buparlisib and Multiple-Myeloma

The correlation between the Phosphoinositide 3-kinase (PI3K) axis and crucial mechanisms involved in the maintenance of the neoplastic nature of multiple myeloma (MM) has recently evolved a general agreement that PI3K inhibition-based therapies could construct an exciting perspective for the future treatment strategies. Our results outlined that abrogation of PI3K using pan-PI3K inhibitor BKM120 decreased survival of MM cells through induction of a caspase-3-dependent apoptosis coupled with SIRT1-mediated G2/M arrest in both KMM-1 and RPMI 8226 cell lines; however, the cell responses to the inhibitor was quite different, introducing wild-type PTEN-expressing RPMI 8226 as less sensitive cells. By investigating the sensitivity extent of a panel of hematological cell lines to BKM120, we found no significant association with respect to PTEN status. As far as we are aware, the results of the present study propose for the first time that the inhibitory effect of BKM120 was overshadowed, at least partially, through over-expression of either c-Myc or nuclear factor (NF)-κB in less sensitive MM cells. While there was no significant effect of the inhibitor on the expression of c-Myc in RPMI 8226, we found an enhanced cytotoxic effect when BKM120 was used in combination with a small molecule inhibitor of c-Myc. Noteworthy, the results of the synergistic experiments also revealed that BKM120 could produce a synergistic anti-cancer effect with carfilzomib (CFZ) and provided an enhanced therapeutic efficacy in MM cells, highlighting that PI3K inhibition might be a befitting approach in MM both in mono and combined therapy.

Topics: Aminopyridines; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Enzyme Inhibitors; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; M Phase Cell Cycle Checkpoints; Morpholines; Multiple Myeloma; Phosphoinositide-3 Kinase Inhibitors; Tumor Protein p73

Proteasome inhibitor bortezomib has proven efficacy against multiple myeloma. However, bortezomib activates the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway (which is essential to the development of myeloma), often resulting in drug resistance and disease recurrence. The addition of BKM120 significantly enhanced the apoptotic effects of bortezomib in both bortezomib-sensitive and bortezomib-resistant cells. Treatment with bortezomib alone increased the phosphorylation of AKT (P-AKT), whereas the addition of BKM120 markedly downregulated P-AKT in both bortezomib-sensitive and bortezomib-resistant cells. The clinical relevance of combined treatment with bortezomib and BKM120 was investigated in a xenograft mouse model and in myeloma patients, and the synergy of the combination was confirmed. In conclusion, the addition of BKM120 enhanced the sensitivity of myeloma cells to bortezomib.

Topics: Aminopyridines; Animals; Apoptosis; Bortezomib; Cell Cycle; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Synergism; Humans; Inhibitory Concentration 50; Mice; Morpholines; Multiple Myeloma; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The plasma cell malignancy multiple myeloma (MM) is unique amongst haematological malignancies in its capacity to cause osteoclast-mediated skeletal destruction. The PI3K/Akt pathway mediates proliferation, survival and drug resistance in MM plasma cells and is also involved in regulating the formation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts. NVP-BKM120 (Buparlisib, Novartis) is a PI3K inhibitor that is currently undergoing clinical evaluation in several tumour settings. In this study, we have examined the anti-tumorigenic effects of BKM120 in an immunocompetent mouse model of MM and its effects on osteoblast and osteoclast formation and function. BKM120 treatment (40 mg/kg) resulted in a significant decrease in serum paraprotein and tumour burden, and μCT analysis of the proximal tibia revealed a significant reduction in the number of osteolytic bone lesions in BKM120-treated animals. BKM120 also mediated a significant increase in serum levels of the osteoblast marker P1NP, and a significant decrease in serum levels of the osteoclast marker TRAcP5. In vitro, BKM120 decreased MM plasma cell proliferation, osteoclast formation and function, and promoted osteoblast formation and function. These findings suggest that, in addition to its anti-tumour properties, BKM120 could be used to treat osteolytic bone disease in MM patients.

Topics: Aminopyridines; Animals; Apoptosis; Blotting, Western; Bone Diseases; Cell Cycle; Cell Proliferation; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Humans; Mice; Mice, Inbred C57BL; Morpholines; Multiple Myeloma; Osteoclasts; Osteolysis; Phosphoinositide-3 Kinase Inhibitors; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The phosphatidylinositol-3 kinase (PI3K) pathway is activated in multiple myeloma (MM) and Waldenstrom Macroglobulenima (WM), and plays a crucial role in tumor progression and drug resistance. In this study, we characterized the role of pan-class I PI3K inhibition on cell trafficking and survival of MM and WM cells. We tested the effect of pan-class I PI3K inhibition by siRNA silencing or pharmacologic inhibition with buparlisib on MM cell survival, apoptosis and cell cycle in vitro and tumor growth and mobilization of MM cells in vivo. We then evaluated buparlisib-dependent mechanisms of induced MM cell mobilization. Moreover, the effect of buparlisib on cell survival, apoptosis, and adhesion of WM cells to bone marrow stromal cells (BMSCs) has been evaluated. We showed that buparlisib induced toxicity in MM cells, supported by induction of apoptosis and cell cycle arrest. Buparlisib was also found to reduce tumor progression in vivo. Importantly, buparlisib enhanced MM cell mobilization in vivo which was driven by decreased adhesion of MM cells to BMSCs and increased chemotaxis via up-regulation of CXCR4 expression. Similar to its effects on MM cells, buparlisib also induced cell survival and apoptosis, and decreased adhesion in WM cells. These data highlight the critical contribution of class I PI3K signaling to the regulation of survival and cell dissemination in B-cell malignancies.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Cell Adhesion; Cell Cycle; Cell Line; Cell Line, Tumor; Chemotaxis; Coculture Techniques; Drug Screening Assays, Antitumor; Female; Fibronectins; Humans; Mesenchymal Stem Cells; Mice; Mice, SCID; Morpholines; Multiple Myeloma; Neoplasm Invasiveness; Neoplasm Proteins; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Receptors, CXCR4; RNA Interference; RNA, Small Interfering; Waldenstrom Macroglobulinemia; Xenograft Model Antitumor Assays

NVP-BKM120 is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor and is currently being investigated in phase I clinical trials in solid tumors. This study aimed to evaluate the therapeutic efficacy of BKM120 in multiple myeloma (MM). BKM120 induces cell growth inhibition and apoptosis in both MM cell lines and freshly isolated primary MM cells. However, BKM120 only shows limited cytotoxicity toward normal lymphocytes. The presence of MM bone marrow stromal cells, insulin-like growth factor, or interleukin-6 does not affect BKM120-induced tumor cell apoptosis. More importantly, BKM120 treatment significantly inhibits tumor growth in vivo and prolongs the survival of myeloma-bearing mice. In addition, BKM120 shows synergistic cytotoxicity with dexamethasone in dexamethasone-sensitive MM cells. Low doses of BKM120 and dexamethasone, each of which alone has limited cytotoxicity, induce significant cell apoptosis in MM.1S and ARP-1. Mechanistic study shows that BKM120 exposure causes cell cycle arrest by upregulating p27 (Kip1) and downregulating cyclin D1 and induces caspase-dependent apoptosis by downregulating antiapoptotic XIAP and upregulating expression of cytotoxic small isoform of Bim, BimS. In summary, our findings demonstrate the in vitro and in vivo anti-MM activity of BKM120 and suggest that BKM120 alone or together with other MM chemotherapeutics, particularly dexamethasone, may be a promising treatment for MM.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Dexamethasone; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Humans; Mice; Mice, SCID; Morpholines; Multiple Myeloma