Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Hematology, Zhejiang University, Hangzhou, China.
J Mater Chem B. 2023 Mar 1;11(9):1929-1939. doi: 10.1039/d2tb02009b.
Multiple myeloma (MM) is the second most common hematologic malignancy. Bortezomib (BOR), a first-generation proteasome inhibitor, is the basic agent for the treatment of MM and has greatly improved the survival of patients with MM. However, the side effects of BOR ( peripheral neuropathy) occur frequently and almost all MM patients eventually develop resistance to BOR and go on to develop refractory relapsed multiple myeloma (RRMM). Therefore, it is of great significance to find a method to increase the sensitivity of MM to BOR to reduce toxicity and drug resistance. Herein, we found that calcium silicate (CS), a silicate bioceramic that releases Si ions (SIs), enhanced the BOR anti-myeloma effect in human myeloma cell lines (HMCLs), including BOR-resistant cell lines (U266/BOR). The enhanced anti-myeloma effect of these two agents was demonstrated in primary MM cells regardless of disease status and in MM xenograft mice. Mechanistically, SI enhanced G2/M cell cycle arrest and the inhibition of the NF-κB pathway induced by BOR. These results imply that the combination of SI and BOR (SI/BOR) is a promising way to overcome BOR resistance in MM and RRMM. The future use of nanotechnology to prepare CS nanomaterials as BOR carriers for the treatment of MM and RRMM is a very promising clinical application.
多发性骨髓瘤（MM）是第二大常见的血液系统恶性肿瘤。硼替佐米（BOR），一种第一代蛋白酶体抑制剂，是 MM 治疗的基本药物，大大提高了 MM 患者的生存率。然而，BOR 的副作用（周围神经病变）频繁发生，几乎所有 MM 患者最终都会对 BOR 产生耐药性，并发展为难治性复发性多发性骨髓瘤（RRMM）。因此，找到一种方法来提高 MM 对 BOR 的敏感性，以降低毒性和耐药性具有重要意义。在这里，我们发现硅酸钙（CS），一种释放 Si 离子（SIs）的硅酸盐生物陶瓷，增强了硼替佐米对人骨髓瘤细胞系（HMCLs）的抗骨髓瘤作用，包括硼替佐米耐药细胞系（U266/BOR）。这两种药物的增强抗骨髓瘤作用在原发性 MM 细胞中得到了证明，无论疾病状态如何，在 MM 异种移植小鼠中也是如此。在机制上，SI 增强了硼替佐米诱导的 G2/M 细胞周期停滞和 NF-κB 通路的抑制。这些结果表明，SI 和 BOR 的联合（SI/BOR）是克服 MM 和 RRMM 中 BOR 耐药的一种很有前途的方法。未来利用纳米技术制备 CS 纳米材料作为 BOR 载体来治疗 MM 和 RRMM 是一种很有前途的临床应用。
