FS536, a novel nitric oxide-releasing doxorubicin hybrid, reverts multidrug resistance in lung cancer cells

: The design of molecular hybrids that chemically conjugate nitric oxide (NO)-donors with anticancer drugs, offering site-specific and time-controlled properties, is a promising strategy in cancer therapy. In this work, we designed, synthesized, and characterized a novel doxorubicin (DOXO)-NO-donor hybrid, named FS536, by chemically conjugating DOXO with a diazeniumdiolate moiety. Upon incubation in human serum, FS536 simultaneously released both DOXO and NO through enzymatic hydrolysis. FS536 significantly inhibited the proliferation of the DOXO-resistant A549 lung cancer cell line (A549-DR), overcoming the resistance typically observed with DOXO alone. This enhanced efficacy is attributed to the release of NO, which induces the nitration of the MRP1 efflux pump, reducing its activity, increasing intracellular drug concentrations, and thus sensitizing resistant cells to DOXO. Our findings suggest that FS536 is a promising therapeutic strategy for combating multidrug-resistant cancers by leveraging the synergistic effects of DOXO and NO.