Rapid Communication Hypericin Hydroquinone: Potential as a Red-Far Red Photosensitizer?

ABSTRACT Hypericin hydroquinone is the product of two-electron reductionof hypericin (quinone), a potent phenanthroperylenequinonephotosensitizer. In contrast to the quinone, the hydroquinoneexhibits strong absorbance in the far-red spectral region. Hereinwe provide initial evidence on the potential of hypericinhydroquinone as a far-red photosensitizer. INTRODUCTION Hypericin (HYP) is a phenanthroperylenequinone, occurringnaturally in plants of the Hypericum genus, especially Hyper-icum perforatum. It is a versatile photosensitizer exhibiting amultifaceted photocytotoxic profile (1–5). This light-activatedcytotoxicity is the complex result of acute photoimpairment ofvarious vital subcellular organelles, the most prominent amongwhich have been identified as the mitochondria (3,4) and theendoplasmic reticulum (ER) (2). The main shortcoming in thetranslation of HYP experimental potential to clinical photo-dynamic therapy of cancer (PDT), is its absorbance in thegreen-orange spectral region. This is substantially blueshiftedto that desired of an ideal photosensitizer, as, at longerwavelengths, activation facilitates deeper light penetration andhence more efficient treatment of the target lesions (6). In thiscontext, there has been substantial effort to chemically modifyHYP in order to bathocromically shift its absorbance (7).It has previously been shown that HYP can be electro-chemically reduced in two steps: The first electron reductionyields the semiquinone (HYP-S), while a two-electron reduc-tion affords the hydroquinone (HYP-H) (4,8). Based on thespectral profile of HYP-H, which fulfils the bathochromicabsorbance requirement for a clinically applicable photosen-sitizer, we investigated the photocytotoxicity of HYP-H. Ourrecent finding that HYP-H is an efficient reductive substratefor complex III of the mitochondrial electron transport chain(ETC) (4), suggested that mitochondrial targeting couldcombine with bathocromic absorbance to accomplish a poten-tially powerful clinical tool.We herein report, for the first time to the best of ourknowledge, the substantial photocytotoxic capacity of HYP-Hfollowing irradiation in the far-red. These data are comparedwith the cytotoxicity of HYP-H in the green-orange as well asthat of HYP irradiated in both spectral regions. The work wasperformed on DU145 human prostate carcinoma cells in thecontext of our ongoing effort to model the effects of HYP (andits derivatives) on prostate cancer.