Adefovir Dipivoxil as a Therapeutic Candidate for Medullary Thyroid Carcinoma: Targeting RET and STAT3
Tariq Alqahtani1,2,3, Vishnu Kumarasamy3,4,5, Sahar Saleh Alghamdi1,2
1Department of Pharmaceutical Sciences, College of Pharmacy, Ministry of National Guard Health Affairs, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia.
Abstract:
Aberrant gene expression is often linked to the progression of various cancers, making the targeting of oncogene transcriptional activation a potential strategy to control tumor growth and development. The RET proto-oncogene's gain-of-function mutation is a major cause of medullary thyroid carcinoma (MTC), which is part of multiple endocrine neoplasia type 2 (MEN2) syndrome. In this study, we used a cell-based bioluminescence reporter system driven by the RET promoter to screen for small molecules that potentially suppress the RET gene transcription. We identified adefovir dipivoxil as a transcriptional inhibitor of the RET gene, which suppressed endogenous RET protein expression in MTC TT cells. Adefovir dipivoxil also interfered with STAT3 phosphorylation and showed high affinity to bind to STAT3. Additionally, it inhibited RET-dependent TT cell proliferation and increased apoptosis. These results demonstrate the potential of cell-based screening assays in identifying transcriptional inhibitors for other oncogenes.
Insights
Researchers identified adefovir dipivoxil as a RET gene transcriptional inhibitor. This drug suppressed medullary thyroid carcinoma cell growth and increased apoptosis, showing promise for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aberrant gene expression drives cancer progression.
- RET proto-oncogene mutations cause medullary thyroid carcinoma (MTC) and MEN2 syndrome.
- Targeting oncogene transcription is a potential cancer control strategy.
Purpose of the Study:
- To screen for small molecules inhibiting RET gene transcription.
- To identify novel therapeutic agents for MTC.
Main Methods:
- Developed a cell-based bioluminescence reporter system using the RET promoter.
- Screened small molecules for RET transcriptional inhibition.
- Assessed adefovir dipivoxil's effects on RET expression, STAT3 phosphorylation, and MTC cell proliferation and apoptosis.
Main Results:
- Identified adefovir dipivoxil as a RET transcriptional inhibitor.
- Adefovir dipivoxil suppressed endogenous RET protein in MTC TT cells.
- Inhibited STAT3 phosphorylation, showing high affinity for STAT3.
- Reduced RET-dependent TT cell proliferation and increased apoptosis.
Conclusions:
- Cell-based screening assays are effective for identifying oncogene transcriptional inhibitors.
- Adefovir dipivoxil demonstrates therapeutic potential for MTC by targeting RET transcription and STAT3 signaling.
- This study highlights a novel approach for developing cancer therapeutics.
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