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Research ArticleExperimental Studies

Pemetrexed Disodium Heptahydrate Induces Apoptosis and Cell-cycle Arrest in Non-small-cell Lung Cancer Carrying an EGFR Exon 19 Deletion

MD MOHIUDDIN and KAZUO KASAHARA
Anticancer Research June 2021, 41 (6) 2963-2977; DOI: https://doi.org/10.21873/anticanres.15078
MD MOHIUDDIN
Department of Respiratory Medicine, Kanazawa University, Ishikawa, Japan
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  • For correspondence: mohiuddin@med.kanazawa-u.ac.jp
KAZUO KASAHARA
Department of Respiratory Medicine, Kanazawa University, Ishikawa, Japan
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Abstract

Background/Aim: Non-small-cell lung cancer (NSCLC) remains a significant cause of death despite the recent introduction of several improved therapeutics. Pemetrexed disodium heptahydrate (pemetrexed) is currently available in combination with a platinum derivative for patients with advanced non-squamous NSCLC for first-line treatment, and as a single agent for second-line treatment. However, the mechanisms underlying its anticancer activities are still not well understood. In this study, we evaluated the growth inhibitory effects of pemetrexed on PC9 (EGFR exon 19 deletion) cells and elucidated the underlying molecular mechanisms. Materials and Methods: PC9 cells were treated with pemetrexed and then assessed for the cell viability, morphological and nuclear changes, antigenic alterations, SA-β-gal staining, and changes in protein expression. Results: Pemetrexed reduced the cell viability of PC9 cells and initiated cell morphological changes in a concentration-dependent manner. Pemetrexed significantly induced G1 phase arrest in a dose-dependent manner. The results demonstrated that pemetrexed induced apoptosis in PC9 cells, a change coupled with an increase in reactive oxygen species and a decrease in mitochondrial membrane potential. Pemetrexed decreased Bcl-2 expression, while Bax expression was increased, and cytochrome c was released. Furthermore, the expression of extrinsic pathway proteins, e.g. Fas/FasL, DR4/TRAIL, and Fas-associated protein with death domain, was increased by pemetrexed, which then activated caspase-8, caspase-9, and caspase-3 and induced poly (ADP-ribose) polymerase proteolysis. Conclusion: This study revealed the mechanisms by which pemetrexed works an anticancer drug in the treatment of NSCLC.

Key Words:
  • Pemetrexed
  • PC9 cells
  • apoptosis
  • caspases
  • cell-cycle arrest
  • Received April 5, 2021.
  • Revision received April 27, 2021.
  • Accepted May 6, 2021.
  • Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Anticancer Research: 41 (6)
Anticancer Research
Vol. 41, Issue 6
June 2021
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Pemetrexed Disodium Heptahydrate Induces Apoptosis and Cell-cycle Arrest in Non-small-cell Lung Cancer Carrying an EGFR Exon 19 Deletion
MD MOHIUDDIN, KAZUO KASAHARA
Anticancer Research Jun 2021, 41 (6) 2963-2977; DOI: 10.21873/anticanres.15078

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Pemetrexed Disodium Heptahydrate Induces Apoptosis and Cell-cycle Arrest in Non-small-cell Lung Cancer Carrying an EGFR Exon 19 Deletion
MD MOHIUDDIN, KAZUO KASAHARA
Anticancer Research Jun 2021, 41 (6) 2963-2977; DOI: 10.21873/anticanres.15078
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Keywords

  • pemetrexed
  • PC9 cells
  • apoptosis
  • caspases
  • cell-cycle arrest
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