Ittiudomrak Teeranai, Puthong Songchan, Roytrakul Sittiruk, Chanchao Chanpen
Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
Institute of Biotechnology and Genetic Engineering, Chulalongkorn University, Bangkok, Thailand.
Toxicol Res. 2019 Apr;35(2):167-179. doi: 10.5487/TR.2019.35.2.167. Epub 2019 Apr 15.
Ovarian cancer is the fifth main cause of pre-senescent death in women. Although chemotherapy is generally an efficient treatment, its side effects and the occurrence of chemotherapeutic resistance have prompted the need for alternative treatments. In this study, α-mangostin and apigenin were evaluated as possible anticancer alternatives to the chemotherapeutic drug doxorubicin, used herein as a positive control. The ovarian adenocarcinoma cell line SKOV-3 (ATCC No. HTB77) was used as model ovarian cancer cells, whereas the skin fibroblast line CCD-986Sk (ATCC No. CRL-1947) and lung fibroblast line WI-38 (ATCC No. CCL-75) were used as model untransformed cells. Apigenin and doxorubicin inhibited the growth of SKOV-3 cells in a dose- and time-dependent manner. After 72 hr exposure, doxorubicin was mostly toxic to SKOV-3 cells, whereas apigenin was toxic to SKOV-3 cells but not CCD-986Sk and WI-38 cells. α-Mangostin was more toxic to SKOV-3 cells than to CCD-986Sk cells. A lower cell density, cell shrinkage, and more unattached (floating round) cells were observed in all treated SKOV-3 cells, but the greatest effects were observed with α-mangostin. With regard to programmed cell death, apigenin caused early apoptosis within 24 hr, whereas α-mangostin and doxorubicin caused late apoptosis and necrosis after 72 hr of exposure. Caspase-3 activity was significantly increased in α-mangostin-treated SKOV-3 cells after 12 hr of exposure, whereas only caspase-9 activity was significantly increased in apigenin-treated SKOV-3 cells at 24 hr. Both α-mangostin and apigenin arrested the cell cycle at the G/M phase, but after 24 and 48 hr, respectively. Significant upregulation of (apoptosis-associated gene) and (inflammation-associated gene) transcripts was observed in apigenin- and α-mangostin-treated SKOV-3 cells, respectively. α-Mangostin and apigenin are therefore alternative options for SKOV-3 cell inhibition, with apigenin causing rapid early apoptosis related to the intrinsic apoptotic pathway, and α-mangostin likely being involved with inflammation.
卵巢癌是女性衰老前死亡的第五大主要原因。尽管化疗通常是一种有效的治疗方法，但其副作用和化疗耐药性的出现促使人们需要寻找替代治疗方法。在本研究中，将α-山竹素和芹菜素评估为化疗药物阿霉素的可能抗癌替代物，本文中阿霉素用作阳性对照。卵巢腺癌细胞系SKOV-3（ATCC编号HTB77）用作模型卵巢癌细胞，而皮肤成纤维细胞系CCD-986Sk（ATCC编号CRL-1947）和肺成纤维细胞系WI-38（ATCC编号CCL-75）用作未转化细胞的模型。芹菜素和阿霉素以剂量和时间依赖性方式抑制SKOV-3细胞的生长。暴露72小时后，阿霉素对SKOV-3细胞毒性最大，而芹菜素对SKOV-3细胞有毒性，但对CCD-986Sk和WI-38细胞无毒性。α-山竹素对SKOV-3细胞的毒性比对CCD-986Sk细胞更大。在所有处理过的SKOV-3细胞中均观察到较低的细胞密度、细胞收缩和更多未附着（漂浮圆形）的细胞，但α-山竹素的效果最为显著。关于程序性细胞死亡，芹菜素在24小时内导致早期凋亡，而α-山竹素和阿霉素在暴露72小时后导致晚期凋亡和坏死。暴露12小时后，α-山竹素处理的SKOV-3细胞中半胱天冬酶-3活性显著增加，而在24小时时，芹菜素处理的SKOV-3细胞中只有半胱天冬酶-9活性显著增加。α-山竹素和芹菜素均使细胞周期停滞在G/M期，但分别在24小时和48小时后。在芹菜素和α-山竹素处理的SKOV-3细胞中分别观察到凋亡相关基因和炎症相关基因转录本的显著上调。因此，α-山竹素和芹菜素是抑制SKOV-3细胞的替代选择，芹菜素导致与内源性凋亡途径相关的快速早期凋亡，而α-山竹素可能与炎症有关。
