4-Hydroxychalcone Induces Cell Death via Oxidative Stress in MYCN-Amplified Human Neuroblastoma Cells

Abstract

Neuroblastoma is an embryonal malignancy that arises from cells of sympathoadrenal lineage during the development of the nervous system. It is the most common pediatric extracranial solid tumor and is responsible for 15% of childhood deaths from cancer. Fifty percent of cases are diagnosed as high-risk metastatic disease with a low overall 5-year survival rate. More than half of patients experience disease recurrence that can be refractory to treatment. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and a poor prognosis, highlighting the need for new therapeutic approaches. In recent years, there has been an increasing focus on identifying anticancer properties of naturally occurring chalcones, which are secondary metabolites with variable phenolic structures. Here, we report that 4-hydroxychalcone is a potent cytotoxin for MYCN-amplified IMR-32 and SK-N-BE (2) neuroblastoma cells, when compared to non-MYCN-amplified SH-SY5Y neuroblastoma cells and to the non-neuroblastoma human embryonic kidney cell line, HEK293t. Moreover, 4-hydroxychalcone treatment significantly decreased cellular levels of the antioxidant glutathione and increased cellular reactive oxygen species. In addition, 4-hydroxychalcone treatment led to impairments in mitochondrial respiratory function, compared to controls. In support of this, the cytotoxic effect of 4-hydroxychalcone was prevented by co-treatment with either the antioxidant N-acetyl-L-cysteine, a pharmacological inhibitor of oxidative stress-induced cell death (IM-54) or the mitochondrial reactive oxygen species scavenger, Mito-TEMPO. When combined with the anticancer drugs cisplatin or doxorubicin, 4-hydroxychalcone led to greater reductions in cell viability than was induced by either anti-cancer agent alone. In summary, this study identifies a cytotoxic effect of 4-hydroxychalcone in MYCN-amplified human neuroblastoma cells, which rationalizes its further study in the development of new therapies for pediatric neuroblastoma.

Programmed Cell Death Alterations Mediated by Synthetic Indole Chalcone Resulted in Cell Cycle Arrest, DNA Damage, Apoptosis and Signaling Pathway Modulations in Breast Cancer Model

“…Among others, the anticancer effect of both natural and synthetic chalcones has been intensively studied in the last decade [ 13 , 14 , 15 , 16 ]. Although the mechanism of the antiproliferative action of chalcones has not yet been fully elucidated, numerous studies documented pleiotropic mode of action [ 17 , 18 , 19 , 20 ] including cell cycle arrest, DNA damage, induction of reactive oxygen species production, modulation of various signaling pathways, etc. [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”

“…Although the mechanism of the antiproliferative action of chalcones has not yet been fully elucidated, numerous studies documented pleiotropic mode of action [ 17 , 18 , 19 , 20 ] including cell cycle arrest, DNA damage, induction of reactive oxygen species production, modulation of various signaling pathways, etc. [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Furthermore, induction of both intrinsic and extrinsic apoptosis pathways associated with caspases activation, modulation of the Bcl-2 family protein activity, impairment of mitochondrial function with subsequent release of proapoptotic factors such as cytochrome c has also been experimentally proven [ 27 , 28 ].…”

Emerging therapeutic targets for neuroblastoma

“…As discussed above, the benefit of ginsenoside-RK1 in targeting NB EMT and malignancy/ metastatic behavior has been realized [103]. Likewise, studies have extensively documented the anti-tumor and chemo/radiosensitizing potential (and mechanisms) of curcumin and its synthetic analogues in NB [155][156][157][158]. 4-hydroxy chalcone (4HC, flavonoid) treatment induced NB cell death by increasing oxidative stress and LDH activity, and prompted chemosensitization to doxorubicin and cisplatin [159].…”