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Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice
Patrizia Garbati1, Raffaella Barbieri1, Matilde Calderoni2
1IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.
Abstract:
High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB.
Insights
This study explored a novel triple-drug therapy for high-risk neuroblastoma (HR-NB). Combining cisplatin, fendiline hydrochloride, and acetazolamide significantly enhanced chemotherapy efficacy and reduced malignancy markers in preclinical models.
Area of Science:
- Pediatric Oncology
- Cancer Pharmacology
- Drug Discovery
Background:
- High-risk neuroblastoma (HR-NB) is a leading childhood cancer with limited treatment options.
- Conventional chemotherapy, like cisplatin, faces challenges due to multidrug resistance.
- Identifying novel therapeutic strategies is crucial for improving outcomes in HR-NB.
Purpose of the Study:
- To evaluate a novel triple-drug combination therapy for HR-NB.
- To investigate the synergistic effects of cisplatin, fendiline hydrochloride, and acetazolamide.
- To assess the impact of this combination on neuroblastoma cell cytotoxicity and malignancy markers.
Main Methods:
- Preclinical study using SKNBE2 xenografts in NOD-SCID mice.
- Co-administration of cisplatin, fendiline hydrochloride (multidrug resistance inhibitor), and acetazolamide (carbonic anhydrase IX inhibitor).
- Evaluation of cytotoxic activity and expression of malignancy markers.
Main Results:
- The triple-drug combination demonstrated a more than twelvefold increase in cytotoxic activity compared to cisplatin alone.
- Significant reduction in the expression of key malignancy markers was observed.
- The combination therapy showed enhanced efficacy in reducing tumor burden in vivo.
Conclusions:
- The combination of cisplatin, fendiline hydrochloride, and acetazolamide represents a promising novel therapeutic approach for HR-NB.
- This strategy, utilizing three FDA-approved drugs, may offer an improved treatment option for high-risk neuroblastoma.
- Further clinical investigation is warranted to translate these findings into patient care.
