Novel anti-myeloma agents and angiogenesis

Abstract

During the last decade several novel agents have been used in the management of patients with multiple myeloma. Immunomodulatory drugs and proteasome inhibitors exert their efficacy both directly by inducing apoptosis of myeloma cells and indirectly through the interruption of the interactions between myeloma and stromal cells in the bone marrow (BM) microenvironment. These interactions are crucial for myeloma cell growth and survival. The adherence of myeloma cells to BM stromal cells leads to the overproduction of several cytokines with angiogenic properties that enhance the survival and growth of myeloma cells through paracrine and autocrine loops. The correlation of these molecules with clinical features and survival of myeloma patients supports the importance of angiogenesis in the pathogenesis of the disease and reveals these cytokines as suitable targets for the development of novel anti-myeloma therapies. This review summarises all available preclinical and clinical data for the effect of novel agents that are used in myeloma therapy, such as thalidomide, lenalidomide, bortezomib and VEGF inhibitors, on angiogenesis, which is at least partially responsible for their remarkable anti-myeloma efficacy.

Angiogenesis and Multiple Myeloma

“…Similarly, it has been shown that Bortezomib at clinically achievable concentrations inhibits endothelial cell proliferation and targets VEGFinduced caveoln-1 phosphorylation in endothelial cells [134]. Bortezomib also blocks MM interaction with BM stromal cells and indirectly blocks the production of proangiogenic factors [125]. Pre-clinical in vivo studies confirm the potential anti-angiogenic effect of the proteasome inhibitors [135] and it has been consistently reported that MM patients treated with Bortezomib show a significant reduction in MVD although serum VEGF are not consistently reduced [136].…”

“…Firstly it was demonstrated that thalidomide inhibits bFGF by a rabbit corneal assay [124]. Others showed that thalidomide inhibits VEGF, HGF, bFGF, IGF-1 and Ang-2 expression by BM endothelial cells isolated from MM patients [125,126]. All IMiDs, including lenalidomide and pomalidomide, have anti-angiogenic activity independent of their immunomodulatory effects [125,127,128], although thalidomide is probably a more prominent inhibitor of angiogenesis than its derivatives.…”

“…Finally, in pre-clinical in vivo mouse MM models both thalidomide and lenalidomide induced a significant reduction of tumor-associated MVD [130,131]. Although this evidence suggests that thalidomide and IMiDs have an anti-angiogenic activity, a reduction of MVD as well as VEGF levels is not always seen with thalidomide response in MM patients [100,125,127,132], suggesting that both the in vivo anti angiogenic effect of these drugs and the contribution of their antiangiogenic activity to the overall anti-tumor effect is uncertain.…”

“…In addition to a direct anti-MM effect, proteasome inhibitors have been shown to have an anti-angiogenic effect as well [125]. These drugs inhibit vascular formation on matrigel and induce apoptosis of endothelial cells in a dose-dependent manner [133].…”

Effects of thalidomide on growth and VEGF-A expression in SW480 colon cancer cells

“…However, the use of THD during pregnancy led to phocomelia and consequently the drug was withdrawn from the market (17). Subsequent studies have reported that THD has anti-inflammatory, immunomodulatory and anti-angiogenic effects (18)(19)(20)(21)(22). Due to its anti angiogenic effects, THD is able to affect fetal development in pregnant women, which leads to fetal deformity.…”