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Motexafin Gadolinium-Induced Cell Death Correlates with Heme oxygenase-1 Expression and Inhibition of P450 Reductase-Dependent Activities

Department of Pharmaceutical Chemistry, University of California, San Francisco, California (J.P.E., F.X., P.R.O.M.); and Pharmacyclics, Inc., Sunnyvale, California (M.S., R.M., L.N.)

Heme oxygenase-1 (HO1), which oxidizes heme to biliverdin, CO, and free iron, conveys protection against oxidative stress and is antiapoptotic. Under stress conditions, some porphyrin derivatives can inhibit HO1 and trigger cell death. Motexafin gadolinium (MGd) is an expanded porphyrin that selectively targets cancer cells through a process of futile redox cycling that decreases intracellular reducing metabolites and protein thiols. Here, we report that hematopoietic-derived cell lines that constitutively express HO1 are more susceptible to MGd-induced apoptosis than those that do not. MGd used in combination with tin protoporphyrin IX, an inhibitor of HO1, resulted in synergistic cell killing. Consistent with these cell culture observations, we found that MGd is an inhibitor of heme oxygenase-1 activity in vitro. We demonstrate that inhibition of HO1 reflects an interaction of MGd with NADPH-cytochrome P450 reductase, the electron donor for HO1, that results in diversion of reducing equivalents from heme oxidation to oxygen reduction. In accord with this mechanism, MGd is also an in vitro inhibitor of CYP2C9, CYP3A4, and CYP4A1. Inhibition of HO1 by MGd may contribute to its anticancer activity, whereas its in vitro inhibition of a broad spectrum of P450 enzymes indicates that a potential exists for drug-drug interactions.

Address correspondence to: Dr. Paul Ortiz de Montellano, University of California, San Francisco, 600 16th St., San Francisco, CA 94143-2280. E-mail: ortiz{at}cgl.ucsf.edu