Tumor microenvironment in a minipig model of spinal cord glioma.

BACKGROUND: Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs. METHODS: Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo. RESULTS: We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1ß, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model. CONCLUSIONS: Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.

C/EBPß/δ-secretase signaling mediates Parkinson's disease pathogenesis via regulating transcription and proteolytic cleavage of α-synuclein and MAOB.

Parkinson's disease (PD) is characterized by dopaminergic neuronal loss and the presence of intra-neuronal Lewy body (LB) inclusions with aggregated α-synuclein (α-Syn) as the major component. MAOB, a crucial monoamine oxidase for dopamine metabolism, triggers oxidative stress in dopaminergic neurons and α-Syn aggregation. However, the key molecular mechanism that mediates PD pathogenesis remains elusive. Here we show that C/EBPß acts as an age-dependent transcription factor for both α-Syn and MAOB, and initiates the PD pathologies by upregulating these two pivotal players, in addition to escalating δ-secretase activity to cleave α-Syn and promotes its neurotoxicity. Overexpression of C/EBPß in human wild-type α-Syn transgenic mice facilitates PD pathologies and elicits motor disorders associated with augmentation of δ-secretase, α-Syn, and MAOB. In contrast, depletion of C/EBPß from human α-Syn Tg mice abolishes rotenone-elicited PD pathologies and motor impairments via downregulating the expression of these key factors. Hence, our study supports that C/EBPß/δ-secretase signaling mediates PD pathogenesis via regulating the expression and cleavage of α-Syn and MAOB.

Mitochondrial dysfunction triggers the pathogenesis of Parkinson's disease in neuronal C/EBPß transgenic mice.

Respiratory chain complex I deficiency elicits mitochondrial dysfunction and reactive oxidative species (ROS), which plays a crucial role in Parkinson's disease (PD) pathogenesis. However, it remains unclear whether the impairment in other complexes in the mitochondrial oxidative phosphorylation chain is also sufficient to trigger PD onset. Here we show that inhibition of Complex II or III in the electron transport chain (ETC) induces the motor disorder and PD pathologies in neuronal Thy1-C/EBPß transgenic mice. Through a cell-based screening of mitochondrial respiratory chain inhibitors, we identified TTFA (complex II inhibitor) and Atovaquone (complex III inhibitor), which robustly block the oxidative phosphorylation functions, strongly escalate ROS, and activate C/EBPß/AEP pathway that triggers dopaminergic neuronal cell death. Oral administration of these inhibitors to Thy1-C/EBPß mice elicits constipation and motor defects, associated with Lewy body-like inclusions. Deletion of SDHD (Succinate dehydrogenase) gene from the complex II in the Substantia Nigra of Thy1-C/EBPß mice triggers ROS and PD pathologies, resulting in motor disorders. Hence, our findings demonstrate that mitochondrial ETC inactivation triggers PD pathogenesis via activating C/EBPß/AEP pathway.

Lentiviral-Induced Spinal Cord Gliomas in Rat Model.

Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this study, we evaluate the ability of each vector alone and combinations of vectors to produce high-grade spinal cord gliomas. Eight groups of rats (n = 8/group) underwent thoracolumbar laminectomy and injection of lentiviral vector in the lateral white matter of the spinal cord. Each group received a different combination of lentiviral vectors expressing PDGF-B, a constitutively active HRAS mutant, or shRNA targeting p53, or a control vector. All animals were monitored once per week for clinical deficits for 98 days. Tissues were harvested and analyzed using hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. Rats injected with PDGF-B+HRAS+sh-p53 (triple cocktail) exhibited statistically significant declines in all behavioral measures (Basso Beattie Bresnahan scoring, Tarlov scoring, weight, and survival rate) over time when compared to the control. Histologically, all groups except the control and those injected with sh-p53 displayed the development of tumors at the injection site, although there were differences in the rate of tumor growth and the histopathological features of the lesions between groups. Examination of immunohistochemistry revealed rats receiving triple cocktail displayed the largest and most significant increase in the Ki67 proliferation index and GFAP positivity than any other group. PDGF-B+HRAS also displayed a significant increase in the Ki67 proliferation index. Rats receiving PDGF-B alone and PDGF-B+ sh-p53 displayed more a significant increase in SOX2-positive staining than in any other group. We found that different vector combinations produced differing high-grade glioma models in rodents. The combination of all three vectors produced a model of high-grade glioma more efficiently and aggressively with respect to behavioral, physiological, and histological characteristics than the rest of the vector combinations. Thus, the present rat model of spinal cord glioma may potentially be used to evaluate therapeutic strategies in the future.

