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Kim et al. The presented compilation is therefore a list of all potential photosensitizers discussed in the literature, but without a guarantee for completeness. In addition, a systematic comparative analysis of the photosensitive potential of different photosensitizers would be desirable but is lacking so far.

Recently discovered photosensitizers and later are labeled with an asterisk. The agents and compounds that constitute a potential risk of inducing phototoxic or photoallergic reactions and in some cases both are summarized in Table 1. The classes that were specified for this review are neither arbitrary nor trivial.

The drugs were assigned to a specific class and subclass based on the following principles. There are difficulties associated with ATC codes in that 1 some countries establish their own ATC classifications and 2 many pharmaceuticals have more than one ATC code attached to them. Nevertheless, the ATC classification used for this review assisted in establishing an initial schematic classification.

The final classification resembles a clinical approach rather than a pharmacological or chemical classification. Agents and compounds are not equally distributed among the different drug classes. Figure 2 illustrates the relative distribution of the seven drug classes and offers a pharmacological perspective.

However, this distribution can be misleading from a clinical point of view. Additional information regarding the distribution of agents and subclasses is shown in Supplementary Figure 1. The compilation and classification of photosensitizing drugs is primarily of academic interest since it provides no information on actual usage. Patients developing photodistributed erythema especially after apparently mild exposure to sunlight should always be regarded as potential cases of photosensitivity.

Diagnosis of photosensitive drug eruptions relies on obtaining a detailed medical history, in particular the chronology of medication with respect to the onset of the event [ 40 ]. Furthermore, differential diagnosis between phototoxic and photoallergic reactions is important, since the two reactions require different treatment and different strategies for preventing relapses.

Treatment of photosensitive eruptions should always be initiated by complete avoidance of the causative drug. In cases where the medication is indispensable to the patient, phototoxic effects can be minimized or prevented by dose reduction of either the drug or UV radiation. Appropriate topical steroids are an option for acute phototoxic cases.

Photoallergic reactions may be treated in the same way as allergic contact dermatitis, with topical steroids, antihistamines and NSAIDs as primary treatment options [ 1 , 9 ] 10 ]. Appropriate tests for phototoxic reactions are usually reserved for unclear cases, since at least in theory all individuals develop them given enough exposure. However, suspected photoallergic dermatitis can be further investigated and confirmed with photopatch testing [ 11 ].

This is an ongoing problem and the subject of controversial scientific discussions. Even if several specific agents have been associated with photocarcinogenesis, probable mechanisms are still under investigation [ 32 ] and subject to debate [ 38 ]. The relationship between the use of photosensitive drugs and an increased risk of developing skin cancer is probably multifactorial. Furthermore, the absorption spectrum of the administered drug has been related to the histologic type of skin cancer.

However, these investigations mostly represented associative analyses, and proof of a causative role of specific photosensitizing drugs in inducing a specific type of skin cancer due to a specific absorption spectrum has only been shown in sporadic cases. A moderate number of phototoxic drugs has already been associated with photocarcinogenesis in various epidemiological studies and in some cases even involving entire drug classes [ 43 , 44 , 45 ]. However, the quality of evidence for single agents is quite diverse.

The strongest evidence for photocarcinogenic effects exists for psoralens furocoumarins , for which the effects have been investigated in animal and human models. This includes studies that demonstrate increased risks of SCC [ 46 ], basal cell carcinoma BCC [ 47 ], and melanoma [ 48 ].

Other drugs for which an increased risk of skin cancer has been reported include: NSAIDs and fluoroquinolones [ 45 ], thiazide diuretics [ 43 , 44 ] 49 , 50 ], tetracyclines [ 44 ], amiloride [ 43 ], amiodarone [ 51 , 52 ], azathioprine [ 53 , 54 ], vemurafenib [ 55 , 56 ] and voriconazole [ 57 , 58 ]. The increased risk of skin cancer after administration of photosensitizing drugs is likely higher for SCC and melanoma than for developing BCC, although for certain drugs there are studies that suggest an increased risk for BCC as well, such as amiodarone, ciprofloxacin or tetracycline [ 44 , 59 ].

