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Obtusilactone B from Machilus Thunbergii targets barrier-to-autointegration factor to treat cancer.

Abstract
Targeting specific molecules is a promising cancer treatment because certain types of cancer cells are dependent on specific oncogenes. This strategy led to the development of therapeutics that use monoclonal antibodies or small-molecule inhibitors. However, the continued development of novel molecular targeting inhibitors is required to target the various oncogenes associated with the diverse types and stages of cancer. Obtusilactone B is a butanolide derivative purified from Machilus thunbergii. In this study, we show that obtusilactone B functions as a small-molecule inhibitor that causes abnormal nuclear envelope dynamics and inhibits growth by suppressing vaccinia-related kinase 1 (VRK1)-mediated phosphorylation of barrier-to-autointegration factor (BAF). BAF is important in maintaining lamin integrity, which is closely associated with diseases that include cancer. Specific binding of obtusilactone B to BAF suppressed VRK1-mediated BAF phosphorylation and the subsequent dissociation of the nuclear envelope from DNA that allows cells to progress through the cell cycle. Obtusilactone B potently induced tumor cell death in vitro, indicating that specific targeting of BAF to block cell cycle progression can be an effective anticancer strategy. Our results demonstrate that targeting a major constituent of the nuclear envelope may be a novel and promising alternative approach to cancer treatment.
AuthorsWanil Kim, Ha-Na Lyu, Hyun-Sook Kwon, Ye Seul Kim, Kyung-Ha Lee, Do-Yeon Kim, Goutam Chakraborty, Kwan Yong Choi, Ho Sup Yoon, Kyong-Tai Kim
JournalMolecular pharmacology (Mol Pharmacol) Vol. 83 Issue 2 Pg. 367-76 (Feb 2013) ISSN: 1521-0111 [Electronic] United States
PMID23150487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents, Phytogenic
  • BANF1 protein, human
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Plant Extracts
  • DNA
  • Protein-Serine-Threonine Kinases
  • VRK1 protein, human
Topics
  • Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
  • Cell Cycle (drug effects)
  • Cell Death (drug effects)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • DNA (drug effects)
  • DNA-Binding Proteins (antagonists & inhibitors, metabolism)
  • Humans
  • Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
  • Neoplasms (drug therapy, enzymology, metabolism, pathology)
  • Nuclear Envelope (drug effects, metabolism)
  • Nuclear Proteins (antagonists & inhibitors, metabolism)
  • Phosphorylation (drug effects)
  • Plant Extracts (chemistry, pharmacology)
  • Plant Stems (chemistry)
  • Protein-Serine-Threonine Kinases (antagonists & inhibitors, metabolism)

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