title: A preclinical evaluation of antimycin a as a potential antilung cancer stem cell agent.
abstract: Drug resistance and tumor recurrence are major obstacles in treating lung cancer patients. Accumulating evidence considers lung cancer stem cells (CSCs) as the major contributor to these clinical challenges. Agents that can target lung CSCs could potentially provide a more effective treatment than traditional chemotherapy. Here, we utilized the side-population (SP) method to isolate lung CSCs from A549 and PC-9 cell lines. Subsequently, a high throughput platform, connectivity maps (CMAPs), was used to identify potential anti-CSC agents. An antibiotic, antimycin A (AMA), was identified as a top candidate. SP A549 cells exhibited an elevated stemness profile, including Nanog, β -catenin, Sox2, and CD133, and increased self-renewal ability. AMA treatment was found to suppress β -catenin signaling components and tumor sphere formation. Furthermore, AMA treatment decreased the proliferation of gefitinib-resistant PC-9/GR cells and percentage of SP population. AMA demonstrated synergistic suppression of PC-9/GR cell viability when combined with gefitinib. Finally, AMA treatment suppressed tumorigenesis in mice inoculated with A549 SP cells. Collectively, we have identified AMA using CMAP as a novel antilung CSC agent, which acts to downregulate β -catenin signaling. The combination of AMA and targeted therapeutic agents could be considered for overcoming drug resistance and relapse in lung cancer patients.
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 11031, Taiwan ; Cancer Center, Taipei Medical University-Shuang Ho Hospital, Taipei 23561, Taiwan ; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Su
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
authors.forename: Justin Kung-Yi
authors.initials: JK
authors.lastname: Lin
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.forename: Peter M-H
authors.initials: PM
authors.lastname: Chang
authors.forename: Yu-Lun
authors.initials: YL
authors.lastname: Kuo
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Liu
authors.forename: Liang-Shun
authors.initials: LS
authors.lastname: Wang
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.forename: Yi-Shing
authors.initials: YS
authors.lastname: Shieh
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jan
authors.forename: Yung-Jen
authors.initials: YJ
authors.lastname: Chuang
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Alexander T H
authors.initials: AT
authors.lastname: Wu