However, the available data are conflicting in several cases. Journal Der Deutschen Dermatologischen Gesellschaft. J Dtsch Dermatol Ges. Published online Jan Georg Amun Hofmann 1 and Benedikt Weber 1. Author information Article notes Copyright and License information Disclaimer. Benedikt Weber, Email: ta. Corresponding author. Received Feb 28; Accepted May 9. This article has been cited by other articles in PMC. Phototoxic reactions Phototoxic reactions have a higher incidence than photoallergic reactions and can theoretically occur in any individual exposed to the respective agent and radiation, if the dose of either of the two involved factors exceeds a critical threshold [ 2 , 5 ] 6 ].

Mechanisms of phototoxic skin damage There are several pathways that ultimately lead to the observed phototoxic skin response, but initiation of a phototoxic drug reaction always starts with the absorption of UV radiation or visible light. Open in a separate window. Figure 1. Photoallergic Reactions In photoallergic reactions the photosensitizer absorbs photons, which convert it into a biologically reactive chromophore [ 24 ]. Distribution of photosensitizers among drug classes The agents and compounds that constitute a potential risk of inducing phototoxic or photoallergic reactions and in some cases both are summarized in Table 1.

Figure 2. Relative share of potential photosensitizers per major drug class. Clinical Consequences Diagnosis and Management Patients developing photodistributed erythema especially after apparently mild exposure to sunlight should always be regarded as potential cases of photosensitivity. Conflict of interest None. Supporting information Figure S1 Click here for additional data file.

References 1. Dubakiene R, Kupriene M. Scientific problems of photosensitivity. Med Kaunas Lith ; 42 8 : — Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol ; 33 4 : —73; quiz — Clin Dermatol ; 34 5 : — Br J Dermatol ; 4 : —9.

Phototoxicity from systemic agents. Dermatol Clin ; 4 2 : — Allen JE. Clin Pharm ; 12 8 : —7. Antimicrobial photosensitive reactions. Arch Intern Med ; 18 : Morison WL. Clinical practice. N Engl J Med ; 11 : —7. Ferguson J. Photosensitivity due to drugs. Photodermatol Photoimmunol Photomed ; 18 5 : —9.

Moore DE. Drug Saf ; 25 5 : — Contact dermatitis. Mammen L, Schmidt CP. Am Fam Physician ; 52 2 : —9. Ljunggren B, Bjellerup M. Systemic drug photosensitivity. Photodermatol ; 3 1 : 26— Mechanisms of photosensitization by phototoxic drugs. Mutat Res ; 1 : — Shimoda K, Kato M. Arch Toxicol ; 72 5 : —6. Psoralens as photoactive probes of nucleic acid structure and function: organic chemistry, photochemistry, and biochemistry.

Annu Rev Biochem ; 54 : — Skin photoaging and the role of antioxidants in its prevention. ISRN Dermatol ; : J Invest Dermatol ; 1 : —4. Briganti S, Picardo M. Antioxidant activity, lipid peroxidation and skin diseases. Sunburn and p53 in the onset of skin cancer. Nature ; : —6. Willis I, Cylus L. UVA erythema in skin: is it a sunburn? J Invest Dermatol ; 68 3 : —9.

Molecular mechanisms of drug photodegradation and photosensitization. Curr Pharm Des ; 22 7 : — Lankerani L, Baron ED. Photosensitivity to exogenous agents. J Cutan Med Surg ; 8 6 : — Neumann NJ, Schauder S. Phototoxic and photoallergic cutaneous drug reactions. Chem Immunol Allergy ; 97 : — Antihypertensive drugs.

Yokoyama WM. Contact hypersensitivity: not just T cells! Nat Immunol ; 7 5 : — The observed decrease of U MG cell migration caused by bacitracin was not significant. The level of random migration was 1. Moreover, perphenazine and prochlorperazine significantly increased the percentage of invasion by 6.

The impact of perphenazine and prochlorperazine on glioblastoma migration and invasion determined with the Transwell assay. A Transwell invasion assay of U MG cells is expressed as a percentage of invaded cells. B Transwell migration assay of U MG cells is expressed as a percentage of migrated cells. The control is expressed as a percentage of cells. Western blot analysis and a graph of the relative amounts of selected proteins, including loading controls in U MG cells.

Lanes were not continuous on the gel. The western blot analysis of E-cadherin showed a significant increase of the protein amount by Prochlorperazine in the concentration of 0. Bacitracin, which was used as an inhibitor of cellular migration, significantly increased the E-cadherin amount by In the case of prochlorperazine, only its concertation of 1. Moreover, bacitracin also did not significantly influence the level of all analyzed integrins Fig.

