Radiation-induced Bystander Effects on Glioblastoma Tumor Cells via NMDA Receptor Signaling.

Proton therapy has been widely applied on treating inaccessible and inoperable tumors, such as tumors deep within the brain or close to the critical brain stem. Nevertheless, the damaging effect of radiation for central nervous system (CNS) tumors is difficult to be confined within the irradiated region and has led to decline of neurological function in especially children with congenital CNS tumors. Currently, the involvement of n-methyl-d-aspartate (NMDA) receptors or secretary cytokines and chemokines in proton-induced bystander effects remains unclear. To understand the modulatory effects of NMDA receptor inhibition on the survival and proliferation of glioblastoma-derived cells, mesenchymal-like U373 cells were applied along with U87 neural glioblastoma cells for single doses of proton radiation at different LET in the presence or absence of pretreatment with memantine and/or collimation. Under collimation, neuronal tumor cells that are not directly irradiated (i.e., bystander cells) encounter similar biological effects potentially through cell coupling and synaptic transmission. Furthermore, whether proton LET plays a role in the mediation of bystander effect awaits to be elucidated. From this study, synaptic transmission was found to play differential roles in the proliferation of U373 and U87 cells after exposure to collimated radiation. Also, radiation-induced cell proliferation at the late stage was more correlated with bystander cell survival than early manifested γH2AX foci, suggesting that proton-induced glutamatergic synapse may act as a more important contributor than proton-induced direct effect on DNA double-stranded breaks to the late-stage responses of glioblastoma cells.

Clinical Effect of Moisturized Skin Care on Radiation Dermatitis of Head and Neck Cancer.

BACKGROUND/AIM: Radiation therapy (RT) for head and neck cancer may cause severe radiation dermatitis (RD) resulting in RT interruption and affecting disease control. A few studies address skin moisture changes during RT for head and neck cancer. The purpose of this study was to explore the effect of moisturized skin care (MSC) on severity of RD. PATIENTS AND METHODS: The study includes newly diagnosed head and neck cancer patients undergoing RT. Participants were divided into MSC group and routine skin care (RSC) group based on patient's preferred decision. Skin moisture in the four quadrants of the neck was measured weekly before and after RT. RD was assessed with the Radiation Induced Skin Reaction Assessment Scale (RISRAS) and the Radiation Therapy Oncology Group (RTOG) acute skin toxicity grading criteria. RESULTS: A total of 54 patients were enrolled, of which 49 patients were suitable for the statistical analysis. There was a statistically significant difference in the RISRAS total score since the 5th week after RT between the groups. The severity of RD was less (B=0.814, p=0.021) and the onset was later (B=-0.384, p=0.006) in the MSC group when compared to the RSC group. Skin moisture decreased with cumulative radiation dose. In the upper neck, the MSC group had a slower rate of skin moisture decrease compared to the RSC group (right upper neck: B=0.935, p=0.007; left upper neck: B=0.93, p=0.018). CONCLUSION: MSC can effectively reduce the severity and delay the onset of RD, while slows down skin moisture decrease during RT.

Magnolol Suppresses ERK/NF-κB Signaling and Triggers Apoptosis Through Extrinsic/Intrinsic Pathways in Osteosarcoma.

BACKGROUND/AIM: Osteosarcoma is an aggressive primary malignant bone tumor that occurs in childhood. Although the diagnostic and treatment options have been improved, osteosarcoma confers poor prognosis. Magnolol, an active component of Magnoliae officinalis cortex, has been widely applied in herb medicine and has been shown to have multiple pharmacological activities. However, whether magnolol possesses anti-osteosarcoma capacity remains unknown. MATERIALS AND METHODS: We examined magnolol is cytotoxicity, and whether it regulates apoptosis and oncogene expression using MTT, flow cytometry and Western blotting assays in osteosarcoma cells. RESULTS: Magnolol exerted toxicity towards U-2 OS cells by inducing intrinsic/extrinsic apoptosis pathways. Additionally, treatment of U-2 OS cells with magnolol inhibited MAPK1 mitogen-activated protein kinase 1 (ERK)/Nuclear factor kappa B (NF-B) signaling involved in tumor progression and reduced the expression of anti-apoptotic and metastasis-associated genes. CONCLUSION: Magnolol may induce apoptosis and inactivate ERK/NF-B signal transduction in osteosarcoma cells.

