Abstract
Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects require a dose reduction or the potential discontinuation of treatment. To overcome this limitation, we conjugated Btz to a bisphosphonate (BP) residue lacking anti-osteoclastic activity using a novel chemical linker and generated a new bone-targeted Btz-based (BP-Btz) proteasome inhibitor. We demonstrated that BP-Btz, but not Btz, bound to bone slices and inhibited the growth of MM cells in vitro. In a mouse model of MM, BP-Btz more effectively reduced tumor burden and bone loss with less systemic side effects than Btz. Thus, BP-Btz may represent a novel therapeutic approach to treat patients with MM.
Highlights
Multiple myeloma (MM) is a plasma cell malignancy and the 2nd most common adult hematologic malignancy in the US
Myeloma cells originate in the bone marrow (BM) where they destroy healthy BM cells, and eventually cause osteolytic lesions, which lead to bone pain and fractures
Medication typically consists of 3 classes of drugs, including chemotherapy drugs that kill rapidly growing cells non-proteasome inhibitors that mainly target cancer cells, and corticosteroids that control inflammation caused by chemotherapy [2,3]
Summary
Multiple myeloma (MM) is a plasma cell malignancy and the 2nd most common adult hematologic malignancy in the US. Medication typically consists of 3 classes of drugs, including chemotherapy drugs that kill rapidly growing cells non-proteasome inhibitors that mainly target cancer cells, and corticosteroids that control inflammation caused by chemotherapy [2,3]. Bortezomib (Btz, marketed as VELCADE) is the first proteasome inhibitor used to treat MM and mantle cell lymphoma. It induces myeloma cell apoptosis by promoting excessive protein accumulation [4]. In 2013, Agyin et al synthesized several permanently linked BP-conjugated proteasome inhibitors, including Btz, and demonstrated that these conjugates killed MM cells in vitro at a similar dose range as their non-bone targeted counterparts [10]. In a mouse model of MM, that BP-Btz binds to bone slices and has sustained and better efficacy than Btz
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