Characterization of Cisplatin Effects in Lenvatinib-resistant Hepatocellular Carcinoma Cells

Background/Aim: Drug resistance to molecular targeted agents, such as lenvatinib, is an important issue. The aim of this study was to explore the mechanism of lenvatinib resistance and to investigate potential drugs that may improve the treatment of lenvatinib-resistant (LR) hepatocellular carcinoma (HCC). Materials and Methods: LR cells were developed by long-term culture under lenvatinib exposure. We analyzed the biological characteristics of LR cells in vitro, and investigated the antitumor effects and endogenous mechanisms of cisplatin in LR cells. Results: The proliferative potential of LR cells was enhanced by activation of ERK signaling and changes in several miRNAs. Cisplatin inhibited cell proliferation of LR cells and induced G2/M cell cycle arrest. Furthermore, cisplatin triggered the DNA damage response, via the ATM/ATR-Chk1/Chk2 signaling pathway. Conclusion: Proliferation of LR cells was induced upon ERK signaling activation. Cisplatin exerted antitumor effects in LR cells and was involved in the regulation of miRNAs associated with drug resistance.

[1]  E. Brzeziańska-Lasota,et al.  Molecular Mechanisms of Chemoresistance Induced by Cisplatin in NSCLC Cancer Therapy , 2021, International journal of molecular sciences.

[2]  Tomoko Tadokoro,et al.  Multimodal treatment involving molecular targeted agents and on-demand transcatheter arterial chemoembolization for advanced hepatocellular carcinoma: A case report and review of the literature , 2021, Molecular and clinical oncology.

[3]  A. Morishita,et al.  Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review , 2021, International journal of molecular sciences.

[4]  N. Kato,et al.  Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells. , 2021, Biochemical and biophysical research communications.

[5]  J. Ji,et al.  Sophoridine suppresses lenvatinib‐resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression , 2020, Journal of cellular and molecular medicine.

[6]  T. Masaki,et al.  Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma—A Review , 2020, International journal of molecular sciences.

[7]  Jianyun Zhang,et al.  MicroRNA‐191 modulates cisplatin‐induced DNA damage response by targeting RCC2 , 2020, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  Yan Zhao,et al.  Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anti-cancer therapy. , 2020, Biochimica et biophysica acta. Reviews on cancer.

[9]  Yanlin Sun,et al.  NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway , 2020, Cell Death & Disease.

[10]  Qingbai Liu,et al.  SNHG16 promotes osteosarcoma progression and enhances cisplatin resistance by sponging miR-16 to upregulate ATG4B expression. , 2019, Biochemical and biophysical research communications.

[11]  T. Masaki,et al.  Telmisartan Inhibits Cell Proliferation and Tumor Growth of Esophageal Squamous Cell Carcinoma by Inducing S-Phase Arrest In Vitro and In Vivo , 2019, International journal of molecular sciences.

[12]  T. Niki,et al.  Galectin-9 Induces Mitochondria-Mediated Apoptosis of Esophageal Cancer In Vitro and In Vivo in a Xenograft Mouse Model , 2019, International Journal of Molecular Sciences.

[13]  Markus Peck-Radosavljevic,et al.  Review article: systemic treatment of hepatocellular carcinoma , 2018, Alimentary pharmacology & therapeutics.

[14]  M. Kudo,et al.  Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial , 2018, The Lancet.

[15]  A. Abdel-Naim,et al.  Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies – A review , 2017, Journal of advanced research.

[16]  Xueda Hu,et al.  Understanding the Genetic Mechanisms of Cancer Drug Resistance Using Genomic Approaches. , 2016, Trends in genetics : TIG.

[17]  J. Blanc,et al.  Prognosis of advanced hepatocellular carcinoma: a new stratification of Barcelona Clinic Liver Cancer stage C results from a French multicenter study , 2015, European journal of gastroenterology & hepatology.

[18]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[19]  Q. Yao,et al.  miR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells , 2015, Cancer Gene Therapy.

[20]  Masao Iwata,et al.  Antitumor Activity of Lenvatinib (E7080): An Angiogenesis Inhibitor That Targets Multiple Receptor Tyrosine Kinases in Preclinical Human Thyroid Cancer Models , 2014, Journal of thyroid research.

[21]  M. Kudo,et al.  Re‐evaluating transarterial chemoembolization for the treatment of Hepatocellular Carcinoma: Consensus recommendations and review by an International Expert Panel , 2014, Liver international : official journal of the International Association for the Study of the Liver.

[22]  A. Venook,et al.  A review of hepatocellular carcinoma (HCC) staging systems. , 2013, Chinese clinical oncology.

[23]  H. Piwnica-Worms,et al.  Regulation of Chk2 Ubiquitination and Signaling through Autophosphorylation of Serine 379 , 2008, Molecular and Cellular Biology.

[24]  J Wade Harper,et al.  The DNA damage response: ten years after. , 2007, Molecular cell.

[25]  M. Nakanishi,et al.  DNA Damage Checkpoints and Cancer , 2006, Journal of Molecular Histology.

[26]  E. Shimizu,et al.  Expression of multidrug resistance proteins and accumulation of cisplatin in human non-small cell lung cancer cells. , 2005, Biological & pharmaceutical bulletin.

[27]  A. Nebreda,et al.  Regulation of Cdc25C Activity During the Meiotic G2/M Transition , 2004, Cell cycle.

[28]  L. Latonen,et al.  Cell cycle control, DNA damage checkpoints and cancer , 2003, Annals of medicine.

[29]  H. Piwnica-Worms,et al.  ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1 , 2001, Molecular and Cellular Biology.

[30]  H. Piwnica-Worms,et al.  Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. , 2000, Cancer research.

[31]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[32]  D. Woodfield.  Hepatocellular carcinoma. , 1986, The New Zealand medical journal.