Dual inhibition of Akt/Mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma

Diana Clrstea, Teru Hideshima, Scott Rodig, Loredana Santo, Samantha Pozzl, Sonia Vallet, Hiroshi Ikeda, Glulia Perrone, Gullu Gorgun, Kishan Patel, Neil Desal, Peter Sportelli, Shweta Kapoor, Shireen Vali, Siddhartha Mukherjee, Nikhil C. Munshi, Kenneth C. Anderson, Noopur Raje

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors, such as rapamycin, with potential anti-MM activity. However, recent data show a positive feedback loop from mTOR/S6K1 to Akt, whereby Akt activation confers resistance to mTOR inhibitors. We confirmed that suppression of mTOR signaling in MM cells by rapamycin was associated with upregulation of Akt phosphorylation. We hypothesized that inhibiting this positive feedback by a potent Akt inhibitor perifosine would augment rapamycin-induced cytotoxicity in MM cells. Perifosine inhibited rapamycin-induced phosphorylated Akt, resulting in enhanced cytotoxicity in MM. IS cells even in the presence of interleukin-6, insulin-like growth factor-I, or bone marrow stromal cells. Moreover, rapamycininduced autophagy in MM.1S MM cells, as evidenced by electron microscopy and immunocytochemistry, was augmented by perifosine. Combination therapy increased apoptosis detected by Annexin V/propidium iodide analysis and caspase/poly(ADP-ribose) polymerase cleavage. Importantly, in vivo antitumor activity and prolongation of survival in a MM mouse xenograft model after treatment was enhanced with combination of nanoparticle albumin-bound-reLpamycin and perifosine. Utilizing the in silico predictive analysis, we confirmed our experimental findings of this drug combination on PI3K, Akt, mTOR kinases, and the caspases. Our data suggest that mutual suppression of the PE3K/Akt/mTOR pathway by rapamycin and perifosine combination induces synergistic MM cell cytotoxicity, providing the rationale for clinical trials in patients with relapsed/refractory MM.

Original languageEnglish (US)
Pages (from-to)963-975
Number of pages13
JournalMolecular cancer therapeutics
Volume9
Issue number4
DOIs
StatePublished - Apr 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Dual inhibition of Akt/Mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma'. Together they form a unique fingerprint.

  • Cite this

    Clrstea, D., Hideshima, T., Rodig, S., Santo, L., Pozzl, S., Vallet, S., Ikeda, H., Perrone, G., Gorgun, G., Patel, K., Desal, N., Sportelli, P., Kapoor, S., Vali, S., Mukherjee, S., Munshi, N. C., Anderson, K. C., & Raje, N. (2010). Dual inhibition of Akt/Mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Molecular cancer therapeutics, 9(4), 963-975. https://doi.org/10.1158/1535-7163.MCT-09-0763