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SP600125 overcomes antimitotic drug-resistance in cancer cells by increasing apoptosis with independence of P-gp inhibition.

Abstract
The purpose of this study was to identify conditions that increase the sensitivity of resistant cancer cells to antimitotic drugs. Using MTS assays, microscopic observation, assessment of cleaved PARP, FACS analysis, and Hoechst staining, we found that the c-Jun N-terminal kinase (Jnk) inhibitor SP600125 (SP) sensitized the antimitotic drug-resistant KBV20C cancer cell line. The sensitization mechanism was independent of p-glycoprotein (P-gp) inhibition. Interestingly, SP-induced sensitization was greater in resistant KBV20C cancer cells than in KB parent cells. The mechanism of SP-induced sensitization involved G2 arrest. KBV20C cells treated with SP and antimitotic drugs were more sensitized than cells treated with SP alone. This suggests that SP can restore sensitization for antimitotic drugs in resistant cancer cells. Our findings may contribute to the development of SP-based combination therapies for patients receiving anti-cancer agents that target microtubules.
AuthorsJu-Hwa Kim, Minji Chae, Ae-Ran Choi, Hyung Sik Kim, Sungpil Yoon
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 723 Pg. 141-7 (Jan 15 2014) ISSN: 1879-0712 [Electronic] Netherlands
PMID24333214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2013 Elsevier B.V. All rights reserved.
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anthracenes
  • Antimitotic Agents
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
  • Anthracenes (pharmacology)
  • Antimitotic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Drug Resistance, Neoplasm (drug effects)
  • Humans
  • JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors)

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