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Paclitaxel Augments Cytotoxic Effect of Photodynamic Therapy Using Verteporfin in Gastric and Bile Duct Cancer Cells

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Paclitaxel Augments Cytotoxic Effect of Photodynamic Therapy Using Verteporfin in Gastric and Bile Duct Cancer Cells PAPER www.rsc.org/pps | Photochemical & Photobiological Sciences Paclitaxel augments cytotoxic effect of photodynamic therapy using verteporfin in gastric and bile duct cancer cells Seungwoo Park,†a Sung Pil Hong,†a Tae Yoon Oh,b Seungmin Bang,a Jae Bock Chunga and Si Young Song*a,b Received 11th December 2007, Accepted 25th April 2008 First published as an Advance Article on the web 15th May 2008 DOI: 10.1039/b719072g Photodynamic therapy (PDT) shows a limited antitumor effect in treating gastrointestinal tumors because of improper light penetration or insufficient photosensitizer uptake. The aim of this study was to evaluate the cytotoxic effect of PDT combined with paclitaxel on in vitro cancer cells. In vitro photodynamic therapy was performed in gastric cancer cells (NCI-N87) and bile duct cancer cells (YGIC-6B) using verteporfin (2 ug mL−1) and a PTH light source (1 000 W, Oriel Co.) with 665–675 nm narrow band pass filter. Cytotoxicity was compared using the MTT assay between cancer cells treated with PDT alone or pretreated with paclitaxel (IC25). Apoptotic changes were evaluated using DAPI staining, DNA fragmentation analysis, Annexin V-FITC apoptosis assay, cell cycle analysis, and western blots for cytochrome c, Bax, and Bid. The PDT-induced cytotoxicity was potentiated by pretreating with low dose paclitaxel (P < 0.001). The enhanced cytotoxicity was due to an augmented apoptotic response mediated by exaggerated cytochrome c released from mitochondria, without Bax or Bid activation. These results show that paclitaxel pretreatment enhances PDT-mediated cancer therapy. Introduction effect by improving tumor oxygenation and increasing red light penetration in tumors.16 New photosensitizers that can be strongly Photodynamic therapy (PDT) has been used to treat various activated at longer wavelengths have been developed to increase gastrointestinal tumors, including esophageal cancer, dysplasia the ablating zones.13 PDT combined with other drugs, such as in Barrett’s esophagus, stomach cancer, cholangiocarcinoma, inhibitor of vascular endothelial growth factor, cyclooxygenase-2, 1–7 metastatic cancer of the liver, and pancreatic cancer. PDT or matrix metalloproteinase, and anticancer agents also enhanced was performed by administering a photosensitizer followed by the apoptotic response.17–20 Among them, anticancer agents applying a specific wavelength of light. This treatment activates could be easily applied to the cancer patients combined with photosensitizer,which transfers photo-energy to molecular oxygen PDT. 8,9 to generate cytotoxic single oxygen within the irradiated tissues. Paclitaxel, a well-known radiosensitizer, was isolated from the ROS generated by PDT have a direct necrotic and apoptotic effect bark of the Pacific yew, Taxus brevifolia, and binds specifically 10 on tumor cells. PDT also induces vascular injury, tumor hypoxia, to microtubules, alters their dynamics, promotes reorganization and immune response with concomitant expression of several of the microtubule network into bundles or asters, and stabilizes 11,12 growth factors and cytokines. microtubules against disruption by various agents. Microtubule A pitfall of PDT is that the induction of cell death is highly stabilization induced by paclitaxel leads to cell cycle arrest dependent on the penetration depth of the laser and the cellular at the G2/M phase, the most vulnerable phase, resulting in 13 uptake of photosensitizers. Optimal cytotoxic effect can be tumor cell sensitization to ionizing radiation.21,22 The paclitaxel obtained when sufficient photosensitizers are activated by enough radiosensitizing effect in the setting of external radiation might number of photons. Due to improper penetration of light, the be beneficial in PDT treatment. Previous report showed that maximum effect of PDT is less than 1 cm in depth, which limits paclitaxel also enhanced the antitumor effect of photodynamic 14 PDT of curative intent only to early cancers. PDT in advanced therapy in vivo mouse model, however, the action mechanism 5,15 cancers, at most, attains palliation of obstructive symptoms. of paclitaxel combined with phototherapy has not been well Suboptimal delivery of light may cause sublethal damage to elucidated.23 Because there was no difference of antitumor effect cancer cells, leading to recurrence of tumor during follow up. between paclitaxel combined with photodynamic therapy without Many efforts to overcome the sublethal tumor cell damage have photosensitizer and paclitaxel alone, which means that pacli- been tested. A hyperbaric condition enhanced the PDT antitumor taxel itself have no direct phototoxicity, there might be another mechanism to enhance the antitumor effect of phototherapy by aDivision of Gastroenterology, Department of Internal Medicine, Yonsei paclitaxel. University College of Medicine, 