HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo.

Abstract
This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation more potently (9- to 10-fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G0-G1 cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti-MM therapies. Significant tumour growth reduction in AS703026- vs. vehicle-treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nmol/l) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC-induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti-MM agents, to improve patient outcome.
AuthorsKihyun Kim, Sun-Young Kong, Mariateresa Fulciniti, Xianfeng Li, Weihua Song, Sabikun Nahar, Peter Burger, Mathew J Rumizen, Klaus Podar, Dharminder Chauhan, Teru Hideshima, Nikhil C Munshi, Paul Richardson, Ann Clark, Janet Ogden, Andreas Goutopoulos, Luca Rastelli, Kenneth C Anderson, Yu-Tzu Tai
JournalBritish journal of haematology (Br J Haematol) Vol. 149 Issue 4 Pg. 537-49 (May 2010) ISSN: 1365-2141 [Electronic] England
PMID20331454 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
  • Protein Kinase Inhibitors
  • Niacinamide
  • MAP2K2 protein, human
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Cell Death (drug effects)
  • Dose-Response Relationship, Drug
  • Humans
  • MAP Kinase Kinase 1 (antagonists & inhibitors)
  • MAP Kinase Kinase 2 (antagonists & inhibitors)
  • MAP Kinase Signaling System (drug effects)
  • Mice
  • Mice, SCID
  • Multiple Myeloma (drug therapy, pathology)
  • Niacinamide (analogs & derivatives, pharmacology, therapeutic use)
  • Protein Kinase Inhibitors (pharmacology, therapeutic use)
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: