Division of Lipid Science and Technology, Indian Institute of Chemical Technology, Hyderabad, Andhra Pradesh 500007, India.
J Med Chem. 2011 Apr 14;54(7):2378-90. doi: 10.1021/jm101530j. Epub 2011 Mar 10.
Haloperidol (HP), a neuroleptic drug, shows high affinity toward σ receptors (SR). HP and reduced-HP at higher concentration were known to induce apoptosis in SR-overexpressing carcinomas and melanomas. Herein, we report the development of cationic lipid-conjugated haloperidol as a new class of anticancer therapeutics. In comparison to HP, the C-8 carbon chain analogue (HP-C8) showed significantly high, SR-assisted antiproliferative activity against cancer cells via caspase-3-mediated apoptosis and down-regulation of pAkt. Moreover, melanoma tumor aggressiveness in HP-C8-treated mice was significantly lower than that in HP-treated mice. HP-C8 simultaneously reduced Akt-protein level and increased Bax/Bcl-2 ratio in vascular endothelial cells, thereby indicating a possible protein kinase down-regulatory and apoptosis inducing role in tumor-associated vascular cells. In conclusion, we developed σ receptor-targeting cationic lipid-modified HP derivatives as a promising class of anticancer therapeutic that concurrently affects cancer and tumor environment associated angiogenic vascular cells through induction of apoptosis and Akt protein down-regulation.
氟哌啶醇（HP）是一种神经安定药，对σ受体（SR）具有高亲和力。已知高浓度的 HP 和还原 HP 可诱导过表达 SR 的癌和黑色素瘤细胞凋亡。本文报道了新型阳离子脂质偶联氟哌啶醇作为抗癌治疗药物的发展。与 HP 相比，C-8 碳链类似物（HP-C8）通过 caspase-3 介导的凋亡和下调 pAkt，表现出对癌细胞具有显著更高的、受 SR 辅助的抗增殖活性。此外，HP-C8 处理的小鼠黑色素瘤肿瘤侵袭性明显低于 HP 处理的小鼠。HP-C8 同时降低了血管内皮细胞中的 Akt 蛋白水平并增加了 Bax/Bcl-2 比值，这表明其在肿瘤相关血管细胞中可能具有蛋白激酶下调和诱导凋亡的作用。总之，我们开发了靶向 σ 受体的阳离子脂质修饰 HP 衍生物，作为一种有前途的抗癌治疗药物，通过诱导凋亡和 Akt 蛋白下调，同时影响癌症和肿瘤环境相关的血管生成血管细胞。
