Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment

Heme oxygenase- 1 ( HO- 1) is an inducible enzyme that catalyzes oxidative degradation of heme to form biliverdin, carbon monoxide ( CO), and free iron. Biliverdin is subsequently reduced to bilirubin by the enzyme biliverdin reductase. Increasing evidence has indicated the critical role of HO- 1 in cytoprotection and more diverse biological functions. Induction of HO- 1 by various chemical inducers that are primarily cell stress inducers or by HO- 1 gene transfection confers a protective capacity to cultured cells as well as to cells in several in vivo animal models. In addition, HO- 1- deficient mice exhibit a significant increase in susceptibility to tissue injury. The cytoprotective action of HO- 1 seems to be mainly a function of the antiapoptotic effects of the enzyme. HO- 1 is believed to exert this antiapoptotic action by multiple mechanisms: ( a) decreased intracellular pro- oxidant levels, ( b) increased bilirubin levels, and ( c) elevated CO production. CO may produce an antiapoptotic effect by inhibiting both expression of p53 and release of mitochondrial cytochrome c. HO- 1 may also be a target in antitumor therapy because the growth of most tumors depends on HO- 1. Our preliminary studies with an HO inhibitor showed a promising antitumor effect. This preliminary work warrants continued investigation for possible novel anticancer chemotherapy.