Regorafenib enhances antitumor immune efficacy of anti-PD-L1 immunotherapy on oral squamous cell carcinoma.

Oral squamous cells carcinoma (OSCC) is the most common oral malignancy that majorly originated from oral cavity. Though the prognostic and predictive value of targeting checkpoint molecules has been reported on OSCC, the treatment efficacy of monotherapy is remaining limited. Several studies suggested that multikinase inhibitors may show potential to facilitate anti-PD-L1-induced anti-tumor immunity. Regorafenib, an oral multikinase inhibitor has been approved by FDA for various types of cancer treatment. Here, we aim to identify whether regorafenib may boost anti-tumor immunity of anti-PD-L1 in MOC1-bearing OSCC animal model. The alteration of immune cells such as M1/M2-like macrophages (MΦ), cytotoxicity T cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) after combination of anti-PD-L1 and regorafenib was validated by flow cytometry and immunohistochemistry staining. The combination index analysis (CI=0.89) supported that regorafenib effectively induce anti-OSCC efficacy of anti-PD-L1. Combination of anti-PD-L1 and regorafenib may not only trigger the polarization of M1-like MΦ (CD11b+CD86+) in mice bone marrow (BM) and spleen (SP), but also induce the accumulation and function of CD8+ T cells in tumor-draining lymph node (TDLN) and tumor. In addition, immunosuppressive related cells (MDSCs and Treg) and factors were all decreased by combination therapy in BM, SP and tumor. In sum, regorafenib may improve anti-OSCC efficacy of anti-PD-L1 through systemically and locally upregulating the immunostimulation immunity and suppressing immunosuppression immunity.

Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo.

Nuclear factor-kappa B (NF-κB), an oncogenic transcription factor, modulates tumor formation and progression by inducing the expression of oncogenes involved in proliferation, survival, angiogenesis, and metastasis. Oral multikinase inhibitors, such as sorafenib, regorafenib, and lenvatinib have been used for the treatment of hepatocellular carcinoma (HCC). Both sorafenib and regorafenib were shown to abolish the NF-κB-mediated progression of HCC. However, the effect of lenvatinib on NF-κB-mediated progression of HCC is ambiguous. Therefore, the primary purpose of the present study was to evaluate the inhibitory effect of lenvatinib and its inhibitory mechanism on the NF-κB-mediated progression of HCC in vitro and in vivo. Here, we used two HCC cell lines to identify the cytotoxicity, apoptosis and metastasis effect of lenvatinib. We also applied a Hep3B-bearing animal model to investigate the therapeutic efficacy of lenvatinib on in vivo model. An NF-κB translocation assay, NF-κB reporter gene assay, a Western blotting assay and immunohistochemistry staining were used to investigate the underlying mechanism by which lenvatinib acts on HCC. In this study, we demonstrated that lenvatinib induced extrinsic/intrinsic apoptosis and suppressed the metastasis of HCC both in vitro and in vivo. Lenvatinib may also suppress NF-κB translocation and activation. We also found both protein kinase C delta (PKC-δ) and p38 mitogen-activated protein kinase (MAPK) inactivation participated in lenvatinib-reduced NF-κB signaling. In conclusion, this study reveals that the suppression of PKC-δ, and the p38 MAPK/NF-κB axis is associated with the lenvatinib-inhibited progression of HCC in vitro and in vivo.

