Sato Akinori
Department of Urology, National Defense Medical College, Tokorozawa, Japan.
Onco Targets Ther. 2015 Apr 8;8:761-8. doi: 10.2147/OTT.S79776. eCollection 2015.
The human immunodeficiency virus protease inhibitor ritonavir has recently been shown to have antineoplastic activity, and its use in urological malignancies is under investigation with an eye toward drug repositioning. Ritonavir is thought to exert its antineoplastic activity by inhibiting multiple signaling pathways, including the Akt and nuclear factor-kappaB pathways. It can increase the amount of unfolded proteins in the cell by inhibiting both the proteasome and heat shock protein 90. Combinations of ritonavir with agents that increase the amount of unfolded proteins, such as proteasome inhibitors, histone deacetylase inhibitors, or heat shock protein 90 inhibitors, therefore, induce endoplasmic reticulum stress cooperatively and thereby kill cancer cells effectively. Ritonavir is also a potent cytochrome P450 3A4 and P-glycoprotein inhibitor, increasing the intracellular concentration of combined drugs by inhibiting their degradation and efflux from cancer cells and thereby enhancing their antineoplastic activity. Furthermore, riotnavir's antineoplastic activity includes modulation of immune system activity. Therapies using ritonavir are thus an attractive new approach to cancer treatment and, due to their novel mechanisms of action, are expected to be effective against malignancies that are refractory to current treatment strategies. Further investigations using ritonavir are expected to find new uses for clinically available drugs in the treatment of urological malignancies as well as many other types of cancer.
人类免疫缺陷病毒蛋白酶抑制剂利托那韦最近已被证明具有抗肿瘤活性，并且其在泌尿生殖系统恶性肿瘤中的应用正在研究中，着眼于药物重新定位。利托那韦被认为通过抑制多种信号通路发挥其抗肿瘤活性，包括Akt和核因子-κB通路。它可以通过抑制蛋白酶体和热休克蛋白90来增加细胞中未折叠蛋白的数量。因此，利托那韦与增加未折叠蛋白数量的药物（如蛋白酶体抑制剂、组蛋白去乙酰化酶抑制剂或热休克蛋白90抑制剂）联合使用，可协同诱导内质网应激，从而有效杀死癌细胞。利托那韦还是一种强效的细胞色素P450 3A4和P-糖蛋白抑制剂，通过抑制联合药物在癌细胞中的降解和外排来增加其细胞内浓度，从而增强其抗肿瘤活性。此外，利托那韦的抗肿瘤活性还包括调节免疫系统活性。因此，使用利托那韦的疗法是一种有吸引力的癌症治疗新方法，并且由于其新颖的作用机制，有望对目前治疗策略难治的恶性肿瘤有效。预计使用利托那韦的进一步研究将发现临床可用药物在治疗泌尿生殖系统恶性肿瘤以及许多其他类型癌症方面的新用途。
