibrosis in a mouse model[J]. Genes & Diseases, 2024, 11(4): 101169.
[8] Li Y, Song Y, Shi Z, et al. Syrosingopine and UK5099 synergistically suppress non-small cell lung cancer by activating the integrated stress response[J]. Cell Death & Disease, 2024, 15(6): 431.
Syrosingopine是一种双重MCT1/MCT4抑制剂，对MCT1和MCT4的IC50值分别为2.5µM和0.04µM[1]。Syrosingopine能增强20S蛋白酶体活性，促进荧光底物及α-突触核蛋白的降解[2]。Syrosingopine已广泛应用于癌细胞模型中抑制细胞增殖，并用于开发抑制肿瘤生长的新型联合疗法[3]。
在体外，Syrosingopine处理4天可有效抑制HL60细胞活力，IC50值为10µM[4]。使用10µM的Syrosingopine处理MDA-MB-231细胞72小时，能显著降低葡萄糖消耗和乳酸分泌，并诱导细胞凋亡[5]。用10µM的Syrosingopine处理白血病细胞48小时，可抑制糖酵解过程导致细胞内乳酸积累，并诱导自噬发生[6]。
在体内，隔天腹腔注射7.5mg/k剂量的Syrosingopine持续5周，可减轻肝纤维化小鼠的体重，并增加肝组织中的胶原沉积[7]。连续14天每日联合腹腔注射Syrosingopine（7.5mg/kg/day）与UK-5099（3mg/kg/day），能显著抑制PC-9细胞移植瘤小鼠模型的肿瘤生长[8]。