Li Zhenhua, Tang Xin, Luo Yu, Chen Bangyu, Zhou Congcong, Wu Xiuqing, Tang Zhenping, Qi Xiaojie, Cao Guangchao, Hao Jianlei, Liu Zonghua, Wang Qingmin, Yin Zhinan, Yang Hengwen
The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou, China.
Department of Immunology, Basic Medical College, Guizhou Medical University, Guiyang, China.
J Cell Physiol. 2019 Sep;234(9):16178-16190. doi: 10.1002/jcp.28278. Epub 2019 Feb 20.
Ovarian cancer resistance to available medicines is a huge challenge in dire need of a solution, which makes its recurrence and mortality rate further exacerbated. A promising approach to overcome chemoresistance is drug screening from natural products. Here, we report that NK007, a (±)-tylophorine malate isolated from the Asclepiadaceae family, selectively inhibited the proliferation of A2780 and A2780 (Taxol) cells and migration of paclitaxel-sensitive and -resistant ovarian cancer cells. Interestingly, the decline of cell viability, including cell multiplication, clonality, and migration capacity was independent on cell apoptosis. At the molecular level, NK007 considerably induced G1/S arrest and upregulated the expression of phospho-p38 mitogen-activated protein kinase (p-p38MAPK). In addition, hexokinase 2 (HK2) protein degradation was considerably elevated in the presence of NK007, which resulted in the reduction of oxygen consumption rate and extracellular acidification rate. Altogether, our results indicate that NK007, an analog of tylophorine, can overcome paclitaxel (PTX) resistance through p38MAPK activation and HK2 degradation. As an effective, alternative antiresistance agent, NK007 exhibits a promising potential to treat PTX-resistant ovarian cancer.
卵巢癌对现有药物产生耐药性是一个亟待解决的巨大挑战，这使得其复发率和死亡率进一步加剧。一种有前景的克服化疗耐药性的方法是从天然产物中进行药物筛选。在此，我们报告称，NK007是一种从萝摩科植物中分离得到的（±）-娃儿藤碱苹果酸盐，它能选择性地抑制A2780和A2780（紫杉醇）细胞的增殖以及紫杉醇敏感和耐药卵巢癌细胞的迁移。有趣的是，细胞活力的下降，包括细胞增殖、克隆性和迁移能力，与细胞凋亡无关。在分子水平上，NK007显著诱导G1/S期阻滞并上调磷酸化p38丝裂原活化蛋白激酶（p-p38MAPK）的表达。此外，在NK007存在的情况下，己糖激酶2（HK2）蛋白降解显著增加，这导致氧消耗率和细胞外酸化率降低。总之，我们的结果表明，娃儿藤碱类似物NK007可通过激活p38MAPK和降解HK2来克服紫杉醇（PTX）耐药性。作为一种有效的替代抗耐药剂，NK007在治疗PTX耐药卵巢癌方面展现出了有前景的潜力。
