5'-OH RNA Oligonucleotide Induces Cancer Apoptosis via ISG56
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Solution Overview
Problem
Current cancer treatments, such as chemotherapy and radiotherapy, have low cure rates and significant side effects, and existing RNA oligonucleotides with a triphosphate group at the 5'-end are not effective in increasing interferon-stimulated gene 56 (ISG56) expression to induce apoptosis in cancer cells.
Innovation Solution
An RNA oligonucleotide with a specific sequence and structure, forming a helical bend structure and a hairpin loop with a hydroxy group at the 5'-end, which increases ISG56 expression and induces apoptosis in cancer cells without affecting normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer treatments (chemotherapy and radiotherapy) are used, then tumor cells can be attacked, but cure rates remain low and side effects are significant
Solution Approach 1:
The patent changes the chemical structure parameter of the RNA oligonucleotide by replacing the triphosphate group at the 5'-end with a hydroxy group. This parameter change allows the RNA to activate interferon-beta expression through a mechanism independent of the RIG-I pathway, thereby achieving anticancer effects with reduced immunogenicity and side effects while improving therapeutic reliability
Solution Approach 2:
The patent uses interferon-beta as an intermediary substance. The modified RNA oligonucleotide (with 5'-OH group) acts as a mediator that indirectly triggers anticancer effects by activating endogenous interferon-beta expression, which then mediates the apoptosis of tumor cells. This intermediary approach reduces direct toxicity compared to conventional chemotherapy
2Reliability
If RNA oligonucleotides with triphosphate group at 5'-end are used to activate interferon, then immune response is enhanced, but they cannot effectively induce ISG56 expression and apoptosis in cancer cells
Solution Approach 1:
The patent extracts the triphosphate group from the 5'-end of the RNA oligonucleotide and replaces it with a hydroxy group. This extraction of the triphosphate moiety eliminates the need for RIG-I-mediated immune activation while preserving and enhancing the ability to induce interferon-beta expression and ISG56 production, thereby achieving anticancer efficacy through a simplified molecular structure
Solution Approach 2:
The patent inverts the conventional approach by removing the immunostimulatory triphosphate group that typically activates RIG-I, and instead using the 5'-OH modified RNA to directly induce interferon-beta expression through an alternative pathway. This inversion leads to effective ISG56 induction and cancer cell apoptosis without relying on the typical immune activation mechanism
3Duration of action of stationary object
If pancreatic cancer is treated with gemcitabine and other drugs, then chemotherapy is administered, but survival rate does not significantly increase
Solution Approach 1:
The patent uses a short-lived RNA oligonucleotide molecule with a specific sequence and 5'-OH modification that triggers a sustained biological response (interferon-beta expression and ISG56 induction) leading to cancer cell apoptosis. Despite the transient nature of the RNA molecule itself, the therapeutic effect is durable, improving survival rates without requiring complex combination regimens
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The described RNA oligonucleotide effectively induces apoptosis in various cancer cell lines, including pancreatic, liver, and stomach cancer cells, while sparing normal cells, thereby offering a promising anticancer agent with reduced side effects.
Implementation Method 1
an uncapped RNA which has a triphosphate group at the 5'-end can activate the expression of interferon by binding to intracellular retinoic acid-inducible gene-I (RIG-I) protein
Implementation Method 2
the base sequence represented by SEQ ID NO:1 (5'-N 1 GUAGAN 2 N 3 -3') and the base sequence represented by SEQ ID NO:2 (5'-N 4 N 5 UUUGCN 6 -3') wherein the base sequences are bound to each other by a complementary binding to form double strands having a helical bend structure
Data Source
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AI summary
The present disclosure provides a pharmaceutical composition for treating cancer comprising an RNA oligonucleotide having a particular sequence and structure. Specifically, when a cell line is treated with an RNA oligonucleotide having specific sequence and helical bend structure according to the present disclosure, the expression of ISG56 is increased and apoptosis of cancer cells is induced. Thus, a composition comprising the RNA oligonucleotide can be used as an anticancer agent.