BOLD-100

BOLD-100 is a ruthenium-based anticancer agent^[1]. BOLD-100 has high tumor targeting potential, strongly binds to serum proteins such as albumin and transferrin, and is activated in the reducing tumor environment^[2]. BOLD-100 can disrupt endoplasmic reticulum (ER) homeostasis and induce ER stress and unfolded protein response (UPR^)[3].

In vitro, BOLD-100 (100μM) treatment of MCF7(2) cells for 72h significantly reduced S phase cells, increased G2/M phase cells, significantly reduced cell cycle proteins (such as RAD51, PCNA, ATM), and induced an increase in intracellular reactive oxygen species (ROS)^[4]. BOLD-100 (100μM) treatment of HCT116 cells for 24h enhanced the phosphorylation of eIF2A serine 51 in cells, but reduced the expression of the basal ER chaperone GRP78^[5]. BOLD-100 (0-200μM) has a significant inhibitory effect on malignant cell lines from various sources, such as liver cancer, melanoma, lung cancer and colon cancer, when treated for 72h, with an IC₅₀ value of 45-200μM^[6].

In vivo, BOLD-100 (30mg/kg) was treated by intravenous injection for 2 weeks in mice with Hep3B cell xenografts, which significantly inhibited the growth of transplanted tumors in mice, improved the survival rate of mice, and increased the number of apoptotic cells in tumor tissues. It has a synergistic therapeutic effect with sorafenib^[6]. BOLD-100 (50mg/kg) was treated by intravenous injection for 3 weeks in mice with VACO432 cell xenografts, but the inhibitory effect on tumor growth was not obvious. Combined treatment with AZD6738 can lead to a slowdown in tumor growth, but the tolerance is poor and the mice lose weight^[7].

References:
[1] Swaminathan S, Haribabu J, Karvembu R. From Concept to Cure: The Road Ahead for Ruthenium‐Based Anticancer Drugs[J]. ChemMedChem, 2024, 19(23): e202400435.
[2] Happl B, Brandt M, Balber T, et al. Synthesis and Preclinical Evaluation of Radiolabeled [103Ru] BOLD-100[J]. Pharmaceutics, 2023, 15(11): 2626.
[3] Ranzato E, Bonsignore G, Martinotti S. ER stress response and induction of apoptosis in malignant pleural mesothelioma: The Achilles heel targeted by the anticancer ruthenium drug BOLD-100[J]. Cancers, 2022, 14(17): 4126.
[4] Bakewell S, Conde I, Fallah Y, et al. Inhibition of DNA repair pathways and induction of ROS are potential mechanisms of action of the small molecule inhibitor BOLD-100 in breast cancer[J]. Cancers, 2020, 12(9): 2647.
[5] Baier D, Schoenhacker-Alte B, Rusz M, et al. The anticancer ruthenium compound BOLD-100 targets glycolysis and generates a metabolic vulnerability towards glucose deprivation[J]. Pharmaceutics, 2022, 14(2): 238.
[6] Heffeter P, Atil B, Kryeziu K, et al. The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo[J]. European Journal of Cancer, 2013, 49(15): 3366-3375.
[7] Griffin D, Carson R, Moss D, et al. Ruthenium Drug BOLD-100 Regulates BRAF MT Colorectal Cancer Cell Apoptosis through AhR/ROS/ATR Signaling Axis Modulation[J]. Molecular Cancer Research, 2024, 22(12): 1088-1101.

BOLD-100是一种基于钌元素的抗癌剂^[1]。BOLD-100具有高肿瘤靶向潜力，与血清蛋白如白蛋白和转铁蛋白强烈结合，并在还原性肿瘤环境中活化^[2]。BOLD-100能够破坏内质网（ER）稳态并诱导ER应激和未折叠蛋白反应 （UPR）^[3]。

在体外，BOLD-100（100μM）处理MCF7(2)细胞72h，显著减少了S期细胞，增加了G2/M期细胞，显著减少了细胞周期蛋白（如RAD51、PCNA、ATM），诱导了细胞内活性氧（ROS）增加^[4]。BOLD-100（100μM）处理HCT116细胞24h，增强了细胞中eIF2A丝氨酸51的磷酸化，但降低了基础ER伴侣GRP78的表达^[5]。BOLD-100 (0-200μM) 处理肝癌、黑色素瘤、肺癌和结肠癌等多种来源的恶性细胞系72h，均有显著抑制作用，IC₅₀值为45-200μM^[6]。

在体内，BOLD-100（30mg/kg）通过静脉注射治疗Hep3B细胞异种移植小鼠2周，显著抑制了小鼠体内移植瘤的生长，提高了小鼠存活率，增加了肿瘤组织中凋亡细胞数量，与索拉非尼（Sorafenib）具有协同治疗效果^[6]。BOLD-100（50mg/kg）通过静脉注射治疗VACO432细胞异种移植小鼠3周，抑制肿瘤生长效果不明显，与AZD6738联合治疗能够导致肿瘤生长减缓，但耐受性较差，小鼠体重下降^[7]。