17-allylamino-17-demethoxygeldanamycin impeded chemotherapy through antioxidant activation via reducing reactive oxygen species-induced cell death.

Hyperthermia enhances the anticancer effects of thymidylate synthase (TYMS) inhibitors (raltitrexed, RTX) and improves the precise biochemical mechanisms partially through enhancement of intracellular drug absorption. Recent research focuses on the potential anticancer drug target Heat Shock Protein 90 (HSP90), which could increase the sensitivity of cancer cells to TYMS inhibitors; however, with different HSP90 inhibitors, several research studies finally showed a poor efficacy in preclinical or clinical research. Here, we showed that 17-allylamino-17-demethoxygeldanamycin (17-AAG, HSP90 inhibitor) affects the efficacy of chemotherapy through antioxidant activation-induced resistance. In this study, we found that RTX, alone or in combination with hyperthermia, triggers reactive oxygen species (ROS) exposure and thus induces cell death. Also, the addition of hyperthermia showed more ROS exposure and function. The pharmacologic inhibition of HSP90 reversed the effects of chemotherapeutical treatments, while the overexpression of HSP90 showed no relation with these effects, which demonstrated that dysregulation of HSP90 might have a significant impact on chemotherapeutic treatments. The addition of 17-AAG increased the activation of antioxidant with increased antioxidant enzymes, thus affecting the RTX efficacy.

Lnc-ATB contributes to gastric cancer growth through a MiR-141-3p/TGFß2 feedback loop.

The long noncoding RNA (lncRNA) ATB is an important regulator in human tumors. Here, we aimed to investigate the potential molecular mechanisms of lnc-ATB in gastric cancer (GC) tumorigenesis. RT-qPCR analysis was used to detect lnc-ATB expression level in 20 pairs of gastric cancer tissues and adjacent normal gastric mucosa tissues (ANTs). Moreover, the biological role of lnc-ATB was determined in vitro. We found that lnc-ATB was significantly upregulated in GC tissues compared to lnc-ATB expression in ANTs. These high lnc-ATB expression levels predicted poor prognosis in GC patients. Low levels of lnc-ATB inhibited GC cell proliferation and cell cycle arrest in vitro. Lnc-ATB was found to directly bind miR-141-3p. Moreover, TGF-ß actives lnc-ATB and TGF-ß2 directly binds mir-141-3p. Finally, we demonstrated that lnc-ATB fulfilled its oncogenic roles in a ceRNA-mediated manner. Our study suggests that lnc-ATB promotes tumor progression by interacting with miR-141-3p and that Lnc-ATB may be a valuable prognostic predictor for GC. In conclusion, the positive feedback loop of lnc-ATB/miR-141-3p/TGF-ß2 may be a potential therapeutic target for the treatment of GC.

3B, a novel of photosensitizer, exhibited anti-tumor effects via mitochondrial apoptosis pathway in MCF-7 human breast carcinoma cells.

Photodynamic therapy (PDT) has been recognized as an innovated therapeutic modality for the treatment of various cancers. In this study, we evaluated the anticancer effect of a new photosensitizer 3B in breast cancer, which was considered one of the most common cancers in women worldwide. Here, we determined the effect of 3B not only on the cell growth, apoptosis, and Bcl-2 signal pathway in vitro but also on the anti-cancer effect in nude mice in vivo. Our results showed that 3B was primarily accumulated in mitochondria, increased the level of ROS, induced apoptotic cells death via Bcl-2 family, and its activity could be blocked by the caspase inhibitor (Z-VAD-FMK). In vivo study, 3B made a significant opening inhibition of tumor growth and showed drug toxicity hardly. TUNEL assay indicated that PDT group showed more positive cells (green) than other groups. These data supported that 3B might develop as potential therapeutic drug for the treatment of breast cancer.

Naphtho[1,8-ef]isoindole-7,8,10(9H)-trione as Novel Theranostic Agents for Photodynamic Therapy and Multi-Subcellular Organelles Localization.

A series of naphtho[1,8-ef]isoindole-7,8,10(9H)-trione derivatives as novel theranostic agents for photodynamic therapy and multi-subcellular organelles localization were designed and synthesized. Most of them possess moderate fluorescence quantum yield and long wavelength absorption simultaneously, which made them possible for dual effects of imaging and therapy. Notably, compounds 7 b and 7 d exhibited significant light-toxicity but slight dark-toxicity. Confocal fluorescence microscopy experiments demonstrated that compound 7 b can locate and image in special multi-subcellular organelles. All the research results implied that naphtho[1,8-ef] isoindole-7,8,10(9H)-trione derivatives can be applied as a new series of theranostic agents with the characteristics of photodynamic therapy and multi-subcellular organelles imaging.

