Summary:

The anthracyclines, such as daunorubicin, doxorubicin, and their derivatives, are widely used in cancer chemotherapy against various solid tumors and leukemia. However, drug resistance and cardiotoxicity of anthracyclines limit their clinical application.

OSU Researchers have discovered a novel class of athracycline analogs to overcome P-glycoprotein (P-gp)-mediated multidrug resistance and to reduce cardiotoxicity. Five lead compounds were optimized in chemical synthesis. The enhanced anticancer efficacy was confirmed in drug-resistant cancer cells in vitro and in vivo xenograft models. The decreased cardiotoxicity was tested in mouse and rat models.

The novel class of anthracycline analogs avert P-glycoprotein (P-gp) recognition and efflux, increase drug intracellular concentration in cancer cells, and thus overcome P-gp-mediated drug resistance. Molecular modeling showed that the new anthracycline analog averts P-gp binding, while FACS assay demonstrated that these new compounds abolished P-gp drug efflux and accumulated high intracellular concentration in the drug-resistant cancer cells. The lead compounds exhibited potent anticancer activity in both drug-sensitive and drug-resistant leukemia cells, with 25-fold lower drug resistance index. In vivo xenograft model demonstrated that the lead compounds showed more than 2.5-fold higher growth inhibition against drug-resistant cancers.

Potential Applications:

• Treatment of various drug resistant solid cancer and leukemia
• Replacement for other anthracyclines having cardiotoxicity

Advantages:

• 25-fold lower drug resistant index than daunorubicin in vitro
• 2.5-fold higher anticancer efficacy against drug resistant cancers in vivo than daunorubicin
• No significant cardiotoxicity in mouse and rat at 10 mg/kg dose, while daunorubicin and doxorubicin caused significant mortality at the same dose levels