NVP-BEZ235-induced autophagy as a potential therapeutic approach for multiple myeloma.

BACKGROUND

The PI3K/Akt/mTOR pathway is constitutively activated in human multiple myeloma (MM) cell lines and in freshly isolated plasmocytes from patients with MM. The mTOR signaling pathway has been designated an attractive anti-tumor target in multiple myeloma. NVP-BEZ235, a novel, dual class I PI3K/mTOR inhibitor, is an imidazoquinoline derivative. NVP-BEZ235 binds to the ATP-binding clefts of PI3K and mTOR kinase, thereby inhibiting their activities. Increasing evidence shows that NVP-BEZ235 is able to effectively and specifically reverse the hyperactivation of the PI3K/mTOR pathway, resulting not only in potent antiproliferative and antitumor activities in a broad range of cancer cell lines and experimental tumors but also in autophagy.

METHOD

The antitumor, apoptosis, and autophagy effects of NVP-BEZ235 were measured in three MM cell lines, two leukemia cell lines, and primary CD138+ myeloma cells from MM patients and nude mouse MM models. In addition, the relationships between autophagy, cell death and apoptosis induced by NVP-BEZ235 were analyzed in MM cells. Furthermore, we explored the mechanism of autophagy induced by NVP-BEZ235 in MM cells.

RESULTS

NVP-BEZ235 inhibited proliferation and induced apoptosis and autophagy in MM cells and in primary MM cells from patients and nude mouse MM models. Autophagy played an important role in the cell death and apoptosis of MM cell lines induced by NVP-BEZ235, and the mechanism involved the mTOR2-Akt-FOXO3a-BNIP3 pathway.

CONCLUSIONS

In this study, NVP-BEZ235 showed the strongest antitumor and autophagy induction activity. Moreover, the mechanism involved the mTOR2-Akt-FOXO3a-BNIP3 pathway. Our study lays a theoretical foundation for NVP-BEZ235 clinical application.