ApoE4 activates C/EBPß/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer's disease.

ApoE4, an apolipoprotein implicated in cholesterol transport and amyloid-ß (Aß) metabolism, is a major genetic risk determinant for Alzheimer's Disease (AD) and drives its pathogenesis via Aß-dependent and -independent pathways. C/EBPß, a proinflammatory cytokines-activated transcription factor, is upregulated in AD and mediates cytokines and δ-secretase expression. However, how ApoE4 contributes to AD pathogenesis remains incompletely understood. Here we show that ApoE4 and 27-hydroxycholesterol (27-OHC) co-activate C/EBPß/δ-secretase signaling in neurons, mediating AD pathogenesis, and this effect is dependent on neuronal secreted Aß and inflammatory cytokines. Inhibition of cholesterol metabolism with lovastatin diminishes neuronal ApoE4's stimulatory effects. Furthermore, ApoE4 and 27-OHC also mediate lysosomal δ-secretase leakage, activation, secretion and endocytosis. Notably, 27-OHC strongly activates C/EBPß/δ-secretase pathway in human ApoE4-TR mice and triggers AD pathologies and cognitive deficits, which is blocked by C/EBPß depletion. Hence, our findings demonstrate that ApoE4 and 27-OHC additively trigger AD pathogenesis via activating C/EBPß/δ-secretase pathway. Lowering cholesterol levels with statins should benefit the ApoE4 AD carriers.

Gene expression profiling of early Parkinson's disease patient reveals redox homeostasis.

Parkinson's disease (PD) is slowly progressive. Due to the lack of specific and sensitive biomarkers, the majority of PD patients are in the advanced stages when diagnosed. This study aimed to investigate biomarkers for early PD diagnosis. We first selected differential mRNAs by analysis of a Gene Expression Omnibus (GEO) data set. Next, we performed RNA sequencing to select differential mRNAs. After an integrated analysis of GEO and RNAseq data, we identified the PD early diagnosis biomarkers associated with oxidative stress. By function analysis, cellular response to hormone stimulus and response to the oxygen-containing compound was involved in the top Gene Set Enrichment Analysis (GSEA)s of the two cohorts. Moreover, SOCS7 was included in these GSEAs coincidentally. Further, by analyzing SOCS7 and its physical interactors, we found they mainly participate in immunity and redox homeostasis related processes, which might play a significant role in PD. Thus, our results suggest SOCS7 might be the potential diagnostic marker for PD.

C/EBPß/AEP Signaling Regulates the Oxidative Stress in Malignant Cancers, Stimulating the Metastasis.

Solid tumors start as a local disease, but some are capable of metastasizing to the lymph nodes and distant organs. The hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating cancer progression and metastasis. However, the molecular mechanisms mediating the disseminated cancer cell metastasis remain incompletely understood. Here, we show that C/EBPß/AEP signaling that is upregulated in breast cancers mediates oxidative stress and lung metastasis, and inactivation of asparagine endopeptidase (AEP, also known as legumain) robustly regulates breast cancer reactive oxygen species (ROS) and metastasis. AEP, a protease activated in acidic conditions, is overexpressed in numerous types of cancer and promotes metastasis. Employing a breast cancer cell line MDA-MD-231, we show that C/EBPß, an oxidative stress or inflammation-activated transcription factor, and its downstream target AEP mediate ROS production as well as migration and invasion in cancer cells. Deficiency of AEP in the MMTV-PyMT transgenic breast cancer mouse model significantly regulates oxidative stress and suppresses lung metastasis. Administration of an innovative AEP inhibitor substantially mitigates ROS production and cancer metastasis. Hence, our study demonstrates that pharmacologic inhibition of AEP activity might provide a disease-modifying strategy to suppress cancer metastasis.

Immune-associated biomarkers for early diagnosis of Parkinson's disease based on hematological lncRNA-mRNA co-expression.

Early stage diagnosis of Parkinson's disease (PD) is challenging without significant motor symptoms. The identification of effective molecular biomarkers as a hematological indication of PD may help improve the diagnostic timeliness and accuracy. In this paper, we analyzed and compared the blood samples of PD and control (CTR) patients to identify the disease-related changes and determine the putative biomarkers for PD diagnosis. Based on the RNA sequencing analysis, differentially expressed genes (DEGs) were identified, and the co-expression network of DEGs was constructed using the weighted correlation network analysis (WGCNA). The analysis leads to the identification of 87 genes that were exclusively regulated in the PD group, whereas 66 genes were significantly increased and 21 genes were significantly decreased in contrast to the control group. The results indicate that the core lncRNA-mRNA co-expression network greatly changes the immune response in PD patients. Specifically, the results showed that PWAR6, LINC00861, AC83843.1, IRF family, IFIT family and CaMK4 may play important roles in the immune system of PD. Based on the findings from this the present study, future research aims at identify novel therapeutic strategies for PD.

