Division of Clinical Physiology and Therapeutics, Keio University Faculty of Pharmacy, Tokyo, Japan.
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Cancer Med. 2023 Apr;12(8):9749-9759. doi: 10.1002/cam4.5691. Epub 2023 Feb 24.
Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high-risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi-shrub Dracocephalum komarovi, i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti-tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo.
ICR/SCID xenograft model of KMS11, a t(4;14) translocation-positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC-MS/MS.
Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high-risk cytogenetic changes. A xenograft model of a high-risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057-treated tumors in vivoshowed revealed apoptosis of MM cells and anti-angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c-MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti-tumorantitumor activity.
Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high-risk cancer.
尽管新开发的药物不断涌现，但大多数患有高风险细胞遗传学异常（如 t(4;14) 或 del17p）的多发性骨髓瘤 (MM) 患者在其临床病程的早期仍会复发。我们之前曾报道过，一种从多年生半灌木 Dracocephalum komarovi 中分离出来的天然产物 komaroviquinone（KQN），即 komaroviquinone（KQN）及其衍生物 GTN024 通过产生活性氧物种（ROS）诱导 MM 细胞凋亡，但两者均表现出显著的血液毒性。本研究旨在阐明 KQN 的优化化合物 GTN057 在体内的抗肿瘤活性、安全性和药代动力学。
我们使用 KMS11，一种 t(4;14)易位阳性 MM 细胞系的 ICR/SCID 异种移植模型进行体内研究。通过 LC-MS/MS 分析 GTN057 及其降解产物在小鼠体内的药代动力学。
我们的体外实验结果表明，GTN057 对正常造血细胞的毒性要小得多，可诱导两种 MM 细胞系和患者样本（包括具有高风险细胞遗传学改变的样本）凋亡。高危 MM 细胞系的异种移植模型表明，GTN057 可显著延缓肿瘤生长，体内无明显血液学或系统毒性。GTN057 治疗的肿瘤的组织病理学检查显示 MM 细胞凋亡和抗血管生成。除了产生 ROS 外，GTN057 还抑制了受体酪氨酸激酶 c-MET 的下游信号传导，c-MET 是肝细胞生长因子 (HGF) 的受体。因此，GTN057 毒性较小，可能是通过多效机制治疗 MM 患者的候选药物。我们还对 GTN057 的药理学进行了广泛研究。GTN057 的代谢物（例如 GTN054）也可能具有抗肿瘤活性。
天然产物或其衍生物可能是抗肿瘤药物的良好来源，即使对于高危癌症也是如此。
