Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling

نویسندگان

  • Fabrizio Accardi
  • Denise Toscani
  • Marina Bolzoni
  • Benedetta Dalla Palma
  • Franco Aversa
  • Nicola Giuliani
چکیده

Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

بررسی اثر داروی ضد سرطانی پومالیدومید بر فعالیت حیاتی و القای آپوپتوز سلول‌های تک هسته‌ای مغز استخوان

Background and Objective: Pomalidomide - a combination of Lenalidomide and Thalidomide drugs- is one of the newest anticancer drugs. Pomalidomide induces apoptosis in cancer cells. Furthermore, few studies indicating its relatively low cytotoxic effects on normal peripheral blood cells have been carried out. However, there is yet no information about the effects of Pomalidomide on bone marrow c...

متن کامل

In vitro Effect of Pomalidomide on Bone Marrow Mononuclear Cells from Multiple Myeloma Patients

Background: Many features of anticancer drugs, including cytotoxicity and/or cytokine induction, are studied using cell lines orhuman blood leukocytes. However, in a disease such as multiple myeloma, most cancerous cells are resided within bone marrowmononuclear cells. In the present study, we investigated the effect of pomalidomide on apoptosis and IL-2 production of bonemarrow mononuclear cel...

متن کامل

Multiple Myeloma Bone Marrow Mesenchymal Stromal Cells Inhibit CD8+ T Cell Function in a Process that May Implicate Fibroblast Activation Protein α

Background: Multiple myeloma (MM) is a malignant plasma cell proliferative disorder with limited immunotherapy treatment because of T cell dysfunction. Objective: To investigate the immunomodulatory function of bone marrow mesenchymal stromal cells (MM-BMSCs) on CD8+ T cells. Methods: Proliferation and cytotoxicity were detected by c...

متن کامل

Molecular Biology of Multiple Myeloma

Multiple myeloma is a disease of malignant plasma cells in the bone marrow. Interaction of malignant plasma cells with the bone marrow microenvironment plays a key role in the pathogenesis of myeloma. Recognition of potential adverse cytogenetic and genomic abnormalities has led to identification of newer targets, translating to development of newer drugs. The introduction of two new such class...

متن کامل

Evolving Paradigms in the Management of Multiple Myeloma: Novel Agents and Targeted Therapies.

Multiple myeloma (MM) is a clonal plasma cell disorder defined by bone marrow infiltration and osteolytic bone lesions and is the second most common hematologic malignancy after non-Hodgkin lymphoma. The landscape of MM treatment was transformed at the dawn of the twenty-first century by the introduction of novel agents including proteasome inhibitors (bortezomib) and immunomodulatory drugs (th...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 2015  شماره 

صفحات  -

تاریخ انتشار 2015