Novel In Vitro Selection of <i>Trans</i>-Acting <i>BCL-2</i> mRNA-Cleaving Deoxyribozymes for Cancer Therapy

Novel In Vitro Selection of <i>Trans</i>-Acting <i>BCL-2</i> mRNA-Cleaving Deoxyribozymes for Cancer Therapy

The B Cell Lymphoma-2 (<i>BCL-2</i>) family proteins are central regulators of apoptosis, and their dysregulation is frequently associated with cancer progression and resistance to therapy. While small molecules like venetoclax have shown promise, nucleic acid-based therapeutics targetin...

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Main Authors: Veera Vijaya Basamshetty, Vijay Kumar Gangipangi, Uppulapu Shravan Kumar, Santhosh Shanthi Bhupathi, Sridhar Reddy Kaulagari, Prashant Giri, Swapnil Sinha, Utpal Mohan, Konstantinos Sdrimas
Format: Article
Language:English
Published: MDPI AG 2025-06-01
Series:Cells
Subjects:
DNAzymes
<i>BCL-2</i>
apoptosis
cancer
synthetic biology
Online Access:https://www.mdpi.com/2073-4409/14/13/945
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Summary:The B Cell Lymphoma-2 (<i>BCL-2</i>) family proteins are central regulators of apoptosis, and their dysregulation is frequently associated with cancer progression and resistance to therapy. While small molecules like venetoclax have shown promise, nucleic acid-based therapeutics targeting <i>BCL-2</i> remain underexplored. Here, we report a novel in vitro evolution strategy to generate trans-acting RNA-cleaving DNAzymes targeting natural <i>BCL-2</i> mRNA without requiring covalent substrate-linking. Using a 50-base region of <i>BCL-2</i> mRNA as a selection target, we evolved several DNAzymes that demonstrate significant RNA cleavage activity. These DNAzymes downregulated <i>BCL-2</i> expression, induced apoptosis, and reduced cell viability in HepG2 and MCF-7 cancer cells. In vivo, our novel DNAzymes significantly suppressed tumor growth in a syngeneic mouse breast cancer model, with efficacy comparable to 5-Fluorouracil. This study presents a proof of concept for a novel strategy to evolve functional DNAzymes against native mRNA sequences and highlights their potential as gene-silencing tools in cancer therapy. Future studies will explore the therapeutic potential of these findings in cancer patients. Additionally, investigating the underlying molecular mechanisms in more complex cancer models will further validate the observed effects.
ISSN:2073-4409

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