Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, University of Sydney, NSW 2006, Australia.
Biochem Pharmacol. 2013 Aug 1;86(3):419-27. doi: 10.1016/j.bcp.2013.05.014. Epub 2013 May 31.
The multi-kinase inhibitor sorafenib is used for the treatment of renal and hepatic carcinomas and is undergoing evaluation for treatment of breast cancer in combination with other agents. Cytochrome P450 (CYP) 3A4 converts sorafenib to multiple metabolites that have been detected in patient plasma. However, recent clinical findings suggest that combination therapy may elicit inhibitory pharmacokinetic interactions involving sorafenib that increase toxicity. While sorafenib N-oxide is an active metabolite, information on the anti-tumor actions of other metabolites is unavailable. The present study evaluated the actions of sorafenib and its five major metabolites in human breast cancer cell lines. All agents, with the exception of N'-hydroxymethylsorafenib N-oxide, decreased ATP formation in four breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7 and T-47D). Prolonged treatment of MDA-MB-231 cells with N'-desmethylsorafenib, N'-desmethylsorafenib N-oxide and sorafenib (10 μM, 72 h) produced small increases in caspase-3 activity to 128-139% of control. Sorafenib and its metabolites, again with the exception of N'-hydroxymethylsorafenib N-oxide, impaired MEK/ERK signaling in MDA-MB-231 cells and modulated the expression of cyclin D1 and myeloid cell leukemia sequence-1, which regulate cell viability. When coadministered with doxorubicin (0.5 or 1 μM), sorafenib and N'-desmethylsorafenib (25 μM) produced greater effects on ATP production than either treatment alone. Thus, it emerges that, by targeting the MEK/ERK pathway, multiple sorafenib metabolites may contribute to the actions of sorafenib in breast cancer. Because N'-desmethylsorafenib is not extensively metabolized and does not inhibit major hepatic CYPs, this metabolite may have a lower propensity to precipitate pharmacokinetic drug interactions than sorafenib.
多激酶抑制剂索拉非尼用于治疗肾和肝细胞癌，并正在评估与其他药物联合治疗乳腺癌。细胞色素 P450（CYP）3A4 将索拉非尼转化为已在患者血浆中检测到的多种代谢物。然而，最近的临床发现表明，联合治疗可能会引起涉及索拉非尼的抑制性药代动力学相互作用，从而增加毒性。虽然索拉非尼 N-氧化物是一种活性代谢物，但其他代谢物的抗肿瘤作用信息尚不清楚。本研究评估了索拉非尼及其五种主要代谢物在人乳腺癌细胞系中的作用。除 N'-羟甲基索拉非尼 N-氧化物外，所有药物均降低了四种乳腺癌细胞系（MDA-MB-231、MDA-MB-468、MCF-7 和 T-47D）中 ATP 的形成。N'-去甲基索拉非尼、N'-去甲基索拉非尼 N-氧化物和索拉非尼（10 μM，72 h）对 MDA-MB-231 细胞的长期处理仅使 caspase-3 活性增加 128-139%。索拉非尼及其代谢物（除 N'-羟甲基索拉非尼 N-氧化物外）再次抑制 MDA-MB-231 细胞中的 MEK/ERK 信号通路，并调节细胞存活的 cyclin D1 和髓样细胞白血病序列 1 的表达。当与多柔比星（0.5 或 1 μM）联合给药时，索拉非尼和 N'-去甲基索拉非尼（25 μM）对 ATP 生成的影响大于单独用药。因此，多种索拉非尼代谢物通过靶向 MEK/ERK 通路可能有助于索拉非尼在乳腺癌中的作用。由于 N'-去甲基索拉非尼未被广泛代谢且不抑制主要的肝 CYP，因此与索拉非尼相比，该代谢物可能具有较低的引发药代动力学药物相互作用的倾向。