C/EBPß mediates NQO1 and GSTP1 anti-oxidative reductases expression in glioblastoma, promoting brain tumor proliferation.

Glioblastoma (GBM) is the most common and most aggressive brain tumor, associated with high levels of reactive oxidative species (ROS) due to metabolic and signaling aberrations. High ROS levels are detrimental to cells, but it remains incompletely understood how cancer cells cope with the adverse effects. Here we show that C/EBPß, a ROS responsive transcription factor, regulates the transcription of NQO1 and GSTP1, two antioxidative reductases, which neutralize ROS in the GBM and mediates their proliferation. C/EBPß is upregulated in EGFR overexpressed GBM cells, inversely correlated with the survival rates of brain tumor patients. Interestingly, C/EBPß binds the promoters of NQO1 and GSTP1 and escalates their expression. Overexpression of C/EBPß selectively decreases the ROS in EGFR-overexpressed U87MG cells and promotes cell proliferation via upregulating NQO1 and GSTP1; whereas knocking down C/EBPß elevates the ROS and reduces proliferation by repressing the reductases. Accordingly, C/EBPß mediates the brain tumor growth in vivo, coupling with NQO1 and GSTP1 expression and ROS levels. Hence, C/EBPß regulates the expression of antioxidative reductases and balances the ROS, promoting brain tumor proliferation.

Baicalin Represses C/EBPß via Its Antioxidative Effect in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the formation of intracellular Lewy bodies (LB) in the brain, which aggregates α-synuclein (α-Syn) as the main component. The interest of flavonoids as potential neuroprotective agents is increasing due to its high efficiency and low side effects. Baicalin is one of the flavonoid compounds, which is a predominant flavonoid isolated from Scutellaria baicalensis Georgi. However, the key molecular mechanism by which Baicalin can prevent the PD pathogenesis remains unclear. In this study, we used bioinformatic assessment including Gene Ontology (GO) to elucidate the correlation between oxidative stress and PD pathogenesis. RNA-Seq methods were used to examine the global expression profiles of noncoding RNAs and found that C/EBPß expression was upregulated in PD patients compared with healthy controls. Interestingly, Baicalin could protect DA neurons against reactive oxygen species (ROS) and decreased C/EBPß and α-synuclein expression in pLVX-Tet3G-α-synuclein SH-SY5Y cells. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model, the results revealed that treatment with Baicalin improved the PD model's behavioral performance and reduced dopaminergic neuron loss in the substantia nigra, associated with the inactivation of proinflammatory cytokines and oxidative stress. Hence, our study supported that Baicalin repressed C/EBPß via redox homeostasis, which may be an effective potential treatment for PD.

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. METHODS: High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. RESULTS: We identified a small molecular inhibitor, "MNPC," that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. CONCLUSIONS: Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.

NQO1 Is Regulated by PTEN in Glioblastoma, Mediating Cell Proliferation and Oxidative Stress.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a dismal prognosis, and the patients carrying EGFR-driven tumors with PTEN mutation do not respond to anti-EGFR therapy. The molecular mechanisms for this resistance remain unknown. Here, we show that PTEN induces the expression of NQO1, a flavoenzyme with dual roles in pro- and antitumorigenesis that decreases the formation of reactive oxygen species (ROS), which mediates the oxidative stress and GBM cell proliferation. NQO1 is reduced in EGFRvIII-overexpressed U87MG cells associated with low ROS, whereas NQO1 is highly escalated in PTEN stably expressed U87MG/EGFRvIII cells with high ROS. Interestingly, knockdown of NQO1 augments ROS and diminishes cell proliferation. Conversely, overexpression of NQO1 attenuates ROS and increases cell proliferation. By contrast, overexpression of PINK1, a PTEN-induced kinase 1, represses ROS and inhibits GBM cell proliferation. Therefore, our findings support that NQO1 displays a paradoxical role in mediating GBM growth in response to tumor suppressor PTEN.

Network-based identification of microRNAs as potential pharmacogenomic biomarkers for anticancer drugs.

