Abraxane, the Nanoparticle Formulation of Paclitaxel Can Induce Drug Resistance by Up-Regulation of P-gp

Minzhi Zhao; Chunni Lei; Yadong Yang; Xiangli Bu; Huailei Ma; He Gong; Juan Liu; Xiangdong Fang; Zhiyuan Hu; Qiaojun Fang

doi:10.1371/journal.pone.0131429

Abraxane, the Nanoparticle Formulation of Paclitaxel Can Induce Drug Resistance by Up-Regulation of P-gp

PLoS One. 2015 Jul 16;10(7):e0131429. doi: 10.1371/journal.pone.0131429. eCollection 2015.

Authors

Affiliations

¹ CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100190, China.
² CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
³ CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100190, China; Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 102206, China.

Abstract

P-glycoprotein (P-gp) can actively pump paclitaxel (PTX) out of cells and induces drug resistance. Abraxane, a nanoparticle (NP) formulation of PTX, has multiple clinical advantages over the single molecule form. However, it is still unclear whether Abraxane overcomes the common small molecule drug resistance problem mediated by P-gp. Here we were able to establish an Abraxane-resistant cell line from the lung adenocarcinoma cell line A549. We compared the transcriptome of A549/Abr resistant cell line to that of its parental cell line using RNA-Seq technology. Several pathways were found to be up or down regulated. Specifically, the most significantly up-regulated gene was ABCB1, which translates into P-glycoprotein. We verified the overexpression of P-glycoprotein and confirmed its function by reversing the drug resistance with P-gp inhibitor Verapamil. The results suggest that efflux pathway plays an important role in the Abraxane-resistant cell line we established. However, the relevance of this P-gp mediated Abraxane resistance in tumors of lung cancer patients remains unknown.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Albumin-Bound Paclitaxel / chemistry
Albumin-Bound Paclitaxel / pharmacology*
Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / pharmacology*
Calcium Channel Blockers / pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Drug Compounding
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Humans
Molecular Sequence Annotation
Multigene Family
Nanoparticles / chemistry*
Protein Isoforms / genetics
Protein Isoforms / metabolism
Respiratory Mucosa / drug effects
Respiratory Mucosa / metabolism
Respiratory Mucosa / pathology
Signal Transduction
Transcriptome
Verapamil / pharmacology

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Calcium Channel Blockers
Protein Isoforms
Verapamil

Associated data

GEO/GSE56742

Grants and funding

The authors acknowledge funding from the National Natural Science Foundation of China (31270875, 31470049), Chinese Academy of Science (YZ201217, Y4362911ZX), the International S&T Cooperation Program of China (2010DFB33880), the State Key Development Program for Basic Research of China grant (2011CB915502), the “Strategic Priority Research Program” of the Chinese Academy of Sciences, Stem Cell and Regenerative Medicine Research (XDA01040405 to X.F.), National Programs for High Technology Research and Development (863 Projects, 2012AA022502 to X.F.), National “Twelfth Five-Year” Plan for Science & Technology Support (2013BAI01B09 to X.F.), Shanghai Leading Academic Discipline Project (B502), Shanghai Key Laboratory Project (08DZ2230500), Science and Technology Commission of Shanghai Municipality Project (11nm0507000), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.