Combination of Oncolytic Measles Virus and Ursolic Acid Synergistically Induces Oncolysis of Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) remains a difficult-to-treat cancer due to late diagnosis and limited curative treatment options. Developing more effective therapeutic strategies is essential for the management of HCC. Oncolytic virotherapy is a novel treatment modality for cancers, and its combination with small molecules merits further exploration. In this study, we combined oncolytic measles virus (MV) with the natural triterpenoid compound ursolic acid (UA) and evaluated their combination effect against HCC cells, including those harboring hepatitis B virus (HBV) or hepatitis C virus (HCV) replication. We found that the combination of MV and UA synergistically induced more cell death in Huh-7 HCC cells through enhanced apoptosis. In addition, increased oxidative stress and loss of mitochondrial potential were observed in the treated cells, indicating dysregulation of the mitochondria-dependent pathway. Similar synergistic cytotoxic effects were also found in HCC cells harboring HBV or HCV genomes. These findings underscore the potential of oncolytic MV and UA combination for further development as a treatment strategy for HCC.

[1]  Liang-Tzung Lin,et al.  Immunogenic cell death: The cornerstone of oncolytic viro-immunotherapy , 2023, Frontiers in Immunology.

[2]  J. Sharifi‐Rad,et al.  Ursolic acid: a natural modulator of signaling networks in different cancers , 2022, Cancer cell international.

[3]  J. Tong,et al.  Oncolytic virus-based hepatocellular carcinoma treatment: Current status, intravenous delivery strategies, and emerging combination therapeutic solutions , 2022, Asian journal of pharmaceutical sciences.

[4]  J. Ferlay,et al.  Global burden of primary liver cancer in 2020 and predictions to 2040 , 2022, Journal of hepatology.

[5]  Wenhua Li,et al.  Ursolic acid enhances the antitumor effects of sorafenib associated with Mcl-1-related apoptosis and SLC7A11-dependent ferroptosis in human cancer. , 2022, Pharmacological research.

[6]  S. Ullevig,et al.  Ursolic Acid and Related Analogues: Triterpenoids with Broad Health Benefits , 2021, Antioxidants.

[7]  Liang-Tzung Lin,et al.  Small molecules baicalein and cinnamaldehyde are potentiators of measles virus-induced breast cancer oncolysis. , 2021, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[8]  L. Rawat,et al.  Ursolic acid disturbs ROS homeostasis and regulates survival-associated gene expression to induce apoptosis in intestinal cancer cells. , 2021, Toxicology research.

[9]  J. Llovet,et al.  Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. , 2021, Annals of oncology : official journal of the European Society for Medical Oncology.

[10]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[11]  C. E. Engeland,et al.  Measles Virus as an Oncolytic Immunotherapy , 2021, Cancers.

[12]  C. Richardson,et al.  Ursolic Acid and Its Nanoparticles Are Potentiators of Oncolytic Measles Virotherapy against Breast Cancer Cells , 2021, Cancers.

[13]  Byung-Hyun Park,et al.  Reactive Oxygen Species-Mediated Autophagy by Ursolic Acid Inhibits Growth and Metastasis of Esophageal Cancer Cells , 2020, International journal of molecular sciences.

[14]  Bin Zhang,et al.  Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy , 2020, Molecular Cancer.

[15]  J. Wedd,et al.  The optimal timing and management of hepatitis B and C in patients with hepatocellular carcinoma. , 2020, Chinese clinical oncology.

[16]  U. Lauer,et al.  Chemovirotherapy for pancreatic cancer: Gemcitabine plus oncolytic measles vaccine virus. , 2019, Oncology letters.

[17]  H. Ko,et al.  Ursolic Acid Suppresses Cholesterol Biosynthesis and Exerts Anti-Cancer Effects in Hepatocellular Carcinoma Cells , 2019, International journal of molecular sciences.

[18]  Naoki Yamamoto,et al.  Combination of Vaccine Strain Measles Virus and Nimotuzumab in the Treatment of Laryngeal Cancer , 2019, AntiCancer Research.

[19]  X. Su,et al.  Anticancer effect of ursolic acid via mitochondria-dependent pathways. , 2019, Oncology letters.

[20]  C. Tai,et al.  Chemovirotherapeutic Treatment Using Camptothecin Enhances Oncolytic Measles Virus-Mediated Killing of Breast Cancer Cells , 2019, Scientific Reports.

[21]  M. S. Rajala,et al.  Combination of Oncolytic Measles Virus Armed With BNiP3, a Pro-apoptotic Gene and Paclitaxel Induces Breast Cancer Cell Death , 2019, Front. Oncol..

[22]  H. Rammensee,et al.  Measles Virus-Based Treatments Trigger a Pro-inflammatory Cascade and a Distinctive Immunopeptidome in Glioblastoma , 2018, Molecular therapy oncolytics.

