PMID- 34183390
OWN - NLM
STAT- MEDLINE
DCOM- 20211122
LR  - 20211204
IS  - 1790-6245 (Electronic)
IS  - 1109-6535 (Print)
IS  - 1109-6535 (Linking)
VI  - 18
IP  - 4
DP  - 2021 Jul-Aug
TI  - Cisplatin and Pemetrexed Have Distinctive Growth-inhibitory Effects in 
      Monotherapy and Combination Therapy on KRAS-dependent A549 Lung Cancer Cells.
PG  - 579-590
LID - 10.21873/cgp.20282 [doi]
AB  - BACKGROUND/AIM: Cisplatin combined with pemetrexed disodium heptahydrate 
      (pemetrexed) is considered the standard treatment for patients with advanced, 
      non-squamous, non-small-cell lung cancer. However, its growth-inhibitory effects 
      on KRAS-dependent lung cancer as monotherapy and combination therapy are not well 
      understood. The aim of this study was to compare the effects of cisplatin and 
      pemetrexed on A549 cells as mono- and combination therapies and elucidate the 
      underlying mechanisms. MATERIALS AND METHODS: For in vitro studies, A549 cells 
      were exposed to cisplatin with/without pemetrexed for 72 h. The results were then 
      evaluated by cell viability, apoptosis, reactive oxygen species, terminal 
      deoxynucleotidyl transferase dUTP nick-end labeling, and western blotting assays. 
      RESULTS: Our results revealed that cisplatin monotherapy was most cytotoxic to 
      A549 cells, while cisplatin plus pemetrexed combination had an intermediate 
      effect, and pemetrexed monotherapy induced a minimal cytotoxic effect on A549 
      cells. This effect was evidenced by cell viability results, inhibition of KRAS 
      proto-oncogene, GTPase (KRAS)/Raf proto-oncogene, serine/threonine 
      kinase/mitogen-activated protein kinase kinase/extracellular signal-regulated 
      kinase pathways and apoptosis induction triggered by reactive oxygen 
      species-mediated DNA damage. The immunoblotting result of conversion of 
      microtubule-associated protein 1 light chain 3 alpha (LC3)-I to -II indicated 
      that the greatest inducer of autophagy was combined treatment with cisplatin plus 
      pemetrexed, while pemetrexed monotherapy had the lowest effect on autophagy 
      induction, with cisplatin monotherapy having an intermediate effect. We found 
      that the AKT serine/threonine kinase 1/mechanistic target of rapamycin kinase 
      (mTOR) and AMP-activated protein kinase/mTOR signaling pathways were associated 
      with autophagy activation. Interestingly, combination therapy with cisplatin plus 
      pemetrexed was the primary eliminator of cellular senescence; cisplatin 
      monotherapy had an intermediate effect, while pemetrexed monotherapy increased 
      cellular senescence of A549 cells, as assessed by the expression of 
      beta-galactosidase protein. CONCLUSION: Cisplatin monotherapy may be more effective 
      than pemetrexed monotherapy or cisplatin plus pemetrexed combination therapy 
      against KRAS-dependent lung cancer.
CI  - Copyright(c) 2021, International Institute of Anticancer Research (Dr. George J. 
      Delinasios), All rights reserved.
FAU - Mohiuddin, Md
AU  - Mohiuddin M
AD  - Department of Respiratory Medicine, Kanazawa University, Ishikawa, Japan 
      mohiuddin@med.kanazawa-u.ac.jp.
FAU - Kasahara, Kazuo
AU  - Kasahara K
AD  - Department of Respiratory Medicine, Kanazawa University, Ishikawa, Japan.
LA  - eng
PT  - Journal Article
PL  - Greece
TA  - Cancer Genomics Proteomics
JT  - Cancer genomics & proteomics
JID - 101188791
RN  - 0 (Antineoplastic Agents)
RN  - 0 (KRAS protein, human)
RN  - 0 (MAS1 protein, human)
RN  - 0 (Proto-Oncogene Mas)
RN  - 0 (Reactive Oxygen Species)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.1 (Raf1 protein, human)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - A549 Cells
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Autophagy/drug effects
MH  - Cell Survival/drug effects
MH  - Cellular Senescence/drug effects
MH  - Cisplatin/*pharmacology
MH  - DNA Damage/drug effects
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - Lung Neoplasms/*metabolism/pathology
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Pemetrexed/*pharmacology
MH  - Proto-Oncogene Mas
MH  - Proto-Oncogene Proteins c-raf/metabolism
MH  - Proto-Oncogene Proteins p21(ras)/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/drug effects
PMC - PMC8404737
OTO - NOTNLM
OT  - Cisplatin
OT  - KRAS
OT  - apoptosis
OT  - autophagy
OT  - pemetrexed
OT  - senescence
COIS- The Authors declare no competing financial interests.
EDAT- 2021/06/30 06:00
MHDA- 2021/11/23 06:00
PMCR- 2021/07/03
CRDT- 2021/06/29 05:53
PHST- 2021/05/11 00:00 [received]
PHST- 2021/06/02 00:00 [revised]
PHST- 2021/06/03 00:00 [accepted]
PHST- 2021/06/29 05:53 [entrez]
PHST- 2021/06/30 06:00 [pubmed]
PHST- 2021/11/23 06:00 [medline]
PHST- 2021/07/03 00:00 [pmc-release]
AID - 18/4/579 [pii]
AID - 10.21873/cgp.20282 [doi]
PST - ppublish
SO  - Cancer Genomics Proteomics. 2021 Jul-Aug;18(4):579-590. doi: 10.21873/cgp.20282.