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Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo.

Abstract
Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiated the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. In contrast, it had no effect on P-glycoprotein-mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells and multidrug resistance-related protein 1-mediated doxorubicin resistance in MRP1-transfected human epidermoid cancer KB-3-1 cells. YHO-13177 increased the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppressed the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells. In mice, YHO-13351 was rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increased the survival time of mice inoculated with BCRP-transduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone had little effect in these tumor models. These findings suggest that YHO-13351, a prodrug of YHO-13177, could be clinically useful for reversing BCRP-mediated drug resistance in cancer chemotherapy.
AuthorsRyuta Yamazaki, Yukiko Nishiyama, Tomio Furuta, Hiroshi Hatano, Yoshiaki Igarashi, Naoyuki Asakawa, Hiroshi Kodaira, Hiroyuki Takahashi, Ritsuo Aiyama, Takeshi Matsuzaki, Nao Yagi, Yoshikazu Sugimoto
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 7 Pg. 1252-63 (Jul 2011) ISSN: 1538-8514 [Electronic] United States
PMID21566063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2011 American Association for Cancer Research.
Chemical References
  • ABCG2 protein, human
  • Antineoplastic Agents
  • Neoplasm Proteins
  • YHO-13177
  • YHO-13351
  • irinotecan
  • Acrylonitrile
  • Camptothecin
Topics
  • ATP-Binding Cassette Transporters (genetics, metabolism)
  • Acrylonitrile (analogs & derivatives, pharmacology)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Camptothecin (analogs & derivatives, pharmacology)
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm (drug effects)
  • Drug Synergism
  • Female
  • HCT116 Cells
  • Humans
  • K562 Cells
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred ICR
  • Mice, Nude
  • Neoplasm Proteins (genetics, metabolism)
  • Neoplasms (genetics, mortality, pathology)
  • Xenograft Model Antitumor Assays

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