Koma Hiromi, Yamamoto Yasuhiro, Fujita Tomonari, Yagami Tatsurou
Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1, kami-ohno 7-Chome, Himeji, Hyogo 670-8524, Japan.
Hyogo Prefectural Kobe High School, 1-5-1 Shironoshita-dori Nada-ku Kobe, Hyogo 657-0804, Japan.
Biochem Biophys Rep. 2019 Feb 14;18:100608. doi: 10.1016/j.bbrep.2019.01.001. eCollection 2019 Jul.
Renal cell carcinoma (RCC) is relatively resistant to chemotherapy and radiotherapy. Clear cell RCC (ccRCC) accounts for the majority of RCC, which have mutations or epigenetic silencing of the () gene. VHL-positive Caki-2 cells are killed by an endogenous anticancer substance, 15-deoxy-Δ-prostaglandin J (15d-PGJ). The MTT reduction assay reflecting mitochondrial succinate dehydrogenase activity was employed for assessment of cell viability. We confirmed anticancer activities of camptothecin (topoisomerase I inhibitor), etoposide (topoisomerase II inhibitor), doxorubicin (topoisomerase II inhibitor) in VHL-positive Caki-2 cells. Combination of topoisomerase inhibitors with 15d-PGJ exhibited the synergistic effect in VHL-positive Caki-2 cells. However, 15d-PGJ did not increase cytotoxicities of topoisomerase inhibitors on VHL-negative 786-O cells. In addition, the 15d-PGJ-enhanced antitumor activity of topoisomerase inhibitors was detected in neither VHL-positive nor VHL-negative RCC4 cells. Our finding indicated that 15d-PGJ enhanced the antitumor activity of topoisomerase inhibitors independently of VHL.
肾细胞癌（RCC）对化疗和放疗相对耐药。透明细胞肾细胞癌（ccRCC）占肾细胞癌的大多数，其（）基因存在突变或表观遗传沉默。VHL阳性的Caki-2细胞可被内源性抗癌物质15-脱氧-Δ-前列腺素J（15d-PGJ）杀死。采用反映线粒体琥珀酸脱氢酶活性的MTT还原试验评估细胞活力。我们证实了喜树碱（拓扑异构酶I抑制剂）、依托泊苷（拓扑异构酶II抑制剂）、阿霉素（拓扑异构酶II抑制剂）对VHL阳性Caki-2细胞的抗癌活性。拓扑异构酶抑制剂与15d-PGJ联合使用对VHL阳性Caki-2细胞具有协同作用。然而，15d-PGJ并未增加拓扑异构酶抑制剂对VHL阴性786-O细胞的细胞毒性。此外，在VHL阳性和VHL阴性的RCC4细胞中均未检测到15d-PGJ增强的拓扑异构酶抑制剂的抗肿瘤活性。我们的研究结果表明，15d-PGJ可独立于VHL增强拓扑异构酶抑制剂的抗肿瘤活性。
