Abstract
Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeutics to improve the outcome of patients. Betulin (Bet), a triterpenoid from the bark of birches, demonstrated interesting anti-cancer potential. The modification of natural phytochemicals with evidenced anti-tumor activity, including Bet, is one of the methods of receiving new compounds for potential implementation in oncological treatment. Here, we showed that two acetylenic synthetic Bet derivatives (ASBDs), EB5 and EB25/1, reduced the viability and proliferation of SK-N-AS and TE671 cells, as measured by MTT and BrdU tests, respectively. Moreover, ASBDs were also more cytotoxic than temozolomide (TMZ) and cisplatin (cis-diaminedichloroplatinum [II], CDDP) in vitro, and the combination of EB5 with CDDP enhanced anti-cancer effects. We also showed the slowdown of cell cycle progression at S/G2 phases mediated by EB5 using FACS flow cytometry. The decreased viability and proliferation of pediatric cancers cells after treatment with ASBDs was linked to the reduced activity of kinases Akt, Erk1/2 and p38 and the induction of apoptosis, as investigated using Western blotting and FACS. In addition, in silico analyses of the ADMET profile found EB5 to be a promising anti-cancer drug candidate that would benefit from further investigation.
Highlights
Cancer still remains a leading public health issue and is a major cause of premature death worldwide, resulting in multiple severe social and economic problems
We evaluated the effect of treatment of acetylenic synthetic Bet derivatives (ASBDs) with CDDP on TE671 and SK-N-AS cells’ viability
By using in silico approach, we found the increased lipophilicity of both ASBDs, as their values of LogP calculated with different methods were higher when compared to
Summary
Cancer still remains a leading public health issue and is a major cause of premature death worldwide, resulting in multiple severe social and economic problems. The global tumor burden is predicted to increase within decades [1,2]. Neuroblastoma (NB) is one of the most frequent solid cancers in infants and young children, representing approximately 8–10% of all childhood malignancies [3,4]. NB, as an embryonal tumor originated from stem cells of the neural crest, may arise within the sympathetic nervous system in the neck, chest, abdomen or pelvis. NB remains a complex disease with diverse clinical and histopathological manifestations [4,5]. Prognoses for patients with NB are quite variable—from spontaneous regression mainly in infants ≤18 months, to aggressive disease, characterized by distant metastases and resistance to standard treatment modalities in older children [3].
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