Differential effects of 5-aminolaevulinic acid photodynamic therapy and psoralen + ultraviolet A therapy on p53 phosphorylation in normal human skin in vivo
ABSTRACT Phosphorylation of the tumour suppressor p53 by the CK2/FACT pathway plays a central role in suppressing ultraviolet (UV)-induced skin cancer in animal models. Although p53 protein stabilization is induced after solar-simulated irradiation of human skin in vivo, p53 phosphorylation has not been defined.
To investigate the effects of clinically effective treatments for skin diseases including psoralen + UVA (PUVA) and photodynamic therapy (PDT) on p53 phosphorylation to determine whether the tumour-suppressing p53 kinase pathways are activated upon use of these therapies.
We used antibodies to the ATM/ATR and CK2/FACT phosphorylation sites on p53.
We found that p53 activation was induced selectively by PUVA treatment, while 8-oxo-7,8-dihydroguanine DNA damage was induced selectively by 5-aminolaevulinic acid (ALA)-PDT treatment. Importantly, PUVA treatment resulted in p53 kinase activation, as defined by p53 modification at AT (serine-15) and CK2/FACT (serine-392) sites within the proliferative compartment.
These data demonstrate that PUVA provokes accumulation and phosphorylation of p53 by AT and CK2/FACT within critical proliferative focal points (as determined by p63 colocalization studies) where DNA damage may lead to tumorigenesis. PDT is mechanistically distinct in that there is a lower level of induction of p53 expression with no evidence of AT- or CK2/FACT-mediated phosphorylation. This suggests that the type of DNA damage created by the reactive oxygen species generated by ALA-PDT does not induce the p53 pathway classically required for the repair of DNA photoadducts induced by UV.
SourceAvailable from: Gwo-Tarng Sheu[Show abstract] [Hide abstract]
ABSTRACT: The emergence of multidrug resistance (MDR), meaning that cancer cells develop simultaneous resistance to different drugs, has limited the clinical efficacy and application of chemotherapy. Pterostilbene, a naturally occurring phytoalexin exerts a variety of pharmacologic activities, including antioxidation, cancer prevention and cytotoxicity to various cancer cells. In this study, results approved the capability of pterostilbene to effectively inhibit the cell growth of docetaxel-induced multidrug resistance human lung cancer cells lines and such inhibition is through an induction of cell cycle arrest and apoptosis. Meanwhile, the observation of the formation of acidic vesicular organelles and LC3-II production revealed an induction of autophagy at an early stage by pterostilbene, which was triggered by an inhibition of the AKT and JNK and an activation of the ERK1/2 pathway. Furthermore, an inhibition of autophagy by pretreatment with 3-methyladenine, bafilomycin A1 or Beclin 1 siRNA was able to enhance pterostilbene-triggered apoptosis. In conclusion, this study demonstrate that pterostilbene causes autophagy and apoptosis in lung cancer cells. Furthermore, a combination of pterostilbene with autophagy inhibitors may strengthen the efficiency of proapoptotic chemotherapeutic strategies in both chemosensitive and chemoresistant lung cancer cells, which may be of great value for the clinical management of lung cancer patients with multidrug resistance.Toxicological Sciences 10/2013; DOI:10.1093/toxsci/kft238 · 4.48 Impact Factor
Article: Photodynamic Therapy.[Show abstract] [Hide abstract]
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ABSTRACT: Chemotherapy is the recommended treatment for advanced-stage cancers. However, the emergence of multidrug resistance (MDR), the ability of cancer cells to become simultaneously resistant to different drugs, limits the efficacy of chemotherapy. Previous studies have shown that herbal medicine or natural food may be feasible for various cancers as potent chemopreventive drug. This study aims to explore the capablility of reversing the multidrug resistance of docetaxel (DOC)-resistant A549 cells (A549/D16) of psoralen and the underlying mechanisms. In this study, results showed that the cell viability of A549/D16 subline is decreased when treated with psoralen plus DOC, while psoralen has no effect on the cell proliferation on A549 and A549/D16 cells. Furthermore, mRNA and proteins levels of ABCB1 were decreased in the presence of psoralen, while decreased ABCB1 activity was also revealed by flow cytometry. Based on these results, we believe that psoralen may be feasible for reversing the multidrug resistance by inhibiting ABCB1 gene and protein expression. Such inhibition will lead to a decrease in ABCB1 activity and anti-cancer drug efflux, which eventually result in drug resistance reversal and therefore, sensitizing drug-resistant cells to death in combination with chemotherapeutic drugs.Phytomedicine: international journal of phytotherapy and phytopharmacology 06/2014; 21(7). DOI:10.1016/j.phymed.2014.03.008 · 2.88 Impact Factor