As the recent development of high-throughput technologies in cancer pharmacogenomics, there is an urgent need to develop new computational approaches for comprehensive identification of new pharmacogenomic biomarkers, such as microRNAs (miRNAs). In this study, a network-based framework, namely the SMiR-NBI model, was developed to prioritize miRNAs as potential biomarkers characterizing treatment responses of anticancer drugs on the basis of a heterogeneous network connecting drugs, miRNAs and genes. A high area under the receiver operating characteristic curve of 0.820 ± 0.013 was yielded during 10-fold cross validation. In addition, high performance was further validated in identifying new anticancer mechanism-of-action for natural products and non-steroidal anti-inflammatory drugs. Finally, the newly predicted miRNAs for tamoxifen and metformin were experimentally validated in MCF-7 and MDA-MB-231 breast cancer cell lines via qRT-PCR assays. High success rates of 60% and 65% were yielded for tamoxifen and metformin, respectively. Specifically, 11 oncomiRNAs (e.g. miR-20a-5p, miR-27a-3p, miR-29a-3p, and miR-146a-5p) from the top 20 predicted miRNAs were experimentally verified as new pharmacogenomic biomarkers for metformin in MCF-7 or MDA-MB-231 cell lines. In summary, the SMiR-NBI model would provide a powerful tool to identify potential pharmacogenomic biomarkers characterized by miRNAs in the emerging field of precision cancer medicine, which is available at http://lmmd.ecust.edu.cn/database/smir-nbi/.

Targeted deletion of miR-139-5p activates MAPK, NF-κB and STAT3 signaling and promotes intestinal inflammation and colorectal cancer.

miR-139-5p, which has been reported to be underexpressed in several types of cancer, is associated with tumorigenesis by participating in various biological processes via the modulation of different target genes. In the present study, we analyzed mice deficient in miR-139-5p, aiming to investigate its role in intestinal inflammation and colitis-associated colorectal cancer. We show that miR-139-5p knockout (KO) mice are highly susceptible to colitis and colon cancer, accompanied by elevated proliferation and decreased apoptosis, as well as an increased production of inflammatory cytokines, chemokines and tumorigenic factors. Furthermore, enhanced colon inflammation and colorectal tumor development in miR-139-5p KO mice are a result of the regulatory effects of miR-139-5p on its target genes for Rap1b and nuclear factor-kappa B, thus affecting the activity of the mitogen-activated protein kinase, nuclear factor-kappa B and signal transducer and activator of transcription 3 signaling pathways. These results reveal a critical part for miR-139-5p in maintaining intestinal homeostasis and protecting against colitis and colorectal cancer in vivo, providing new insights into the function of miR-139-5p with respect to linking inflammation to carcinogenesis.

Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism.

The resistance to oxaliplatin (L-OHP) is a major obstacle to ideal therapeutic outcomes in colorectal cancer. Photodynamic therapy (PDT) induces tumor damage through photosensitizer-mediated oxidative cytotoxicity. Hypericin is a well-studied photosensitizer. In this study, we explored the role of hypericin-mediated PDT (HY-PDT) in sensitizing human colorectal cancer cells towards L-OHP. Pre-treatment with HY-PDT enhanced the anti-tumor activity of L-OHP via decreasing drug efflux and increasing platinum accumulation. Further research showed that HY-PDT-mediated resensitization of resistance cells towards L-OHP was dependent on regulation of MRP-2, instead of p-gp. HY-PDT was also found to inhibit intracellular glutathione (GSH) and Glutathione S-transferase (GST), suggesting the involvement of GSH-related detoxification in the sensitization effect. Additionally, enhanced DNA double-strand breaks (DSBs) was observed following HY-PDT/L-OHP combined treatment. HY-PDT lowered the removing rate of platinum from DNA and down-regulated the expression of ERCC1 and XPF, two critical enzymes involved in nucleotide excision repair (NER) pathway. GSH monoethyl ester (GSH-EE) antagonized HY-PDT-induced ROS and repressed sensitization to platinum. Taken together, HY-PDT mediated sensitization of L-OHP in human colorectal cancer is mediated by ROS, whose mechanism involves affecting drug efflux, GSH-related detoxification and NER-mediated DNA repair.

Thio-bisnaphthalimides as Heavy-Atom-Free Photosensitizers with Efficient Singlet Oxygen Generation and Large Stokes Shifts: Synthesis and Properties.

By structure transformation of benzo[k,l]thioxanthene-naphthalimide derivatives (ND-S), a novel series of nonplanar thio-heterocyclic bisnaphthalimide derivatives are designed and synthesized. They display high molar absorptivity and large Stokes shifts. They are also heavy-atom-free photosensitizers with high singlet oxygen quantum yields of 0.75 and 0.82. Thus, these new structures based on the naphthalimide skeleton have great potential for singlet oxygen applications.