Heme oxygenase-1 protects tumor cells against photodynamic therapy-mediated cytotoxicity.

Photodynamic therapy is a promising antitumor treatment modality approved for the management of both early and advanced tumors. The mechanisms of its antitumor action include generation of singlet oxygen and reactive oxygen species that directly damage tumor cells and tumor vasculature. A number of mechanisms seem to be involved in the protective responses to PDT that include activation of transcription factors, heat shock proteins, antioxidant enzymes and antiapoptotic pathways. Elucidation of these mechanisms might result in the design of more effective combination strategies to improve the antitumor efficacy of PDT. Using DNA microarray analysis to identify stress-related genes induced by Photofrin-mediated PDT in colon adenocarcinoma C-26 cells, we observed a marked induction of heme oxygenase-1 (HO-1). Induction of HO-1 with hemin or stable transfection of C-26 with a plasmid vector encoding HO-1 increased resistance of tumor cells to PDT-mediated cytotoxicity. On the other hand, zinc (II) protoporphyrin IX, an HO-1 inhibitor, markedly augmented PDT-mediated cytotoxicity towards C-26 and human ovarian carcinoma MDAH2774 cells. Neither bilirubin, biliverdin nor carbon monoxide, direct products of HO-1 catalysed heme degradation, was responsible for cytoprotection. Importantly, desferrioxamine, a potent iron chelator significantly potentiated cytotoxic effects of PDT. Altogether our results indicate that HO-1 is involved in an important protective mechanism against PDT-mediated phototoxicity and administration of HO-1 inhibitors might be an effective way to potentiate antitumor effectiveness of PDT.

Pentoxifylline inhibits perforin-dependent natural cytotoxicity in vitro.

Pentoxifylline (PTX) is commonly used in peripheral blood vessel diseases, however it has also been found to decrease the level of proinflammatory cytokines such as IL-12, TNF-alpha and IFN-gamma. Moreover, some authors reported that PTX suppresses spontaneous cytotoxicity of peripheral blood mononuclear cells (PBMC) in vitro. It could influence the mechanism of killing target cells by PBMC. For this reason we evaluated the influence of PTX on spontaneous cytotoxicity of PBMC against K562 and CaSki cell lines. Subsequently, we compared this effect to that evoked by dexamethasone, one of the most effective anti-inflammatory drugs. Our study revealed that PTX inhibits natural cytotoxicity preferentially through inhibition of perforin-mediated cell membrane damage, without a statistically significant influence on apoptosis induction. Furthermore, pentoxifylline inhibits natural cytotoxicity as effectively as dexamethasone. However, the result of PTX inhibitory influence is observed much earlier than that of dexamethasone. Currently PTX is commonly used in diseases that occur more frequently in elderly patients. We suggest that PTX, inhibiting perforin-dependent PBMC cytotoxic activity, could weaken anti-cancer action of immune system thus accelerating the progress of neoplasm formation in these patients.