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Ceftriaxone exerts antitumor effects in MYCN-driven retinoblastoma and neuroblastoma by targeting DDX3X for
Pamorn Chittavanich1, Duangporn Saengwimol2, Sittiruk Roytrakul3
1Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Abstract:
MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification is associated with aggressive retinoblastoma (RB) and neuroblastoma (NB) cancer recurrence that is resistant to chemotherapies. Therefore, there is an urgent need to identify new therapeutic tools. This study aimed to evaluate the potential repurposing of ceftriaxone for the treatment of MYCN-amplified RB and NB, based on the clinical observations that the drug was serendipitously found to decrease the volume of the MYCN-driven RB subtype. Using patient-derived tumor organoids and tumor cell lines, we demonstrated that ceftriaxone is a potent and selective growth inhibitor targeting MYCN-driven RB and NB cells. Profiling of drug-induced transcriptomic changes, cell-cycle progression, and apoptotic death indicated cell-cycle arrest and death of drug-treated MYCN-amplified tumor cells. Drug target identification, using an affinity-based proteomic and molecular docking approach, and functional studies of the target proteins revealed that ceftriaxone targeted DEAD-box helicase 3 X-linked (DDX3X), thereby inhibiting translation in MYCN-amplified tumors but not in MYCN-nonamplified cells. The data suggest the feasibility of repurposing ceftriaxone as an anticancer drug and provide insights into the mechanism of drug action, highlighting DDX3X as a potential target for treating MYCN-driven tumors.
Insights
Ceftriaxone effectively inhibits MYCN-amplified retinoblastoma and neuroblastoma by targeting DDX3X, offering a potential new therapy for these aggressive cancers. This repurposing strategy shows promise for treating MYCN-driven tumors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- MYCN amplification drives aggressive retinoblastoma (RB) and neuroblastoma (NB) with chemotherapy resistance.
- There is a critical need for novel therapeutic strategies against MYCN-amplified cancers.
- Clinical observations suggested ceftriaxone may reduce MYCN-driven RB tumor volume.
Purpose of the Study:
- To investigate the potential repurposing of ceftriaxone as a treatment for MYCN-amplified RB and NB.
- To elucidate the mechanism of action and identify the molecular target of ceftriaxone in these cancers.
Main Methods:
- Utilized patient-derived tumor organoids and cell lines for drug efficacy testing.
- Conducted transcriptomic profiling, cell-cycle analysis, and apoptosis assays.
- Employed affinity-based proteomics and molecular docking for drug target identification.
Main Results:
- Ceftriaxone demonstrated potent and selective growth inhibition of MYCN-driven RB and NB cells.
- Treatment induced cell-cycle arrest and apoptotic cell death in MYCN-amplified tumor cells.
- Ceftriaxone was identified to target DEAD-box helicase 3 X-linked (DDX3X), inhibiting translation in MYCN-amplified tumors.
Conclusions:
- Ceftriaxone shows feasibility for repurposing as an anticancer agent against MYCN-amplified retinoblastoma and neuroblastoma.
- The study highlights DDX3X as a potential therapeutic target for MYCN-driven cancers.
- This research provides mechanistic insights into ceftriaxone's anti-tumor activity.
