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Adv Pharm Bull. 2024;14(3): 665-674.
doi: 10.34172/apb.2024.058
  Abstract View: 381
  PDF Download: 127

Research Article

PGV-1 Causes Disarrangement of Spindle Microtubule Organization Resulting in Aberrant Mitosis in HLF and HuH6 Cells Associated with Altered MYCN Status

Nadzifa Nugraheni 1 ORCID logo, Ummi Maryam Zulfin 1,2 ORCID logo, Beni Lestari 1 ORCID logo, Novia Permata Hapsari 1, Muthi Ikawati 1,3 ORCID logo, Rohmad Yudi Utomo 1,4 ORCID logo, Yusuke Suenaga 2 ORCID logo, Yoshitaka Hippo 2,5 ORCID logo, Edy Meiyanto 1,3* ORCID logo

1 Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Sleman, Yogyakarta, Indonesia.
2 Laboratory of Evolutionary Oncology, Chiba Cancer Center Research Institute, Chiba, Japan.
3 Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Sleman, Yogyakarta, Indonesia.
4 Laboratory of Medicinal Chemistry, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Sleman, Yogyakarta, Indonesia.
5 Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan.
*Corresponding Author: Edy Meiyanto, Email: edy_meiyanto@ugm.ac.id

Abstract

Purpose: The HLF and HuH-6 cell lines represent hepatocellular carcinoma (HCC) with different characteristics in chromosome content that may give different drug responses. Here, PGV-1 was intended to challenge the growth-suppressing effect on HLF and HuH-6 and trace the molecular target mechanism of action compared to sorafenib.

Methods: We applied MTT cytotoxic assay, colony forming assay, flow cytometry analysis, immunofluorescence assay and western blot assay.

Results: PGV-1 exhibited cytotoxic effects on HLF and HuH-6 with IC-50 values of 1 µM and 2 µM, respectively, whereas sorafenib showed less cytotoxicity with IC-50 values of 5 µM and 8 µM respectively. PGV-1 suppressed the cell growth permanently but not for sorafenib. Sorafenib did not change the cell cycle profiles on both cells, but PGV-1 arrested the cells at G2/M with the characteristic of senescent cells and mitotic disarrangement. PGV-1 and sorafenib showed the same effect in downregulating p-EGFR, indicating that both compounds have the same target on EGFR activation or as Tyrosine kinase inhibitors. PGV-1 suppressed the MYCN expression in HuH-6 and HLF cells but stabilized cMYC-T58 indicating that even though the MYCN was downregulated, the cells maintained the active form of cMYC. In this regard, PGV-1 also stabilized the expression of PLK-1 and AurA.

Conclusion: PGV-1 elicits stronger cytotoxic properties compared to sorafenib. The lower the MYCN expression, the higher the cytotoxic effect of PGV-1. PGV-1 abrogates cell cycle progression of both cells in mitosis through EGFR inhibition and stabilizes PLK-1 and AurA in correlation with the suppression of MYCN expression.

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Submitted: 14 Dec 2023
Revision: 12 Jul 2024
Accepted: 30 Jul 2024
ePublished: 31 Jul 2024
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