Hsieh Ming-Ju, Lin Chiao-Wen, Su Shih-Chi, Reiter Russel J, Chen Andy Wei-Ge, Chen Mu-Kuan, Yang Shun-Fa
Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Institute of Oral Sciences, Chung Shan Medical University, Taichung 402, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital 402, Taichung, Taiwan.
Mol Ther Nucleic Acids. 2020 Mar 6;19:877-889. doi: 10.1016/j.omtn.2019.12.022. Epub 2020 Jan 9.
Multidrug resistance (MDR) is the resistance of cells toward various drugs commonly used in tumor treatment. The mechanism of drug resistance in oral cancer is not completely understood. Melatonin is an endogenously produced molecule involved in active biological mechanisms including antiproliferation, oncogene expression modulation, antitumor invasion and migration, and anti-inflammatory, antioxidant, and antiangiogenic effects. Despite these functions, the effects of melatonin on vincristine (VCR)-resistant human oral cancer cells remain largely unknown. This study analyzed the role of melatonin in VCR-resistant human oral cancer cells along with the underlying mechanism. We determined that melatonin induced the apoptosis and autophagy of VCR-resistant oral cancer cells; these actions were mediated by AKT, p38, and c-Jun N-terminal kinase (JNK). Melatonin inhibited ATP-binding cassette B1 (ABCB1) and ABCB4 expression in vitro and in vivo. Melatonin reduced the drug resistance and promoted the apoptosis of VCR-resistant oral cancer cells through the upregulation of microRNA-892a (miR-892a) and miR-34b-5p expressions. The expression of miR-892a and miR-34b-5p was related to melatonin-induced apoptosis, but not autophagy. Therefore, melatonin is a potential novel chemotherapeutic agent for VCR-resistant human oral cancer cell lines.
多药耐药性（MDR）是指细胞对肿瘤治疗中常用的各种药物产生的耐药性。口腔癌的耐药机制尚未完全明确。褪黑素是一种内源性产生的分子，参与多种生物活性机制，包括抗增殖、癌基因表达调控、抗肿瘤侵袭和迁移以及抗炎、抗氧化和抗血管生成作用。尽管具有这些功能，但褪黑素对长春新碱（VCR）耐药的人口腔癌细胞的影响仍 largely unknown。本研究分析了褪黑素在VCR耐药的人口腔癌细胞中的作用及其潜在机制。我们确定褪黑素可诱导VCR耐药口腔癌细胞的凋亡和自噬；这些作用是由AKT、p38和c-Jun氨基末端激酶（JNK）介导的。褪黑素在体外和体内均抑制ATP结合盒转运体B1（ABCB1）和ABCB4的表达。褪黑素通过上调微小RNA-892a（miR-892a）和miR-34b-5p的表达降低VCR耐药口腔癌细胞的耐药性并促进其凋亡。miR-892a和miR-34b-5p的表达与褪黑素诱导的凋亡有关，但与自噬无关。因此，褪黑素是一种潜在的新型化疗药物，可用于治疗VCR耐药的人口腔癌细胞系。
