Okada Takamitsu, Tanaka Kazuhiro, Nakatani Fumihiko, Sakimura Riku, Matsunobu Tomoya, Li Xu, Hanada Masuo, Nakamura Tomoyuki, Oda Yoshinao, Tsuneyoshi Masazumi, Iwamoto Yukihide
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Int J Cancer. 2006 Jan 1;118(1):90-7. doi: 10.1002/ijc.21297.
Despite recent improvements in multimodal therapies for osteosarcoma (OS) and Ewing's family of tumors (EFTs), the prognosis of relapsed cases remains very poor because of the resistance to chemotherapy. Histone deacetylase inhibitors (HDACIs), including members of the cyclic tetrapeptide family such as FK228 and apicidin, are novel antitumor agents that can induce cell cycle arrest and apoptosis in various cancer cells. HDACIs also exhibit potent antitumor effects on OS and EFTs. However, to date there have been no studies to our knowledge reporting the effects of HDACIs on drug-resistant OS and EFTs. Here, we demonstrated that FK228 and apicidin exhibited strong resistance in doxorubicin-resistant clones of OS and EFTs expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) and that P-gp and MRP1 might play a crucial role in the resistance mechanism to FK228 and apicidin. A P-gp inhibitor (verapamil) and an MRP1 inhibitor (MK571) could independently reverse the resistance to FK228 and apicidin in the drug-resistant clones. Moreover, the combination of verapamil and MK571 could enhance HDACI-induced cell number reduction in drug-resistant clones to a similar extent as that in their parental clones. Although these findings suggest the difficulty in treating drug-resistant tumors expressing P-gp and/or MRP1 with these HDACIs, the combination of P-gp and MRP1 inhibitors might reverse the resistance to the HDACIs in the treatment of those tumors. Because HDACIs are potent and promising antitumor drugs and seem to be close to clinical use, it is necessary to pay attention to the resistance mechanisms against HDACIs.
尽管骨肉瘤（OS）和尤因家族肿瘤（EFTs）的多模式治疗最近有所改进，但由于对化疗的耐药性，复发病例的预后仍然很差。组蛋白脱乙酰酶抑制剂（HDACIs），包括环四肽家族成员如FK228和阿皮西丁，是新型抗肿瘤药物，可诱导各种癌细胞的细胞周期停滞和凋亡。HDACIs对OS和EFTs也表现出强大的抗肿瘤作用。然而，据我们所知，迄今为止尚无研究报道HDACIs对耐药OS和EFTs的影响。在此，我们证明FK228和阿皮西丁在表达P-糖蛋白（P-gp）和多药耐药相关蛋白1（MRP1）的OS和EFTs的阿霉素耐药克隆中表现出强烈的耐药性，并且P-gp和MRP1可能在对FK228和阿皮西丁的耐药机制中起关键作用。P-gp抑制剂（维拉帕米）和MRP1抑制剂（MK571）可独立逆转耐药克隆对FK228和阿皮西丁的耐药性。此外，维拉帕米和MK571的联合使用可将HDACI诱导的耐药克隆中细胞数量的减少增强到与其亲本克隆相似的程度。尽管这些发现表明用这些HDACIs治疗表达P-gp和/或MRP1的耐药肿瘤存在困难，但P-gp和MRP1抑制剂的联合使用可能会逆转这些肿瘤治疗中对HDACIs的耐药性。由于HDACIs是强效且有前景的抗肿瘤药物，并且似乎已接近临床应用，因此有必要关注针对HDACIs的耐药机制。
