PMID- 35834029
OWN - NLM
STAT- MEDLINE
DCOM- 20220718
LR  - 20220822
IS  - 1559-131X (Electronic)
IS  - 1357-0560 (Print)
IS  - 1357-0560 (Linking)
VI  - 39
IP  - 10
DP  - 2022 Jul 14
TI  - GANT61/BI-847325 combination: a new hope in lung cancer treatment.
PG  - 144
LID - 10.1007/s12032-022-01738-4 [doi]
LID - 144
AB  - Despite the huge efforts employed to implement novel chemotherapeutic paradigms 
      for lung cancer, the disease still remains a major concern worldwide. Targeting 
      molecular pathways as Hedgehog (Hh) and Mitogen-activated protein kinase (MAPK) 
      represent a new hope in lung cancer treatment. This work was undertaken to 
      evaluate the antitumor effects of GANT61 (5 muM), BI-847325(30 muM), and GANT61 
      (5 muM)/BI-847325(30 muM) combination on A549 adenocarcinoma lung cancer cell line. 
      The growth inhibition 50 (GI50) for both drugs was performed using MTT. The 
      protein levels of Caspase-3, Bcl-2-associated X protein (Bax), Myeloid cell 
      leukemia sequence 1 (MCL-1), cyclin D1, vascular endothelial growth factor 
      (VEGF), extracellular signal-regulated kinases (ERK), p-Akt, and phosphohistone 
      H3 (pHH3) were measured using ELISA. Glioma-associated oncogene homolog 1(Gli1) 
      gene expression was assessed by quantitative real-time PCR. The GI50 for GANT61 
      and BI-8473255 were 5 microM and 30 microM, respectively. Caspase-3 and Bax protein 
      levels were significantly elevated while MCL-1, cyclin D1, VEGF, ERK 1/2, p-Akt, 
      and pHH3 levels were significantly reduced by both drugs and their combination 
      relative to the control group. Gli1 gene expression was down-regulated in 
      all groups relative to the control group. GANT61, BI-847325 and their combination 
      inhibited proliferation and angiogenesis but activated the apoptotic pathway. 
      Both drugs conferred a profound negative impact on the crosstalk between each of 
      Hh and MAPK pathways and Phosphoinositide 3 -kinases (PI3K)/Akt/Mammalian target 
      of Rapamycin (mTOR). To the best of our knowledge, the antitumor effects of 
      BI-847325/GANT61 combination have not been tested before. Further 
      in-vitro and in-vivo studies are warranted to support the findings.
CI  - (c) 2022. The Author(s).
FAU - El-Kishky, Abdel Halim M
AU  - El-Kishky AHM
AD  - Department of Biotechnology, Institute of Graduate Studies and Research, 
      Alexandria University, Alexandria, Egypt.
FAU - Moussa, Nermine
AU  - Moussa N
AUID- ORCID: 0000-0001-8362-9717
AD  - Department of Biotechnology, Institute of Graduate Studies and Research, 
      Alexandria University, Alexandria, Egypt. igsr.nerminemoussa@alexu.edu.eg.
FAU - Helmy, Maged W
AU  - Helmy MW
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhur 
      University, Damanhur, Egypt.
FAU - Haroun, Medhat
AU  - Haroun M
AD  - Department of Biotechnology, Institute of Graduate Studies and Research, 
      Alexandria University, Alexandria, Egypt.
LA  - eng
PT  - Journal Article
DEP - 20220714
PL  - United States
TA  - Med Oncol
JT  - Medical oncology (Northwood, London, England)
JID - 9435512
RN  - 0 (Aniline Compounds)
RN  - 0 (BI-847325)
RN  - 0 (GANT 61)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Indoles)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 136601-57-5 (Cyclin D1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Aniline Compounds
MH  - Apoptosis
MH  - Caspase 3/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cyclin D1/metabolism
MH  - *Hedgehog Proteins
MH  - Humans
MH  - Indoles
MH  - *Lung Neoplasms/drug therapy/genetics
MH  - Myeloid Cell Leukemia Sequence 1 Protein/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyridines
MH  - Pyrimidines
MH  - Signal Transduction
MH  - Vascular Endothelial Growth Factor A
MH  - Zinc Finger Protein GLI1/metabolism/pharmacology
PMC - PMC9283175
OTO - NOTNLM
OT  - Aurora Kinase
OT  - BI-847325
OT  - GANT61
OT  - Hedgehog
OT  - Lung cancer
OT  - MAPK
COIS- 'No relevant financial or non-financial interests to disclose. The authors 
      declare that this research was conducted in the absence of any commercial or 
      financial relationships that could be considered as a potential conflict of 
      interest'.
EDAT- 2022/07/15 06:00
MHDA- 2022/07/19 06:00
PMCR- 2022/07/14
CRDT- 2022/07/14 11:18
PHST- 2022/03/23 00:00 [received]
PHST- 2022/04/22 00:00 [accepted]
PHST- 2022/07/14 11:18 [entrez]
PHST- 2022/07/15 06:00 [pubmed]
PHST- 2022/07/19 06:00 [medline]
PHST- 2022/07/14 00:00 [pmc-release]
AID - 10.1007/s12032-022-01738-4 [pii]
AID - 1738 [pii]
AID - 10.1007/s12032-022-01738-4 [doi]
PST - epublish
SO  - Med Oncol. 2022 Jul 14;39(10):144. doi: 10.1007/s12032-022-01738-4.