134 Shinchon-Dong, Seodaemun-Gu, 120- In the present study, we evaluated the cytotoxic effect and 752, Seoul, South Korea. E-mail: [email protected]; Fax: 82-2- mechanism of PDT using verteporfin combined with paclitaxel 2227-7900; Tel: 82-2-2228-1981 bBrain Korea 21 Project for Medical Science, Yonsei Institute of Gastroen- in gastric and bile duct cancer cells. We treated cells with low terology, Yonsei University College of Medicine, South Korea dose paclitaxel before PDT to minimize the cytotoxicity of † Seungwoo Park and Sung Pil Hong contributed equally to this article. paclitaxel. This journal is © The Royal Society of Chemistry and Owner Societies 2008 Photochem. Photobiol. Sci., 2008, 7, 769–774 | 769 Results and discussion Table 1 Dose enhancement ratio after PDT combined with low dose paclitaxel. DER was calculated as the dose for PDT alone divided by the Photodynamic therapy using verteporfin induced cell death in dose of PDT plus paclitaxel (normalized for drug toxicity) for a surviving fraction of 0.25, 0.5, and 0.75 NCI-N87 and YGIC-6B cells Cells DER (IC25) DER (IC50) DER (IC75) The MTT assay was performed to determine the IC25 and IC50 light doses at 24 h after PDT using verteporfin (2.78 uM) in NCI-N87 NCI-N87 1.27 1.25 1.24 and YGIC-6B cells. Cancer cell survival decreased according to YGIC-6B 1.28 1.19 1.16 −2 light dose intensity.The IC25 and IC50 light doses were 310 mJ cm and 565 mJ cm−2 in NCI-N87, and 240 mJ cm−2 and 450 mJ cm−2 of paclitaxel. Fig. 1 shows dose-response survival curves of the in YGIC-6B cells, respectively (Fig. 1). NCI-N87 and YGIC-6B cells when treated with PDT with or without paclitaxel. The IC50 value was significantly decreased in paclitaxel pretreated NCI-N87 cells compared with PDT alone cells (565 mJ cm−2 versus 453 mJ cm−2, P < 0.001). In YGIC- 6B cells, IC50 value showed significant fall after PDT combined with paclitaxel (451 mJ cm−2 versus 379 mJ cm−2, P < 0.001). To evaluate the enhancing cytotoxicity of paclitaxel pretreatment, we borrowed the concept of dose enhancement ratio which has been used to measure the radiosensitizing effect of an anticancer drug.24,25 A value greater than 1.0 denotes an enhancer and greater than 1.1 denotes a strong enhancer. the dose enhancement ratio (DER) was calculated at IC25,IC50,andIC75 dose of photosensi- tization in NCI-N87 and YGIC-6B cells (Table 1). DER of IC25, IC50,andIC75 were 1.27, 1.25, and 1.24 in NCI-N87 cells and 1.28, 1.19, and 1.16 in YGIC-6B cells, respectively. These results that DERs were greater than 1.1 for both cells demonstrated that paclitaxel pretreatment augmented PDT-induced cytotoxicity. Paclitaxel, a microtubule stabilizer, showed promising antitu- mor activity and a radiosentitizing effect when combined with external radiation for gastric and bile duct cancer.26–29 Paclitaxel inhibits chromosomal segregation by stabilizing microtubules and leads to a cell cycle arrest at the G2-M phase. This arrest results in apoptosis and tumor cell sensitization to ionizing radiation.21,22 Our results suggested that paclitaxel could be a potent radiosensitizer to overcome limited antitumor effect of PDT. Pretreatment with low dose paclitaxel potentiated PDT-induced apoptosis To elucidate the mechanism of PDT-induced cytotoxicity, we first investigated cellular morphologic changes by 4-6-diamidino- 2-phenylindole (DAPI) staining at 4 h and 24 h after PDT (IC50) in NCI-N87 and YGIC-6B cells. As shown in Fig. 2, Fig. 1 Survival curve of NCI-N87 and YGIC-6B cells treated with PDT pycknotic nuclear changes and chromatin condensation were alone versus PDT combined with paclitaxel pretreatment. Cytotoxicity seen 4 h after PDT, which is suggestive apoptotic change. The was measured using the MTT assay 24 h after PDT using verteporfin (2 ug mL−1) with or without paclitaxel (NCI-N87, 4.8 nM; YGIC-6B, 5.1 nM). morphological changes were exaggerated 24 h after PDT. As Survival curves were corrected for the cytotoxic effect of paclitaxel. Bars, showninFig.3,DNAfragmentation,whichisatypicalsignof mean ± standard deviation. apoptosis, appeared as early as 1 h after PDT in NCI-N87 cells and the DNA fragmentation was augmented as time dependent manner. Apoptotic fractions measured by flow cytometry with Pretreatment with low dose paclitaxel enhanced PDT-induced Annexin V-FITC staining at 0 h, 1 h, and 3 h after PDT in ± ± ± cytotoxicity NCI-N87 cells were 11.1 1.7%, 13.6 2.2%, and 30.9 4.1%, respectively (data was not shown). These results showed that PDT- Initially, the paclitaxel IC25 and IC50 doses were measured using induced cytotoxicity with verteporfin was mediated by apoptotic the MTT assay (4.8 nM and 11.3 nM in NCI-N87, and 5.1 nM mechanism, which occurred shortly after photosensitization. and 13.1 nM in YGIC-6B cells, respectively; data not shown). To evaluate the mechanism of enhanced cytotoxicity of PDT The MTT assay was done after PDT in cancer cells with or after paclitaxel pretreatment, DAPI staining, DNA fragmentation without paclitaxel pretreatment to evaluate enhancing cytotoxicity analysis, Annexin V-FITC apoptosis assay, and cell cycle analysis 770 | Photochem.
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