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

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 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.

• Authors: 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
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 4 (Feb 05 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33562773 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Immunological
• Cyclic S-Oxides
• IL6 protein, human
• Interleukin-6
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• stattic
• Polylysine
• poly ICLC
• EIF2AK2 protein, human
• eIF-2 Kinase
• 2',5'-Oligoadenylate Synthetase
• Carboxymethylcellulose Sodium
• Poly I-C

Topics

• 2',5'-Oligoadenylate Synthetase (chemistry, genetics, metabolism)
• A549 Cells
• Antineoplastic Agents, Immunological (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Binding Sites
• Carboxymethylcellulose Sodium (analogs & derivatives, pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclic S-Oxides (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Interleukin-6 (antagonists & inhibitors)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Models, Molecular
• Poly I-C (pharmacology)
• Polylysine (analogs & derivatives, pharmacology)
• Tumor Microenvironment (drug effects)
• Tyrphostins (pharmacology)
• eIF-2 Kinase (chemistry, genetics, metabolism)