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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Arsenic Trioxide inhibits Activation of Hedgehog Pathway in Human Neuroblastoma Cell Line SK-N-BE(2) Independent of Itraconazole

Author(s): Xiaoshan Liu, Zhixuan Wang, Xilin Xiong, Chunmou Li, Yu Wu, Mingwei Su, Shu Yang, Meilin Zeng, Wenjun Weng, Ke Huang, Dunhua Zhou, Jianpei Fang, Lvhong Xu, Peng Li, Yafeng Zhu, Kunyin Qiu, Yuhan Ma, Jiaying Lei and Yang Li*

Volume 23, Issue 20, 2023

Published on: 02 October, 2023

Page: [2217 - 2224] Pages: 8

DOI: 10.2174/0118715206259952230919173611

Price: $65

Abstract

Background: Neuroblastoma (NB) remains associated with a low overall survival rate over the long term. Abnormal activation of the Hedgehog (HH) signaling pathway can activate the transcription of various downstream target genes that promote NB. Both arsenic trioxide (ATO) and itraconazole (ITRA) can inhibit tumor growth.

Objective: To determine whether ATO combined with ITRA can be used to treat NB with HH pathway activation, we examined the effects of ATO and ITRA monotherapy or combined inhibition of the HH pathway in NB.

Methods: Analysis of CCK8 and flow cytometry showed cell inhibition and cell cycle, respectively. Real-time PCR analysis was conducted to assess the mRNA expression of HH pathway.

Results: We revealed that as concentrations of ATO and ITRA increased, the killing effects of both agents on SK-N-BE(2) cells became more apparent. During G2/M, the cell cycle was largely arrested by ATO alone and combined with ITRA, and in the G0/G1 phase by ITRA alone. In the HH pathway, ATO inhibited the transcription of the SHH, PTCH1, SMO and GLI2 genes, however, ITRA did not. Instead of showing synergistic effects in a combined mode, ITRA decreased ATO inhibitory effects.

Conclusion: We showed that ATO is an important inhibitor of HH pathway but ITRA can weaken the inhibitory effect of ATO. This study provides an experimental evidence for the clinical use of ATO and ITRA in the treatment of NB with HH pathway activation in cytology.

Keywords: Neuroblastoma, arsenic trioxide, itraconazole, hedgehog pathway, chemotherapy, cell cycle.

Graphical Abstract
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