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Published on: March 30, 2019
A preclinical evaluation of antimycin a as a potential antilung cancer stem cell agent
Chi-Tai Yeh1, Chun-Li Su, Chi-Ying F Huang
1Graduate 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.
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.
Insights
Antimcyin A targets lung cancer stem cells (CSCs) by downregulating beta-catenin signaling, offering a potential new treatment to overcome drug resistance and tumor recurrence in lung cancer patients.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Pharmacology
Background:
- Drug resistance and tumor recurrence are significant challenges in lung cancer treatment.
- Lung cancer stem cells (CSCs) are implicated as key drivers of these clinical issues.
- Targeting CSCs presents a promising strategy for more effective lung cancer therapies.
Purpose of the Study:
- To identify novel agents targeting lung CSCs.
- To investigate the efficacy of antimycin A (AMA) as an anti-CSC agent.
- To elucidate the mechanism of action of AMA in lung CSCs.
Main Methods:
- Isolation of lung CSCs using the side-population (SP) method from A549 and PC-9 cell lines.
- High-throughput screening using connectivity maps (CMAPs) to identify potential anti-CSC agents.
- Assessment of AMA's effects on CSC stemness markers, self-renewal, proliferation, and tumorigenesis in vitro and in vivo.
Main Results:
- Antimcyin A (AMA) was identified as a top candidate agent targeting lung CSCs.
- AMA suppressed key stemness markers (Nanog, β-catenin, Sox2, CD133) and tumor sphere formation in lung CSCs.
- AMA reduced proliferation of gefitinib-resistant cells, decreased the SP population, and inhibited tumorigenesis in vivo.
- AMA demonstrated synergistic effects when combined with gefitinib against resistant cells.
Conclusions:
- Antimcyin A is a novel anti-lung CSC agent that functions by downregulating β-catenin signaling.
- AMA holds potential for overcoming drug resistance and preventing relapse in lung cancer.
- Combination therapy with AMA and targeted agents could improve treatment outcomes for lung cancer patients.