Magnolol Induces the Extrinsic/Intrinsic Apoptosis Pathways and Inhibits STAT3 Signaling-Mediated Invasion of Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most common form of malignant brain tumor, with poor prognosis; the efficacy of current standard therapy for GBM remains unsatisfactory. Magnolol, an herbal medicine from Magnolia officinalis, exhibited anticancer properties against many types of cancers. However, whether magnolol suppresses GBM progression as well as its underlying mechanism awaits further investigation. In this study, we used the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay, apoptosis marker analysis, transwell invasion and wound-healing assays to identify the effects of magnolol on GBM cells. We also validated the potential targets of magnolol on GBM with the GEPIA (Gene Expression Profiling Interactive Analysis) and Western blotting assay. Magnolol was found to trigger cytotoxicity and activate extrinsic/intrinsic apoptosis pathways in GBM cells. Both caspase-8 and caspase-9 were activated by magnolol. In addition, GEPIA data indicated the PKCδ (Protein kinase C delta)/STAT3 (Signal transducer and activator of transcription 3) signaling pathway as a potential target of GBM. Magnolol effectively suppressed the phosphorylation and nuclear translocation of STAT3 in GBM cells. Meanwhile, tumor invasion and migration ability and the associated genes, including MMP-9 (Matrix metalloproteinase-9) and uPA (Urokinase-type plasminogen activator), were all diminished by treatment with magnolol. Taken together, our results suggest that magnolol-induced anti-GBM effect may be associated with the inactivation of PKCδ/STAT3 signaling transduction.

Suppression of EGFR/PKC-δ/NF-κB Signaling Associated With Imipramine-Inhibited Progression of Non-Small Cell Lung Cancer.

BACKGROUND: Anti-depressants have been reported to own anti-tumor potential types of cancers; however, the role of imipramine in non-small cell lung cancer (NSCLC) has not been elucidated. Epidermal growth factor receptor (EGFR) was known to be one of the key regulators that control NSCLC progression. Whether EGFR would be the target of imipramine for suppressing tumor signaling transduction and results in anti-tumor potential is remaining unclear. METHODS: We used CL-1-5-F4 cells and animal models to identify the underlying mechanism and therapeutic efficacy of imipramine. Cytotoxicity, apoptosis, invasion/migration, DNA damage, nuclear translocation of NF-κB, activation of NF-κB, phosphorylation of EGFR/PKC-δ/NF-κB was assayed by MTT, flow cytometry, transwell, wound healing assay, comet assay, immunofluorescence staining, NF-κB reporter gene assay and Western blotting, respectively. Tumor growth was validated by CL-1-5-F4/NF-κB-luc2 bearing animal model. RESULTS: Imipramine effectively induces apoptosis of NSCLC cells via both intrinsic and extrinsic apoptosis signaling. DNA damage was increased, while, invasion and migration potential of NSCLC cells was suppressed by imipramine. The phosphorylation of EGFR/PKC-δ/NF-κB and their downstream proteins were all decreased by imipramine. Similar tumor growth inhibition was found in imipramine with standard therapy erlotinib (EGFR inhibitor). Non-obvious body weight loss and liver pathology change were found in imipramine treatment mice. CONCLUSION: Imipramine-triggered anti-NSCLC effects in both in vitro and in vivo model are at least partially attributed to its suppression of EGFR/PKC-δ/NF-κB pathway.

Bismuth breast-shield use in chest computed tomography for efficient dose reduction and sufficient image quality.

BACKGROUND: Radiosensitivity in the breasts increases the risk of carcinogenesis from exposure to the ionizing radiation of computed tomography (CT) administered in the course of medical attention. Bismuth shielding techniques have been used to reduce radiation, but image noise increased, degrading image quality. PURPOSE: The aim of this study was to investigate how the use of iterative reconstruction (IR) combined with bismuth shielding influences image quality. MATERIALS AND METHODS: Women aged at least 20 years with body mass indexes <28 were recruited and randomly assigned to 1 of 3 CT scanning protocols without shielding, with a bismuth breast shield before the scout view, or with a bismuth breast shield after the scout view. All obtained images were reconstructed using an IR algorithm. To evaluate radiation dose, 2 Gafchromic films were placed over the clothes, 1 near each nipple. RESULTS: Average dose reduction was significant (27.99%, P < .05) when bismuth shielding was applied after the scout view. Using the contrast-to-noise ratio, the image quality was found to be superior when the IR algorithm was applied. Using quantitative evaluations by 2 radiologists applying a 4-point Likert scale, significant differences in image quality were not found among the 3 protocols. CONCLUSION: Bismuth breast shields, particularly when used after acquiring scout images, are effective at reducing radiation dose without undermining the diagnostic value of the images when the IR technique is applied.

