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Article

Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment

1
The PhD Program for Translational Medicine, College for Medical Science and Technology, Taipei Medical University, 250 Wusing Street, Taipei 110, Taiwan
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International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, 250 Wusing Street, Taipei 110, Taiwan
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Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University Hospital, 252 Wusing Street, Taipei 110, Taiwan
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Clinical Big Data Research Center, Taipei Medical University Hospital, 252 Wusing Street, Taipei 110, Taiwan
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Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wusing Street, Taipei 110, Taiwan
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Department of Thoracic Surgery, Department of Surgery, Taipei Medical University Shuang Ho Hospital, Taipei 110, Taiwan
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Joint Biobank, Office of Human Research, Taipei Medical University, 250 Wusing Street, Taipei 110, Taiwan
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Oncovir, Inc., 3203 Cleveland Avenue Northwest, Washington, DC 20008, USA
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Big Data Research Center, Taipei Medical University, 250 Wusing Street, Taipei 110, Taiwan
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Biostatistics Center, Office of Data Science, Taipei Medical University, 250 Wusing Street, Taipei 110, Taiwan
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Graduate Institute of Data Science, College of Management, Taipei Medical University, 250 Wusing Street, Taipei 110, Taiwan
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Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
*
Authors to whom correspondence should be addressed.
Co-senior authors.
Academic Editor: Monica Cantile
Int. J. Mol. Sci. 2021, 22(4), 1626; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041626
Received: 7 January 2021 / Revised: 29 January 2021 / Accepted: 2 February 2021 / Published: 5 February 2021
(This article belongs to the Special Issue Tumor Biobanks at the Service of Precision Medicine)
NSCLC (non-small cell lung cancer) is a leading cause of cancer-related deaths worldwide. Clinical trials showed that Hiltonol, a stable dsRNA representing an advanced form of polyI:C (polyinosinic-polycytidilic acid), is an adjuvant cancer-immunomodulator. However, its mechanisms of action and effect on lung cancer have not been explored pre-clinically. Here, we examined, for the first time, how a novel Hiltonol cocktail kills NSCLC cells. By retrospective analysis of NSCLC patient tissues obtained from the tumor biobank; pre-clinical studies with Hiltonol alone or Hiltonol+++ cocktail [Hiltonol+anti-IL6+AG490 (JAK2 inhibitor)+Stattic (STAT3 inhibitor)]; cytokine analysis; gene knockdown and gain/loss-of-function studies, we uncovered the mechanisms of action of Hiltonol+++. We demonstrated that Hiltonol+++ kills the cancer cells and suppresses the metastatic potential of NSCLC through: (i) upregulation of pro-apoptotic Caspase-9 and Caspase-3, (ii) induction of cytosolic cytochrome c, (iii) modulation of pro-inflammatory cytokines (GRO, MCP-1, IL-8, and IL-6) and anticancer IL-24 in NSCLC subtypes, and (iv) upregulation of tumor suppressors, PKR (protein kinase R) and OAS (2′5′ oligoadenylate synthetase). In silico analysis showed that Lys296 of PKR and Lys66 of OAS interact with Hiltonol. These Lys residues are purportedly involved in the catalytic/signaling activity of the tumor suppressors. Furthermore, knockdown of PKR/OAS abrogated the anticancer action of Hiltonol, provoking survival of cancer cells. Ex vivo analysis of NSCLC patient tissues corroborated that loss of PKR and OAS is associated with cancer advancement. Altogether, our findings unraveled the significance of studying tumor biobank tissues, which suggests PKR and OAS as precision oncological suppressor candidates to be targeted by this novel Hiltonol+++ cocktail which represents a prospective drug for development into a potent and tailored therapy for NSCLC subtypes. View Full-Text
Keywords: NSCLC (non-small cell lung cancer); combinatorial treatment with Hiltonol+++ cocktail [Hiltonol+anti-IL6+stattic+AG490]; tumorigenic microenvironment; anti- and pro-tumorigenic cytokine production; tumor-suppressors PKR (protein kinase R) and OAS (2′5′ oligoadenylate synthetase) NSCLC (non-small cell lung cancer); combinatorial treatment with Hiltonol+++ cocktail [Hiltonol+anti-IL6+stattic+AG490]; tumorigenic microenvironment; anti- and pro-tumorigenic cytokine production; tumor-suppressors PKR (protein kinase R) and OAS (2′5′ oligoadenylate synthetase)
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MDPI and ACS Style

Chang, S.-C.; Zhang, B.-X.; Su, E.C.-Y.; Wu, W.-C.; Hsieh, T.-H.; Salazar, A.M.; Lin, Y.-K.; Ding, J.L. Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 1626. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041626

AMA Style

Chang S-C, Zhang B-X, Su EC-Y, Wu W-C, Hsieh T-H, Salazar AM, Lin Y-K, Ding JL. Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment. International Journal of Molecular Sciences. 2021; 22(4):1626. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041626

Chicago/Turabian Style

Chang, Shu-Chun, Bo-Xiang Zhang, Emily C.-Y. Su, Wei-Ciao Wu, Tsung-Han Hsieh, Andres M. Salazar, Yen-Kuang Lin, and Jeak L. Ding. 2021. "Hiltonol Cocktail Kills Lung Cancer Cells by Activating Cancer-Suppressors, PKR/OAS, and Restraining the Tumor Microenvironment" International Journal of Molecular Sciences 22, no. 4: 1626. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041626

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