Anticancer Activities of 9-chloro-6-(piperazin-1-yl)-11H-indeno[1,2-c] quinolin-11-one (SJ10) in Glioblastoma Multiforme (GBM) Chemoradioresistant Cell Cycle-Related Oncogenic Signatures

Ntlotlang Mokgautsi; Yu-Cheng Kuo; Sung-Ling Tang; Feng-Cheng Liu; Shiang-Jiun Chen; Alexander T H Wu; Hsu-Shan Huang

doi:10.3390/cancers14010262

Anticancer Activities of 9-chloro-6-(piperazin-1-yl)-11H-indeno[1,2-c] quinolin-11-one (SJ10) in Glioblastoma Multiforme (GBM) Chemoradioresistant Cell Cycle-Related Oncogenic Signatures

Cancers (Basel). 2022 Jan 5;14(1):262. doi: 10.3390/cancers14010262.

Authors

Ntlotlang Mokgautsi^{1

2}, Yu-Cheng Kuo^{3

4}, Sung-Ling Tang⁵, Feng-Cheng Liu⁶, Shiang-Jiun Chen⁷, Alexander T H Wu^{8

9

10

11}, Hsu-Shan Huang^{1

2

7

8

12}

Affiliations

¹ PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.
² Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
³ Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁴ School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
⁵ Department of Pharmacy Practice, Tri-Service General Hospital, School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan.
⁶ Department of Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Neihu Dist., Taipei City 114, Taiwan.
⁷ School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan.
⁸ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
⁹ The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
¹⁰ Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan.
¹¹ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
¹² PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.

Abstract

Current anticancer treatments are inefficient against glioblastoma multiforme (GBM), which remains one of the most aggressive and lethal cancers. Evidence has shown the presence of glioblastoma stem cells (GSCs), which are chemoradioresistant and associated with high invasive capabilities in normal brain tissues. Moreover, accumulating studies have indicated that radiotherapy contributes to abnormalities in cell cycle checkpoints, including the G₁/S and S phases, which may potentially lead to resistance to radiation. Through computational simulations using bioinformatics, we identified several GBM oncogenes that are involved in regulating the cell cycle. Cyclin B1 (CCNB1) is one of the cell cycle-related genes that was found to be upregulated in GBM. Overexpression of CCNB1 was demonstrated to be associated with higher grades, proliferation, and metastasis of GBM. Additionally, increased expression levels of CCNB1 were reported to regulate activation of mitogen-activated protein kinase 7 (MAPK7) in the G₂/M phase, which consequently modulates mitosis; additionally, in clinical settings, MAPK7 was demonstrated to promote resistance to temozolomide (TMZ) and poor patient survival. Therefore, MAPK7 is a potential novel drug target due to its dysregulation and association with TMZ resistance in GBM. Herein, we identified MAPK7/extracellular regulated kinase 5 (ERK5) genes as being overexpressed in GBM tumors compared to normal tissues. Moreover, our analysis revealed increased levels of the cell division control protein homolog (CDC42), a protein which is also involved in regulating the cell cycle through the G₁ phase in GBM tissues. This therefore suggests crosstalk among CCNB1/CDC42/MAPK7/cluster of differentiation 44 (CD44) oncogenic signatures in GBM through the cell cycle. We further evaluated a newly synthesized small molecule, SJ10, as a potential target agent of the CCNB1/CDC42/MAPK7/CD44 genes through target prediction tools and found that SJ10 was indeed a target compound for the above-mentioned genes; in addition, it displayed inhibitory activities against these oncogenes as observed from molecular docking analysis.

Keywords: National Cancer Institute (NCI)-60; bioinformatics; chemoradioresistance; genetic heterogeneity; glioblastoma multiforme (GBM); molecular docking; temozolomide (TMZ).

Abstract

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