Hiltonol cocktail kills lung cancer cells by activating cancer-suppressors, pkr/oas and restraining the tumor microenvironment

Shu Chun Chang, Bo Xiang Zhang, Emily Chia Yu Su, Wei Ciao Wu, Tsung Han Hsieh, Andres M. Salazar, Yen Kuang Lin, Jeak Ling Ding

Research output: Contribution to journalArticlepeer-review

Abstract

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 meta-static 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 suppres-sors, 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 tis-sues, 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.

Original languageEnglish
Article number1626
Pages (from-to)1-23
Number of pages23
JournalInternational journal of molecular sciences
Volume22
Issue number4
DOIs
Publication statusPublished - Feb 2 2021

Keywords

  • Anti-and pro-tumorigenic cytokine pro-duction
  • Combinatorial treatment with Hiltonol cocktail [Hil-tonol+anti-IL6+stattic+AG490]
  • NSCLC (non-small cell lung cancer)
  • Tumor-suppressors PKR (protein kinase R) and OAS (2′5′ oligoadenylate synthetase)
  • Tumorigenic microenvironment

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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