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Evaluation of curcumin-mediated photodynamic therapy on the reverse of multidrug resistance in tumor cells.

ABSTRACT: Curcumin (CUR) possesses photosensitive anti-tumor activity. However, photoactive CUR mainly targets tumor cells sensitive to chemotherapy, whereas the effect on multi-drug resistant cancer cells has not been fully investigated. The study aimed to investigate the anti-tumor activity of CUR on resistant MCF-7/ADM cells and its underlying mechanism providing insights into CUR-mediated PDT and a reference for reversing multidrug resistance. Cell apoptosis and morphological changes were detected by Annexin V-FITC/PI double staining and immunofluorescence, respectively. The apoptosis mechanism of CUR-mediated PDT was investigated by detecting the levels of reactive oxygen species (ROS), mitochondrial membrane potential, and related proteins. MTT and apoptosis results showed that CUR-mediated PDT significantly enhanced cytotoxicity and induced considerable cell apoptosis. After treatment with CUR-mediated PDT, cells became round in shape and shrunk, F-actin was loosely arranged, and the nucleus decreased in size. In addition, the level of ROS increased over time compared to the control and peaked at 6 h. CUR-mediated PDT induced alterations in the mitochondrial membrane potential, increased the release of mitochondrial cytochrome C (Cyt-c), and downregulated caspase-3/7/9, PARP, and P-gp. In conclusion, CUR-PDT induced apoptosis in resistant MCF-7/ADM cells primarily through endogenous mitochondrial apoptosis pathway. Besides apoptosis activation in resistant cells, the reverse of multidrug resistance was ascribed to the downregulation of P-gp expression to a degree.

SUBMITTER: Li Y

PROVIDER: S-EPMC9047416 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Evaluation of curcumin-mediated photodynamic therapy on the reverse of multidrug resistance in tumor cells.

Li Ying Y Xiao Pei P Huang Zipeng Z Chen Xinru X Yan Xia X Zhai Junqiu J Ma Yan Y

RSC advances 20191201 1

Curcumin (CUR) possesses photosensitive anti-tumor activity. However, photoactive CUR mainly targets tumor cells sensitive to chemotherapy, whereas the effect on multi-drug resistant cancer cells has not been fully investigated. The study aimed to investigate the anti-tumor activity of CUR on resistant MCF-7/ADM cells and its underlying mechanism providing insights into CUR-mediated PDT and a reference for reversing multidrug resistance. Cell apoptosis and morphological changes were detected by ...[more]

PMID: 35492566

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Project description:Skin photoaging due to ultraviolet B (UVB) exposure generates reactive oxygen species (ROS) that increase matrix metalloproteinase (MMP). Chlorin e6-photodynamic therapy (Ce6-PDT), in addition to being the first-line treatment for malignancies, has been shown to lessen skin photoaging, while curcumin is well known for reducing the deleterious effects of ROS. In the current study, PDT with three novel Ce6-curcumin derivatives, a combination of Ce6 and curcumin with various linkers, including propane-1,3-diamine for Ce6-propane-curcumin; hexane-1,6-diamine for Ce6-hexane-curcumin; and 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) for Ce6-dipolyethylene glycol (diPEG)-curcumin, were studied for regulation of UVB-induced photoaging on human skin fibroblast (Hs68) and mouse embryonic fibroblast (BALB/c 3T3) cells. We assessed the antiphotoaging effects of Ce6-curcumin derivatives on cell viability, antioxidant activity, the mechanism of matrix metalloproteinase-1 and 2 (MMP-2) expression, and collagen synthesis in UVB-irradiated in vitro models. All three Ce6-curcumin derivatives were found to be non-phototoxic in the neutral red uptake phototoxicity test. We found that Ce6-hexane-curcumin-PDT and Ce6-propane-curcumin-associated PDT exhibited less cytotoxicity in Hs68 and BALB/c 3T3 fibroblast cell lines compared to Ce6-diPEG-curcumin-PDT. Ce6-diPEG-curcumin and Ce6-propane-curcumin-associated PDT showed superior antioxidant activity in Hs68 cell lines. Further, in UVB-irradiated in vitro models, the Ce6-diPEG-curcumin-PDT greatly attenuated the expression levels of MMP-1 and MMP-2 by blocking mitogen-activated protein kinases (MAPKs), activator protein 1 (AP-1), and tumor necrosis factor-α (NF-κB) signaling. Moreover, Ce6-diPEG-curcumin effectively inhibited inflammatory molecules, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, while accelerating collagen synthesis. These results demonstrate that Ce6-diPEG-curcumin may be a potential therapy for treating skin photoaging.

Project description:BackgroundWhile immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required to overcome resistance to immunotherapies.MethodsWe investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms of action, pre- and post- Ad-p53 treatment biopsies were evaluated for changes in gene-expression profiles by Nanostring IO 360 assays.ResultsThe substantial synergy of "triplet" Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with the complete tumor remissions of both the primary and contralateral tumors. Interestingly, contralateral tumors, which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p < 0.001). None of the monotherapies or doublet treatments induced the complete tumor regressions. Ad-p53 treatment increased interferon, CD8+ T cell, immuno-proteosome antigen presentation, and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune-suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 downregulated genes associated with stromal pathways and IL10 expression identified novel anticancer therapeutic applications.ConclusionsThese results imply the ability of Ad-p53 to induce efficacious local and systemic antitumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complementary immune mechanisms of action, which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist, and immune checkpoint inhibitor combination treatment.

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Evaluation of curcumin-mediated photodynamic therapy on the reverse of multidrug resistance in tumor cells.

Publications

Evaluation of curcumin-mediated photodynamic therapy on the reverse of multidrug resistance in tumor cells.

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