[23]  P. Schirmacher,et al.  Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  Yao-Li Chen,et al.  Ursolic Acid-Induced Apoptosis via Regulation of the PI3K/Akt and MAPK Signaling Pathways in Huh-7 Cells , 2018, Molecules.

[25]  Jiayuh Lin,et al.  Inhibition of STAT3 signaling pathway by ursolic acid suppresses growth of hepatocellular carcinoma. , 2017, International journal of oncology.

[26]  N. Chandel,et al.  The Two Faces of Reactive Oxygen Species in Cancer , 2017 .

[27]  Chia-Chieh Wu,et al.  Combined Use of Zoledronic Acid Augments Ursolic Acid-Induced Apoptosis in Human Osteosarcoma Cells through Enhanced Oxidative Stress and Autophagy , 2016, Molecules.

[28]  U. Lauer,et al.  Novel epi-virotherapeutic treatment of pancreatic cancer combining the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus. , 2016, International journal of oncology.

[29]  U. Lauer,et al.  Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma , 2015, Molecular therapy oncolytics.

[30]  F. Zheng,et al.  Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKα-mediated reduction of DNA methyltransferase 1 , 2015, Molecular and Cellular Biochemistry.

[31]  Justin Shields,et al.  Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry. , 2015, Journal of hepatology.

[32]  J. Azizkhan-Clifford,et al.  Sp1 and the ‘hallmarks of cancer’ , 2015, The FEBS journal.

[33]  F. Zheng,et al.  Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKα-mediated reduction of DNA methyltransferase 1 , 2014, Molecular and Cellular Biochemistry.

[34]  J. Bukh,et al.  Efficient Infectious Cell Culture Systems of the Hepatitis C Virus (HCV) Prototype Strains HCV-1 and H77 , 2014, Journal of Virology.

[35]  R. Kratzke,et al.  Measles Vaccine Strains for Virotherapy of Non–Small-Cell Lung Carcinoma , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[36]  S. Russell,et al.  Systemically delivered measles virus-infected mesenchymal stem cells can evade host immunity to inhibit liver cancer growth. , 2013, Journal of hepatology.

[37]  A. Bishayee,et al.  Ursolic acid in cancer prevention and treatment: molecular targets, pharmacokinetics and clinical studies. , 2013, Biochemical pharmacology.

[38]  R. Lehmann,et al.  An armed oncolytic measles vaccine virus eliminates human hepatoma cells independently of apoptosis , 2013, Gene Therapy.

[39]  Jun Wang,et al.  Oleanolic acid and ursolic acid: novel hepatitis C virus antivirals that inhibit NS5B activity. , 2013, Antiviral research.

[40]  M. Tsao,et al.  Tumor Cell Marker PVRL4 (Nectin 4) Is an Epithelial Cell Receptor for Measles Virus , 2011, PLoS pathogens.

[41]  X. Su,et al.  Ursolic Acid Inhibits Proliferation and Induces Apoptosis of Cancer Cells In Vitro and In Vivo , 2011, Journal of biomedicine & biotechnology.

[42]  Ping-Yuan Lin,et al.  Suppression of hepatitis B virus x protein-mediated tumorigenic effects by ursolic Acid. , 2011, Journal of agricultural and food chemistry.

[43]  Gow-Chin Yen,et al.  Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP. , 2010, Journal of agricultural and food chemistry.

[44]  Christopher T. Jones,et al.  Cell culture–produced hepatitis C virus does not infect peripheral blood mononuclear cells , 2008, Hepatology.

[45]  E. Galanis,et al.  Heat shock protein inhibitors increase the efficacy of measles virotherapy , 2008, Gene Therapy.

[46]  C. James,et al.  Combination of Measles Virus Virotherapy and Radiation Therapy Has Synergistic Activity in the Treatment of Glioblastoma Multiforme , 2007, Clinical Cancer Research.

[47]  S. Tsui,et al.  Anti-Proliferative effect of ursolic acid on multidrug resistant hepatoma cells R-HepG2 by apoptosis induction , 2007 .

[48]  N. LaRusso,et al.  Engineered measles virus as a novel oncolytic viral therapy system for hepatocellular carcinoma , 2006, Hepatology.

[49]  Ting-Chao Chou,et al.  Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies , 2006, Pharmacological Reviews.

[50]  P. Xiao,et al.  Anti-hepatoma activity and mechanism of ursolic acid and its derivatives isolated from Aralia decaisneana. , 2006, World journal of gastroenterology.

[51]  J. Zucman‐Rossi,et al.  Hepatocellular carcinoma , 1998, Nature Reviews Disease Primers.

[52]  D. Griffin,et al.  Apoptosis as a cause of death in measles virus-infected cells , 1995, Journal of virology.

[53]  N. Davidson,et al.  Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. , 1993, Cancer research.

[54]  G. Acs,et al.  Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. , 1987, Proceedings of the National Academy of Sciences of the United States of America.