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In vitro cellular uptake and dimerization of signal transducer and activator of transcription-3 (STAT3) identify the photosensitizing and imaging-potential of isomeric photosensitizers derived from chlorophyll-a and bacteriochlorophyll-a.

ABSTRACT: Among the photosensitizers investigated, both ring-D and ring-B reduced chlorins containing the m-iodobenzyloxyethyl group at position-3 and a carboxylic acid functionality at position-17(2) showed the highest uptake by tumor cells and light-dependent photoreaction that correlated with maximal tumor-imaging [positron emission tomography (PET) and fluorescence] and long-term photodynamic therapy (PDT) efficacy in BALB/c mice bearing Colon26 tumors. However, among the ring-D reduced compounds, the isomer containing the 1'-m-iobenzyloxyethyl group at position-3 was more effective than the corresponding 8-(1'-m-iodobenzyloxyethyl) derivative. All photosensitizers showed maximum uptake by tumor tissue 24 h after injection, and the tumors exposed with light at low fluence and fluence rates (128 J/cm(2), 14 mW/cm(2)) produced significantly enhanced tumor eradication than those exposed at higher fluence and fluence rate (135 J/cm(2), 75 mW/cm(2)). Interestingly, dose-dependent cellular uptake of the compounds and light-dependent STAT3 dimerization have emerged as sensitive rapid indicators for PDT efficacy in vitro and in vivo and could be used as in vitro/in vivo biomarkers for evaluating and optimizing the in vivo treatment parameters of the existing and new PDT candidates.

SUBMITTER: Srivatsan A

PROVIDER: S-EPMC3188669 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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In vitro cellular uptake and dimerization of signal transducer and activator of transcription-3 (STAT3) identify the photosensitizing and imaging-potential of isomeric photosensitizers derived from chlorophyll-a and bacteriochlorophyll-a.

Srivatsan Avinash A Wang Yanfang Y Joshi Penny P Sajjad Munawwar M Chen Yihui Y Liu Chao C Thankppan Krishnakumar K Missert Joseph R JR Tracy Erin E Morgan Janet J Rigual Nestor N Baumann Heinz H Pandey Ravindra K RK

Journal of medicinal chemistry 20110906 19

Among the photosensitizers investigated, both ring-D and ring-B reduced chlorins containing the m-iodobenzyloxyethyl group at position-3 and a carboxylic acid functionality at position-17(2) showed the highest uptake by tumor cells and light-dependent photoreaction that correlated with maximal tumor-imaging [positron emission tomography (PET) and fluorescence] and long-term photodynamic therapy (PDT) efficacy in BALB/c mice bearing Colon26 tumors. However, among the ring-D reduced compounds, the ...[more]

PMID: 21842893

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Project description:Study questionAre STAT3 signaling molecules differentially expressed in endometriosis?Summary answerLevels of phospho-STAT3 and HIF1A, its downstream signaling molecule, are significantly higher in eutopic endometrium from women with endometriosis when compared with women without the disease.What is known alreadyEndometriosis is an estrogen-dependent inflammatory condition. Interleukin 6 (IL-6) is an inflammatory survival cytokine known to induce prolonged activation of STAT3 via association with the IL-6 receptor.Study design, size, durationCross-sectional measurements of STAT3 and HIF1A protein levels in eutopic endometrium from women with endometriosis versus those without.Participants/materials, setting, methodsLevels of phospho-STAT3 (pSTAT3) and HIF1A were examined in the endometrium of patients with and without endometriosis as well as in a non-human primate animal model using western blot and immunohistochemical analysis.Main results and the role of chanceLevels of pSTAT3 were significantly higher in the eutopic endometrium from women with endometriosis when compared with women without the disease in both the proliferative and secretory phases. HIF1A is known to be stabilized by STAT3 and IL-6. Our immunohistochemistry results show abundant HIF1A expression within the eutopic endometrial epithelial cells of women with endometriosis. Furthermore, pSTAT3 and HIF1A proteins are co-localized in endometriosis. This aberrant activation of pSTAT3 and HIF1A is confirmed by sequential analysis of eutopic endometrium using a baboon animal model of induced endometriosis. Lastly, we confirmed this IL-6 induction of both STAT3 phosphorylation and HIF1A mRNA expression in Ishikawa human endometrial adenocarcinoma cell line.Limitations, reasons for cautionIshikawa cancer cell line was used to study a benign disease. The peritoneal fluid contains various inflammatory cytokines in addition to IL-6 and so it is possible that other cytokines may affect the activity and expression of STAT3 signaling molecules.Wider implications of the findingsOur results imply that aberrant activation of STAT3 signaling plays an important role in the pathogenesis of endometriosis. Our findings could progress in our understanding of the etiology and pathophysiology of endometriosis and potential therapeutic interventions by targeted pharmacological.Study funding/competing interestsThis work was supported by NIH R01 HD067721 (to S.L.Y and B.A.L) and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG (to J.-W.J.). There are no conflicts of interest.

Dataset Information

In vitro cellular uptake and dimerization of signal transducer and activator of transcription-3 (STAT3) identify the photosensitizing and imaging-potential of isomeric photosensitizers derived from chlorophyll-a and bacteriochlorophyll-a.

Publications

In vitro cellular uptake and dimerization of signal transducer and activator of transcription-3 (STAT3) identify the photosensitizing and imaging-potential of isomeric photosensitizers derived from chlorophyll-a and bacteriochlorophyll-a.

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