Nitric oxide-mediated activity in anti-cancer photodynamic therapy.
Cell recurrence in cancer photodynamic therapy (PDT) is an important issue that is poorly understood. It is becoming clear that nitric oxide (NO) is a modulator of PDT. By acting on the NF-κB/Snail/RKIP survival/anti-apoptotic loop, NO can either stimulate or inhibit apoptosis. We found that pheophorbide a/PDT (Pba/PDT) induces the release of NO in B78-H1 murine amelanotic melanoma cells in a concentration-dependent manner. Low-dose PDT induces low NO levels by stimulating the anti-apoptotic nature of the above loop, whereas high-dose PDT stimulates high NO levels inhibiting the loop and activating apoptosis. When B78-H1 cells are treated with low-dose Pba/PDT and DETA/NO, an NO-donor, intracellular NO increases and cell growth is inhibited according to scratch-wound and clonogenic assays. Western blot analyses showed that the combined treatment reduces the expression of the anti-apoptotic NF-κB and Snail gene products and increases the expression of the pro-apoptotic RKIP gene product. The combined effect of Pba and DETA/NO was also tested in C57BL/6 mice bearing a syngeneic B78-H1 melanoma. We used pegylated Pba (mPEG-Pba) due to its better pharmacokinetics compared to free Pba. mPEG-Pba (30 mg/Kg) and DETA/NO (0.4 mg/Kg) were i.p. injected either as a single molecule or in combination. After photoactivation at 660 nM (fluence of 193 J/cm(2)), the combined treatment delays tumor growth more efficiently than each individual treatment (p<0.05). Taken together, our results showed that the efficacy of PDT is strengthened when the photosensitizer is used in combination with an NO donor.
Department of Medical and Biological Sciences, School of Medicine, University of Udine, P.le Kolbe 4, 33100 Udine, Italy. valentina.rapozzi@uniud.it
Valentina
V
Rapozzi
Emilia
E
Della Pietra
Sonia
S
Zorzet
Marina
M
Zacchigna
Benjamin
B
Bonavida
Luigi Emilio
LE
Xodo
D000818:Animals; D045744:Cell Line, Tumor; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D018328:Melanoma, Amelanotic / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D017319:Photosensitizing Agents; D002734:Chlorophyll; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; C032623:pheophorbide a; D019331:NG-Nitroarginine Methyl Ester