Anticancer Efficacy and Mechanism of Amentoflavone for Sensitizing Oral Squamous Cell Carcinoma to Cisplatin.

BACKGROUND/AIM: Nuclear factor kappa B (NF-κB) inactivation and apoptosis activation have been shown to enhance the anticancer effect of cisplatin in oral squamous cell carcinoma (OSCC). Amentoflavone may suppress NF-κB activity and trigger apoptosis in different types of cancer. The aim of this study was to investigate the anticancer effect and mechanism of amentoflavone in combination with cisplatin in OSCC. MATERIALS AND METHODS: We investigated the combination effect and mechanism of amentoflavone and cisplatin via cell viability analysis, flow cytometry-based apoptosis analyses, transwell migration/invasion assay, immunofluorescence staining and western blotting assay. RESULTS: Both amentoflavone and QNZ (NF-κB inhibitor) significantly increased cisplatin-induced cytotoxicity. Amentoflavone reduced cisplatin-triggered NF-κB activity and enhanced cisplatin-induced intrinsic caspase-dependent and independent apoptotic pathways. Moreover, amentoflavone augments cisplatin-suppressed invasion and migration ability of OSCC cells. CONCLUSION: Inactivation of NF-κB and induction of apoptosis through intrinsic caspase-dependent and independent apoptotic pathways are associated with amentoflavone enhanced anti-OSCC efficacy of cisplatin.

Therapeutic Efficacy and Inhibitory Mechanism of Regorafenib Combined With Radiation in Colorectal Cancer.

BACKGROUND: Although both chemotherapy and radiotherapy (RT) can sufficiently maintain tumor suppression of colorectal cancer (CRC), these treatments may trigger the expression of nuclear factor kappa B (NF-κB) and compromise patients' survival. Regorafenib suppresses NF-κB activity in various tumor types. However, whether regorafenib may act as a suitable radiosensitizer to enhance therapeutic efficacy of RT remains unknown. MATERIALS AND METHODS: Here, we established a CRC-bearing animal model to investigate the therapeutic efficacy of regorafenib in combination with RT, through measurement of tumor growth, body weight, whole-body computed tomography (CT) scan and immunohisto-chemistry staining. RESULTS: Smallest tumor size and weight were found in the combination treatment group. In addition, RT-induced up-regulation of NF-κB and downstream proteins were diminished by regorafenib. Moreover, the body weight and liver pathology in the treated group were similar to those of the non-treated control group. CONCLUSION: Regorafenib may enhance the anti-CRC efficacy of RT.

Modulating mitochondrial morphology enhances antitumor effect of 5-ALA-mediated photodynamic therapy both in vitro and in vivo.

5-aminolevulinic acid mediated PDT (5-ALA-PDT) is an approved therapeutic procedure for treating carcinomas of the cervix. However, when employed as a monotherapy, 5-ALA-PDT could not produce satisfactory results toward large and deep tumors. Therefore, developing a method to improve the efficacy of 5-ALA-PDT becomes important. In this study, we demonstrate an enhanced antitumor effect of 5-ALA-PDT by the modulation of mitochondrial morphology. The mitochondria in the cells were regulated into tubular mitochondria or fragmented mitochondria through over expression of Drp1 or Mfn2. Then these cells were treated with identical dose of 5-ALA-PDT. Our results suggest that HeLa cells predominantly containing fragmented mitochondria were more sensitive to 5-ALA-PDT than the cells predominantly containing tubular mitochondria. The morphology of mitochondria changed as the cell cycle progressed, with tubular mitochondria predominantly exhibited in the S phase and uniformly fragmented mitochondria predominantly displayed in the M phase. Paclitaxel significantly increased the population of M-phase cells, while 5-fluorouracil significantly increased the population of S-phase cells in xenograft tumors. Furthermore, low-dose paclitaxel significantly increased the antitumor effects of PDT. However, 5-fluorouracil didn't improve the antitumor effects of PDT. These results demonstrated an enhanced antitumor effect of 5-ALA-PDT from the modulation of mitochondrial morphology. We anticipate that our results will provide an insight for selecting potential chemotherapeutic agents to combine with PDT for tumor treatment.

