In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells.

Abstract

PURPOSE:

The success of bortezomib therapy for treatment of multiple myeloma (MM) led to the development of structurally and pharmacologically distinct novel proteasome inhibitors. In the present study, we evaluated the efficacy of one such novel orally bioactive proteasome inhibitor MLN9708/MLN2238 in MM using well-established in vitro and in vivo models.

EXPERIMENTAL DESIGN:

MM cell lines, primary patient cells, and the human MM xenograft animal model were used to study the antitumor activity of MN2238.

RESULTS:

Treatment of MM cells with MLN2238 predominantly inhibits chymotrypsin-like activity of the proteasome and induces accumulation of ubiquitinated proteins. MLN2238 inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal cells. In animal tumor model studies, MLN2238 is well tolerated and inhibits tumor growth with significantly reduced tumor recurrence. A head-to-head analysis of MLN2238 versus bortezomib showed a significantly longer survival time in mice treated with MLN2238 than mice receiving bortezomib. Immununostaining of MM tumors from MLN2238-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Mechanistic studies showed that MLN2238-triggered apoptosis is associated with activation of caspase-3, caspase-8, and caspase-9; increase in p53, p21, NOXA, PUMA, and E2F; induction of endoplasmic reticulum (ER) stress response proteins Bip, phospho-eIF2-α, and CHOP; and inhibition of nuclear factor kappa B. Finally, combining MLN2238 with lenalidomide, histone deacetylase inhibitor suberoylanilide hydroxamic acid, or dexamethasone triggers synergistic anti-MM activity.

CONCLUSION:

Our preclinical study supports clinical evaluation of MLN9708, alone or in combination, as a potential MM therapy.

• Authors: Dharminder Chauhan, Ze Tian, Bin Zhou, Deborah Kuhn, Robert Orlowski, Noopur Raje, Paul Richardson, Kenneth C Anderson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 16 Pg. 5311-21 (Aug 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21724551 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2011 AACR.

Chemical References

• Antineoplastic Agents
• Boron Compounds
• Boronic Acids
• NF-kappa B
• Proteasome Inhibitors
• Pyrazines
• Thalidomide
• Bortezomib
• ixazomib
• Dexamethasone
• Caspase 3
• Caspase 8
• Caspase 9
• Proteasome Endopeptidase Complex
• Lenalidomide
• Glycine

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biological Availability
• Blotting, Western
• Boron Compounds (pharmacokinetics, pharmacology)
• Boronic Acids (pharmacology)
• Bortezomib
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dexamethasone (pharmacology)
• Drug Synergism
• Enzyme Activation (drug effects)
• Glycine (analogs & derivatives, pharmacokinetics, pharmacology)
• Humans
• Lenalidomide
• Mice
• Mice, SCID
• Multiple Myeloma (drug therapy, metabolism, pathology)
• NF-kappa B (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors
• Pyrazines (pharmacology)
• Thalidomide (analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays