Miyashita Kazuya, Yagi Takuya, Kagaya Noritaka, Takechi Azusa, Nakata Chihiro, Kanda Risa, Nuriya Hideko, Tanegashima Kosuke, Hoyano Shota, Seki Fumiya, Yoshida Chihiro, Hachiro Yoshifumi, Higashi Tomoya, Kitada Nobuo, Toya Takashi, Kobayashi Takeshi, Najima Yuho, Goyama Susumu, Maki Shojiro A, Kitamura Toshio, Doki Noriko, Shin-Ya Kazuo, Hara Takahiko
Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan.
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Japan.
Cancer Sci. 2023 Oct;114(10):4032-4040. doi: 10.1111/cas.15918. Epub 2023 Jul 31.
T-cell acute lymphoblastic leukemia (T-ALL) is one of the most frequently occurring cancers in children and is associated with a poor prognosis. Here, we performed large-scale screening of natural compound libraries to identify potential drugs against T-ALL. We identified three low-molecular-weight compounds (auxarconjugatin-B, rumbrin, and lavendamycin) that inhibited the proliferation of the T-ALL cell line CCRF-CEM, but not that of the B lymphoma cell line Raji in a low concentration range. Among them, auxarconjugatin-B and rumbrin commonly contained a polyenyl 3-chloropyrrol in their chemical structure, therefore we chose auxarconjugatin-B for further analyses. Auxarconjugatin-B suppressed the in vitro growth of five human T-ALL cell lines and two T-ALL patient-derived cells, but not that of adult T-cell leukemia patient-derived cells. Cultured normal T cells were several-fold resistant to auxarconjugatin-B. Auxarconjugatin-B and its synthetic analogue Ra#37 depolarized the mitochondrial membrane potential of CCRF-CEM cells within 3 h of treatment. These compounds are promising seeds for developing novel anti-T-ALL drugs.
T细胞急性淋巴细胞白血病（T-ALL）是儿童中最常见的癌症之一，且预后较差。在此，我们对天然化合物库进行了大规模筛选，以确定针对T-ALL的潜在药物。我们鉴定出三种低分子量化合物（auxarconjugatin-B、rumbrin和lavendamycin），它们在低浓度范围内可抑制T-ALL细胞系CCRF-CEM的增殖，但不抑制B淋巴瘤细胞系Raji的增殖。其中，auxarconjugatin-B和rumbrin的化学结构中均含有一个多烯基3-氯吡咯，因此我们选择auxarconjugatin-B进行进一步分析。Auxarconjugatin-B可抑制五种人T-ALL细胞系和两种T-ALL患者来源细胞的体外生长，但不抑制成人T细胞白血病患者来源细胞的生长。培养的正常T细胞对auxarconjugatin-B具有数倍的抗性。Auxarconjugatin-B及其合成类似物Ra#37在处理3小时内使CCRF-CEM细胞的线粒体膜电位去极化。这些化合物是开发新型抗T-ALL药物的有前景的种子。