Assessment of radiation safety in cardiac CT angiography.

This study investigates the radiation dose and image quality of patients not receiving ß-blockers for cardiac CT angiography (CCTA) with or without the optimization of electrocardiographic (ECG) pulsing window. The differences in patient characteristics are also characterized.Normal-weight and obese patients (n = 154) with heart rates between 65 and 80 beats per minutes (bpm) during the prospective axial scanning were enrolled retrospectively. The ECG pulsing windows were set at 50% to 75% (Group A) or 60% to 75% (Group B) of the R-R interval for patients with heart rate variability higher than or not exceeding ±5 bpm, respectively. The effective doses of individual patient were estimated from the dose length product of the CCTA scan. Two radiologists independently reviewed the images and applied a 4-point Likert scale for image quality assessment. The patients' characteristics were compared along with the patients' effective doses between groups.The optimized pulsing window significantly reduced the average radiation dose for normal-weight and obese patients by 33% and 27%, respectively. The CCTA image quality of patients in Group A was not different overall from those obtained from Group B. Nondiabetic obese patients were more likely to be accepted for the use of the optimized pulsing window. Unlike obese patients, normal-weight patients revealed no characteristic difference between Groups A and B.This study indicates an equivalent efficacy of using optimized pulsing windows for reducing the radiation dose for patients without ß-blocker administration between different body weight groups. Nevertheless, gender and diabetic status became prominent characteristics in the obese group when matching up with the optimized pulsing window.

Mutated Fanconi anemia pathway in non-Fanconi anemia cancers.

An extremely high cancer incidence and the hypersensitivity to DNA crosslinking agents associated with Fanconi Anemia (FA) have marked it to be a unique genetic model system to study human cancer etiology and treatment, which has emerged an intense area of investigation in cancer research. However, there is limited information about the relationship between the mutated FA pathway and the cancer development or/and treatment in patients without FA. Here we analyzed the mutation rates of the seventeen FA genes in 68 DNA sequence datasets. We found that the FA pathway is frequently mutated across a variety of human cancers, with a rate mostly in the range of 15 to 35 % in human lung, brain, bladder, ovarian, breast cancers, or others. Furthermore, we found a statistically significant correlation (p < 0.05) between the mutated FA pathway and the development of human bladder cancer that we only further analyzed. Together, our study demonstrates a previously unknown fact that the mutated FA pathway frequently occurs during the development of non-FA human cancers, holding profound implications directly in advancing our understanding of human tumorigenesis as well as tumor sensitivity/resistance to crosslinking drug-relevant chemotherapy.

In vitro monitoring of oxidative processes with self-aggregating gold nanoparticles using all-optical photoacoustic spectroscopy.

In this work, the assembly of gold nanoparticles of (AuNPs) is used to detect the presence of the biomolecule glutathione (GSH) using a novel technique called "all-optical photoacoustic spectroscopy" (AOPAS). The AOPAS technique coupled with AuNPs forms the basis of a biosensing technique capable of probing the dynamic evolution of nano-bio interfaces within a microscopic volume. Dynamic Light Scattering (DLS) and ultraviolet-visible (UV-vis) spectra were measured to describe the kinetics governing the interparticle interactions by monitoring the AuNPs assembly and evolution of the surface plasmon resonance (SPR) band. A comparison of the same dynamic evolution of AuNPs assembly was performed using the AOPAS technique to confirm the validity of this method. The fundamental study is complemented by a demonstration of the performance of this biosensing technique in the presence of cell culture medium containing fetal bovine serum (FBS), which forms a protein corona on the surface of the AuNPs. This work demonstrates that the in vitro monitoring capabilities of the AOPAS provides sensitive measurement at the microscopic level and low nanoparticle concentrations without the artifacts limiting the use of conventional biosensing methods, such as fluorescent indicators. The AOPAS technique not only provides a facile approach for in vitro biosensing, but also shed a light on the real-time detection of thiol containing oxidative stress biomarkers in live systems using AuNPs.

