Department of Pediatric Hematology/Oncology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510120, PR China.
Biomed Pharmacother. 2019 May;113:108665. doi: 10.1016/j.biopha.2019.108665. Epub 2019 Mar 16.
Arsenic trioxide is effective in the treatment of acute promyelocytic leukemia and is currently in use in clinical trials for the treatment of solid tumor types. Given that arsenic trioxide is able to arrest neuroblastoma cell cycle in the G2/M phase, the present study is, to the best of our knowledge, the first to investigate whether the combination of arsenic trioxide with mitosis-phase-specific antineoplastic agents (vinorelbine or docetaxel) or non-mitosis-phase-specific antineoplastic agents (etoposide or cisplatin) exert synergistic effects in cytotoxicity on the human SK-N-SH neuroblastoma cell line.
Neuroblastoma cells were either incubated with one of the four drugs individually, or preincubated with arsenic trioxide and then followed by another drug when cell cycle was arrested at the G2/M phase with the highest proportion.
The results of the present study revealed that arsenic trioxide potentiated the apoptotic rate of neuroblastoma cells induced by chemotherapeutic drugs. The present study further demonstrated that preincubation with arsenic trioxide followed by a mitosis-phase-specific antineoplastic agent result in a higher cytotoxicity effect compared with a non mitosis-phase-specific antineoplastic agent. Along with the enhanced cytotoxicity in combination group, the cell cycle distribution demonstrated a decreased proportion of G2/M phase in the combination group.
The in vitro study revealed that the pre-application of arsenic trioxide followed by mitosis-phase-specific antineoplastic agents potentiate the cytotoxic effects on neuroblastoma cells, therefore arsenic trioxide may be a promising therapeutic option for treating neuroblastoma.
三氧化二砷在治疗急性早幼粒细胞白血病方面具有疗效，目前正在临床试验中用于治疗实体瘤类型。鉴于三氧化二砷能够使神经母细胞瘤细胞周期阻滞在 G2/M 期，本研究是目前为止首次研究三氧化二砷与有丝分裂期特异性抗肿瘤药物（长春瑞滨或多西他赛）或非有丝分裂期特异性抗肿瘤药物（依托泊苷或顺铂）联合使用对人 SK-N-SH 神经母细胞瘤细胞系的细胞毒性是否具有协同作用。
神经母细胞瘤细胞分别单独用四种药物之一孵育，或者用三氧化二砷预孵育，当细胞周期被阻滞在 G2/M 期且比例最高时，再用另一种药物处理。
本研究结果表明，三氧化二砷增强了化疗药物诱导的神经母细胞瘤细胞的凋亡率。本研究进一步表明，用三氧化二砷预孵育后再用有丝分裂期特异性抗肿瘤药物比用非有丝分裂期特异性抗肿瘤药物的细胞毒性作用更强。随着联合组细胞毒性的增强，细胞周期分布显示联合组 G2/M 期的比例降低。
体外研究表明，三氧化二砷预处理后再应用有丝分裂期特异性抗肿瘤药物增强了对神经母细胞瘤细胞的细胞毒性作用，因此三氧化二砷可能是治疗神经母细胞瘤的一种有前途的治疗选择。
