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.

• Authors: Ryuta Yamazaki, Yukiko Nishiyama, Tomio Furuta, Hiroshi Hatano, Yoshiaki Igarashi, Naoyuki Asakawa, Hiroshi Kodaira, Hiroyuki Takahashi, Ritsuo Aiyama, Takeshi Matsuzaki, Nao Yagi, Yoshikazu Sugimoto
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 7 Pg. 1252-63 (Jul 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21566063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 American Association for Cancer Research.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Neoplasm Proteins
• YHO-13177
• YHO-13351
• Irinotecan
• Acrylonitrile
• Camptothecin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• 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
• Irinotecan
• 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