Hattori Yutaka, Sugiyama Hiromu, Miyashita Yamato, Shibata Shinsuke, Okaue Taiga, Matsumoto Yoshinao, Yamada Taketo, Yamamoto Tomofumi, Yamaguchi Takashi, Yamazaki Kohei, Kunieda Hisako, Saya Hideyuki, Matsushita Maiko
Division of Clinical Physiology and Therapeutics, Keio University Faculty of Pharmacy, Tokyo, Japan.
Division of Hematology, International University of Health and Welfare Hospital, Tochigi, Japan.
Blood Neoplasia. 2025 Apr 3;2(3):100100. doi: 10.1016/j.bneo.2025.100100. eCollection 2025 Aug.
In the last decade, newly developed drugs have significantly improved the prognosis of patients with multiple myeloma (MM). However, most patients relapse sooner or later, and thus MM remains an incurable hematological malignancy. In addition, serious adverse events occasionally hamper the continuation of treatment. Exploitation of new drugs that potentiate antitumor activities and alleviate the adverse effects of existing drugs is needed. Here, we found through drug repositioning that ambroxol hydrochloride (ambroxol) induces apoptosis of MM cells. Interestingly, turnover and reporter assays revealed that ambroxol inhibits the late stage of autophagy. Transmission electron microscopy observation also revealed that MM cells treated with ambroxol accumulated autophagic vacuoles in the cytoplasm, further supporting the inhibition of late-stage autophagy. Existing anti-MM drugs demonstrate various effects on autophagy; panobinostat, a histone deacetylase inhibitor, induces autophagy, whereas bortezomib and lenalidomide do not. When administered together, ambroxol and panobinostat exhibited a synergistic antimyeloma effect, likely due to ambroxol inhibiting the activation of panobinostat-induced autophagy while downregulating MCL-1 expression. In the KMS11 xenograft model, ambroxol significantly delayed tumor growth when administered alone; when co-administered with panobinostat, ambroxol synergistically enhanced the panobinostat-induced inhibition of tumor growth. Interestingly, concomitant use of ambroxol and panobinostat alleviated panobinostat-induced diarrhea. Gene set enrichment and pathway analyses also revealed that ambroxol increased the expression of genes related to autophagy inhibition and unfolded protein response. These results suggested that autophagy is a promising therapeutic target for MM.
在过去十年中，新开发的药物显著改善了多发性骨髓瘤（MM）患者的预后。然而，大多数患者迟早会复发，因此MM仍然是一种无法治愈的血液系统恶性肿瘤。此外，严重的不良事件偶尔会妨碍治疗的持续进行。需要开发能够增强抗肿瘤活性并减轻现有药物不良反应的新药。在此，我们通过药物重新定位发现盐酸氨溴索（氨溴索）可诱导MM细胞凋亡。有趣的是，周转和报告基因检测显示氨溴索抑制自噬后期。透射电子显微镜观察还显示，用氨溴索处理的MM细胞在细胞质中积累自噬空泡，进一步支持对后期自噬的抑制。现有的抗MM药物对自噬表现出不同的作用；组蛋白脱乙酰酶抑制剂帕比司他诱导自噬，而硼替佐米和来那度胺则不然。当联合使用时，氨溴索和帕比司他表现出协同抗骨髓瘤作用，可能是因为氨溴索抑制帕比司他诱导的自噬激活，同时下调MCL-1表达。在KMS11异种移植模型中，氨溴索单独给药时显著延迟肿瘤生长；当与帕比司他联合给药时，氨溴索协同增强帕比司他诱导的肿瘤生长抑制作用。有趣的是，同时使用氨溴索和帕比司他可减轻帕比司他引起的腹泻。基因集富集和通路分析还显示，氨溴索增加了与自噬抑制和未折叠蛋白反应相关基因的表达。这些结果表明自噬是MM一个有前景的治疗靶点。
