Department of Urology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 165-8582, Japan.
Int J Oncol. 2010 May;36(5):1299-307. doi: 10.3892/ijo_00000615.
Multiple myeloma (MM) is an incurable disease of malignant plasma cells. Recent therapeutic advancements have resulted in improved response rates, however, there is no improvement in overall survival, therefore, new therapeutics are needed. Since the transferrin receptor is upregulated on the surface of MM cells, we previously developed an antibody fusion protein consisting of an IgG3 specific for the human transferrin receptor 1 (TfR1, CD71) genetically fused to avidin at its carboxy-terminus (ch128.1Av). We have previously shown that ch128.1Av exhibits intrinsic cytotoxicity against certain malignant B-cells by disrupting the cycling of the TfR and decreasing TfR cell surface expression resulting in lethal iron starvation. In addition, ch128.1Av can sensitize malignant cells to apoptosis induced by gambogic acid, a herbal drug used in Chinese medicine. In this study, we hypothesized that ch128.1Av may also sensitize drug-resistant malignant B-cells to chemotherapeutic agents by inhibiting key survival pathways. In this study we show that ch128.1Av sensitizes malignant B-cells to apoptosis induced by cisplatin (CDDP). The sensitization by ch128.1Av resulted in the inhibition of the constitutively activated Akt and NF-kappaB survival/antiapoptotic pathways and downstream decreased expression of antiapoptotic gene products such as BclxL and survivin. The direct role of the inhibition of the Akt and NF-kappaB pathways by ch128.1Av in CDDP-mediated cytotoxicity was demonstrated by the use of specific chemical inhibitors and siRNA which mimicked the effects of ch128.1Av. Overall, this study provides evidence of the therapeutic potential of ch128.1Av as a chemo-sensitizing agent in drug-resistant tumor cells.
多发性骨髓瘤（MM）是一种无法治愈的恶性浆细胞疾病。最近的治疗进展提高了缓解率，但总生存率没有提高，因此需要新的治疗方法。由于转铁蛋白受体在 MM 细胞表面上调，我们之前开发了一种抗体融合蛋白，该蛋白由针对人转铁蛋白受体 1（TfR1，CD71）的 IgG3 特异性抗体通过其羧基末端与生物素基因融合而成（ch128.1Av）。我们之前已经表明，ch128.1Av 通过破坏 TfR 的循环和降低 TfR 细胞表面表达来破坏某些恶性 B 细胞的铁饥饿，从而导致内在的细胞毒性，从而导致致命的铁饥饿。此外，ch128.1Av 可以使恶性细胞对来自中国传统药物的藤黄酸诱导的细胞凋亡敏感。在这项研究中，我们假设 ch128.1Av 通过抑制关键存活途径也可能使耐药恶性 B 细胞对化学治疗剂敏感。在这项研究中，我们表明 ch128.1Av 使恶性 B 细胞对顺铂（CDDP）诱导的细胞凋亡敏感。ch128.1Av 的敏化作用导致组成性激活的 Akt 和 NF-kappaB 存活/抗凋亡途径的抑制以及下游抗凋亡基因产物如 BclxL 和 survivin 的表达降低。ch128.1Av 通过抑制 Akt 和 NF-kappaB 途径在 CDDP 介导的细胞毒性中的直接作用通过使用特异性化学抑制剂和模拟 ch128.1Av 作用的 siRNA 来证明。总的来说，这项研究提供了证据表明 ch128.1Av 作为一种化学增敏剂在耐药肿瘤细胞中具有治疗潜力。