Regulation of DNA Damage Response by Estrogen Receptor ß-Mediated Inhibition of Breast Cancer Associated Gene 2.

Accumulating evidence suggests that ubiquitin E3 ligases are involved in cancer development as their mutations correlate with genomic instability and genetic susceptibility to cancer. Despite significant findings of cancer-driving mutations in the BRCA1 gene, estrogen receptor (ER)-positive breast cancers progress upon treatment with DNA damaging-cytotoxic therapies. In order to understand the underlying mechanism by which ER-positive breast cancer cells develop resistance to DNA damaging agents, we employed an estrogen receptor agonist, Erb-041, to increase the activity of ERß and negatively regulate the expression and function of the estrogen receptor α (ERα) in MCF-7 breast cancer cells. Upon Erb-041-mediated ERα down-regulation, the transcription of an ERα downstream effector, BCA2 (Breast Cancer Associated gene 2), correspondingly decreased. The ubiquitination of chromatin-bound BCA2 was induced by ultraviolet C (UVC) irradiation but suppressed by Erb-041 pretreatment, resulting in a blunted DNA damage response. Upon BCA2 silencing, DNA double-stranded breaks increased with Rad51 up-regulation and ataxia telangiectasia mutated (ATM) activation. Mechanistically, UV-induced BCA2 ubiquitination and chromatin binding were found to promote DNA damage response and repair via the interaction of BCA2 with ATM, γH2AX and Rad51. Taken together, this study suggests that Erb-041 potentiates BCA2 dissociation from chromatin and co-localization with Rad51, resulting in inhibition of homologous recombination repair.

Ursolic acid differentially modulates apoptosis in skin melanoma and retinal pigment epithelial cells exposed to UV-VIS broadband radiation.

The signaling pathways via mTOR (mammalian target of rapamycin) and AMPK (AMP-activated protein kinase) play key roles in transcription, translation and carcinogenesis, and may be activated by light exposure. These pathways can be modulated by naturally occurring compounds, such as the triterpenoid, ursolic acid (UA). Previously, the transcription factors p53 and NF-κB, which transactivate mitochondrial apoptosis-related genes, were shown to be differentially modulated by UA. UA-modulated apoptosis, following exposure to UV-VIS radiation (ultraviolet to visible light broadband radiation, hereafter abbreviated to UVR), is observed to correspond to differential levels of oxidative stress in retinal pigment epithelial (RPE) and skin melanoma (SM) cells. The cellular response to this phytochemical was characterized using western blot, flow cytometry, microscopy with reactive oxidative species probes MitoTracker and dihydroethidium, and membrane permeability assay. UA pretreatment potentiated cell cycle arrest and UVR-induced apoptosis selectively in SM cells while reducing photo-oxidative stress in the DNA of RPE cells presumably by antioxidant activity of UA. Mechanistically, the nuclear transportation of p65 and p53 was reduced by UA administration prior to UVR exposure while the levels of p65 and p53 nuclear transportation in SM cells were sustained at a substantially higher level. Finally, the mitochondrial functional assay showed that UVR induced the collapse of the mitochondrial membrane potential, and this effect was exacerbated by rapamycin or UA pretreatment in SM preferentially. These results were consistent with reduced proliferation observed in the clonogenic assay, indicating that UA treatment enhanced the phototoxicity of UVR, by modulating the activation of p53 and NF-κB and initiating a mitogenic response to optical radiation that triggered mitochondria-dependent apoptosis, particularly in skin melanoma cells. The study indicates that this compound has multiple actions with the potential for protecting normal cells while sensitizing skin melanoma cells to UV irradiation.

