Development of methotrexate proline prodrug to overcome resistance by MDA-MB-231 cells

作者：Wu Zhiqian^*; Shah Anandkumar; Patel Namrata; Yuan Xudong

来源：Bioorganic & Medicinal Chemistry Letters, 2010, 20(17): 5108-5112.

DOI：10.1016/j.bmcl.2010.07.024

• Proline methotrexate prodrug
• Prolidase
• Methotrexate resistance
• Enzyme-targeted delivery
• Enzyme-dependent activation
• MDA-MB-231

The resistance to methotrexate by a number of cancer cells such as breast cancer cell-line MDA-MB-231 due to poor permeability renders it less effective as an anticancer agent for these cells. Proline prodrug of methotrexate (Pro-MTX) was designed as a substrate of prolidase which is specific for imido bond of dipeptide containing proline and expected to penetrate MDA-MB-231 cells more efficiently. The prodrug was synthesized by solid-phase peptide synthesis method and examined as a substrate of pure prolidase as well as cell homogenate. The cytotoxicity against MDA-MB-231 and non-methotrexate resistant breast cancer cell line, MCF-7 was also examined by XTT assay. The results showed that Pro-MTX was a substrate of prolidase. It was also shown that the prodrug could be converted to parent drug methotrexate in Caco-2 and HeLa cell homogenate. When tested with Caco-2 and MCF-7 cells, Pro-MTX showed weaker cytotoxicity compared with methotrexate. But for methotrexate resistant MDA-MB-231 cells, Pro-MTX showed stronger activity than methotrexate. The results indicated that the proline prodrug of methotrexate may overcome the resistance of human breast cancer cells in culture.

• 出版日期2010-9-1