Aprepitant, a Neurokinin-1 Receptor Antagonist, as a Disruptive Drug for the Treatment of Pediatric Cancer

Although advances in pediatric oncology have resulted in cure rates exceeding 80% among children with cancer, progress in survival outcomes has begun to plateau in recent years. Mortality in this population remains largely associated with aggressive disease features, particularly tumor resistance to chemotherapy and metastatic spread. At the same time, the growing population of childhood cancer survivors has drawn increasing attention to the persistent and potentially serious late effects associated with conventional chemotherapy. Thus, it is crucial to discover drugs with specific antitumor action, effective and safe drugs that, combined with chemotherapy or radiotherapy, could chemosensitize or radiosensitize the tumor and reduce the severe side effects of both. Substance P (SP) peptide and its Neurokinin-1 receptor (NK-1R) are known to be involved in pediatric cancer, promotion and progression. Pediatric cancer overexpresses SP/NK-1R and NK-1R is essential for viability of cancer cells and is not essential for normal non-tumor cells. SP induces mitogenesis, exerts anti-apoptotic effects, and promotes angiogenesis, invasion and migration for metastasis in cancer cells and produces inflammation. Conversely, NK-1R antagonists, such as aprepitant and similar drugs, inhibit mitogenesis and induce apoptosis in pediatric cancer cells in a concentration-dependent manner. They also inhibit angiogenesis, invasion, and migration in pediatric cancer cells and have an anti-inflammatory effect. Moreover, aprepitant in combination with chemotherapy or radiotherapy can produce chemosensitization or radiosensitisation and decreases the severe side effects of both. This review updates the role of the SP/NK-1R axis in pediatric cancers and analyzes its potential as a therapeutic target. It highlights NK-1R antagonists, particularly aprepitant, and their potential as drugs for the treatment of pediatric cancer.