Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma

Abstract

Multiple myeloma is still uncurable. Myeloma cells become resistant to common drugs and patients eventually die of tumour progression. Therefore, new targets and drugs are urgently needed. NVP-BGT226 is a novel, orally bioavailable small-molecule inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin. Here, we show that NVP-BGT226 inhibits growth in common myeloma cell lines and primary myeloma cells at nanomolar concentrations in a time-dependent and dose-dependent manner. Western blots for the detection of caspase 3 cleavage and annexin-V-fluorescein isothiocyanate/propidium iodide assays revealed induction of apoptosis in common myeloma cells lines. Induction of apoptosis was accompanied by upregulation of proapoptotic Bim and a moderate upregulation of Mcl-1 and Bad and a downregulation of Bcl-2, Bax and Bcl-Xl. Inhibition of cell growth was mainly due to inhibition of myeloma cell proliferation, as shown by the 5-bromo-2'-deoxyuridine assay. Cell cycle analysis revealed induction of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin D1, cyclin D2, pRb and cdc25a. NVP-BGT226 inhibited phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1 in a time-dependent and dose-dependent manner. Furthermore, we show that the stimulatory effect of insulin-like growth factor 1, interleukin-6 and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BGT226. Overall, inhibition of phosphoinositol-3-kinase/mammalian target of rapamycin by NVP-BGT226 is highly effective, and NVP-BGT226 represents a potential new candidate for targeted therapy in multiple myeloma.

Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma

“…Thus, PET imaging was able to discriminate between sensitive and resistant lymphoma and correlated with in vitro antitumor activity as well as immunohistochemistry of explanted lymphomas, revealing the antiproliferative and proapoptotic effects of BGT226 in vivo. In line with previous reports for other malignancies,21,23,27 treatment of sensitive ALCL cells (SU-DHL-1) with BGT226 in vitro resulted in a dose-dependent and to some extent time-dependent decrease of cell viability in the low nanomolar range. Whereas mTORC1-dependent phosphorylation of S6K was completely abrogated with concentrations as low as 10 nM, PI3K-dependent phosphorylation of AKT was still present to a lower degree at 100 nM, suggesting that BGT226 suppresses mTORC1 activity more effectively than PI3K activity and that the release of the negative feedback loop exerted by p70S6K leading to Akt reactivation is not completely abolished.…”

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…It has shown efficacy in inhibiting estrogen-deprived ER positive breast cancer cell lines, multiple myelomas and head and neck cancers [95][96][97] . The modes of inhibition by BGT226 vary in different types of cancer cell lines.…”

Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia

“…BGT226 is an ATP-competitive dual PI3K/mTORC1/2 inhibitor used for treatment of advanced solid tumors [30, 31]. As previously reported by our group, it was cytotoxic to a panel of hepatocarcinoma cell lines, under both normoxia and hypoxia conditions [32].…”