KT-5720, a new bacterial alkaloid antibiotic, reverses multidrug resistance (MDR) in lymphoma and carcinoma cells overexpressing MDR1 gene

Clinical resistance to chemotherapy is a major problem in cancer therapy. One resistance mechanism involves amplification of the MDR1 gene and overexpression of its product P-glycoprotein, a plasma membrane ATPase pump which binds lipophilic, anticancer drugs and removes them from the tumor cell, therefore preventing cytotoxity. Thus, inhibitors (chemosensitizers) of the MDR P-glycoprotein are required in chemotherapy. Mouse lymphoma cells were infected with a retrovirus containing the human MDR1 cDNA, establishing a new cellular model to screen for potential chemosensitizers such as the antibiotic alkaloids of Nocardiopsis sp. bacterial. Among the K-252a family of compounds tested, only KT-5720 (9-n-hexyl derivative of K-252a), a cAMP dependent - protein kinase inhibitor, could overcome multidrug resistance. Since at noncytotoxic concentrations, KT-5720 fully reversed MDR, it might be considered a prototype natural compound for clinical chemosensitization in combined chemotherapy.