Ursolic Acid-Regulated Energy Metabolism-Reliever or Propeller of Ultraviolet-Induced Oxidative Stress and DNA Damage?

Ultraviolet (UV) light is a leading cause of diseases, such as skin cancers and cataracts. A main process mediating UV-induced pathogenesis is the production of reactive oxygen species (ROS). Excessive ROS levels induce the formation of DNA adducts (e.g., pyrimidine dimers) and result in stalled DNA replication forks. In addition, ROS promotes phosphorylation of tyrosine kinase-coupled hormone receptors and alters downstream energy metabolism. With respect to the risk of UV-induced photocarcinogenesis and photodamage, the antitumoral and antioxidant functions of natural compounds become important for reducing UV-induced adverse effects. One important question in the field is what determines the differential sensitivity of various types of cells to UV light and how exogenous molecules, such as phytochemicals, protect normal cells from UV-inflicted damage while potentiating tumor cell death, presumably via interaction with intracellular target molecules and signaling pathways. Several endogenous molecules have emerged as possible players mediating UV-triggered DNA damage responses. Specifically, UV activates the PIKK (phosphatidylinositol 3-kinase-related kinase) family members, which include DNA-PKcs, ATM (ataxia telangiectasia mutated) and mTOR (mammalian target of rapamycin), whose signaling can be affected by energy metabolism; however, it remains unclear to what extent the activation of hormone receptors regulates PIKKs and whether this crosstalk occurs in all types of cells in response to UV. This review focuses on proteomic descriptions of the relationships between cellular photosensitivity and the phenotypic expression of the insulin/insulin-like growth receptor. It covers the cAMP-dependent pathways, which have recently been shown to regulate the DNA repair machinery through interactions with the PIKK family members. Finally, this review provides a strategic illustration of how UV-induced mitogenic activity is modulated by the insulin sensitizer, ursolic acid (UA), which results in the metabolic adaptation of normal cells against UV-induced ROS, and the metabolic switch of tumor cells subject to UV-induced damage. The multifaceted natural compound, UA, specifically inhibits photo-oxidative DNA damage in retinal pigment epithelial cells while enhancing that in skin melanoma. Considering the UA-mediated differential effects on cell bioenergetics, this article reviews the disparities in glucose metabolism between tumor and normal cells, along with (peroxisome proliferator-activated receptor-γ coactivator 1α)-dependent mitochondrial metabolism and redox (reduction-oxidation) control to demonstrate UA-induced synthetic lethality in tumor cells.

Modulation of photochemical damage in normal and malignant cells by naturally occurring compounds.

Certain phytochemicals, such as the stilbene, resveratrol (RES, found in red grapes and berries), and the triterpenoid, ursolic acid (UA, found in waxy berries and herbs such as rosemary and oregano), have antioxidant, anti-inflammatory and antiproliferative effects. Two human-derived cell lines, hTERT-RPE with a nonmalignant phenotype derived from retinal pigment epithelium, and ATCC CRL-11147 derived from a malignant skin melanoma, were used as in vitro models of photooxidative stress produced by exposure to the broadband output of a 150 W Hg vapor arc lamp at an irradiance of 19-26 mW cm(-2). In untreated cells, UV-VIS broadband light exposure produced a loss of proliferative ability, an activation of NF-κB and an increase in protein carbonyl adducts at 24 h postexposure. Pretreatment of the cells with RES or UA at 1-2 µmsignificantly reduced the amount of phosphorylated NF-κB at 24 h postexposure. RES pretreatment reduced the burden of light-induced protein carbonyl adducts by up to 25% in exposed cells. UA treatment markedly increased the sensitivity of melanoma cells to UV radiation, while conferring some photoprotection to RPE cells. These observations indicate that phytochemicals modulate the cellular response to photochemical stress by interacting with specific cell-signaling pathways.