In glioblastoma therapy, many factors should be taken into consideration. The small populations of glioblastoma cells can survive the therapy despite surgery, radiation therapy, or chemotherapy because of their ability to invade the surrounding brain tissue at any stage of tumor progression Thus, the current study focused on the impact of phenothiazine derivatives perphenazine and prochlorperazine on migration, invasion, and the ABC transporters levels in human glioblastoma U MG cells.

In the present study, we observed a decrease in ABCB1 amount after 24 h-incubation with perphenazine and prochlorperazine in the concentration of 1. Therefore, a similar cytotoxicity effect of perphenazine and prochlorperazine 1.

Interestingly, in the case of perphenazine and prochlorperazine in the concentration of 0. The ABCG2 transporter protects tissues against deadly xenobiotic exposures by the contribution to the absorption, distribution, and elimination of the drugs and endogenous compounds Interestingly, phenothiazine derivatives such as chlorpromazine 36 — 38 , prochlorperazine 38 , thioridazine 39 , and fluphenazine 36 impair drug efflux mediated by P-gp or BCRP.

Inhibition properties of those drugs in the mentioned mechanism has their own significance due to the possibility of using phenothiazine derivatives in glioblastoma treatment. We also observed two bands of ABCG2 protein. It may be assumed that two bands could be visible on western blot of ABCG2 due to different glycosylated forms of the protein. Diop and Hrycyna found that replacing asparagine with glycine in three possible N-linked glycosylation sites of ABCG2 , , and changed molecular mass.

On the other hand, the authors noticed that the presence of two bands might be caused by the time of incubation. The half-lives of each of the ABCG2 proteins are similar in analyzed cells about 4 to 5 h. Interestingly, the incubation time up to 3 h resulted in 1 visible band of ABCG2, while 9 to 20 h of incubation resulted in 2 visible bands confirming different varieties of ABCG2 In our study cells were incubated for 24 h before the western blot analysis, consequently 2 bands 60 and 80 kDa could be visible.

We also evaluated the effect of perphenazine and prochlorperazine on wound closure, invasion and migration of human glioblastoma cell line, determined with the Transwell assay, since migrating cells at the marginal zones of GBM tumors are less sensitive to apoptosis, leading in consequence to the frequent recurrences The wound-healing assay showed a time-dependent increase in wound area closure. Moreover, stronger stimulation of U MG migration after perphenazine 1.

The analysis of the rate of cell migration after 24 h-incubation showed that the U MG cells in perphenazine or prochlorperazine tended to migrate more slowly in comparison to the control. The observed difference between perphenazine and prochlorperazine concerning the rate of cell migration may be caused by differences in their chemical structure Fig.

Perphenazine has a 3-[4- 2-hydroxyethyl piperazinyl]propyl group at N which interacts mainly with D2 receptor. On the other hand, prochlorperazine has a 3- 4-methylpiperazinyl propyl group at the N position and interacts mainly with D2 and D3. Thus, prochlorperazine may stimulate more strongly the rate of migration than perphenazine since the migration of glioblastoma cells depends on D2 and D3 receptors. Since regulation of invasion is an important objective in glioblastoma treatment, by employing the Transwell assay we analyzed migration and invasion of U MG cells using the drug concentration 0.

In this case using the concentration of 1. Using of 0. The present study showed that both of the analyzed drugs could decrease migration and invasion of the cells. It is worth observing that the analysis of internal control showed that perphenazine 0.

Our findings may be confirmed and explained by the results of other groups. In , Kast et al suggested that the migration of subventricular zone SVZ cells to glioblastoma as well as glioblastoma to SVZ was regulated by the D3 dopamine receptor 4 , while in the same authors showed that perphenazine reduced migration of malignant or non-malignant SVZ cells to glioblastoma Thus, the ability of phenothiazines perphenazine and prochlorperazine to decrease migration and invasion of U MG cells may be related to dopamine receptors activity, which was confirmed, by Aaberg-Jessen 45 , Bartek and Hodny 12 , Caragher et al 46 , Weissenrieder et al 47 , Bhat et al 48 , and Agrawal et al In Aaberg-Jessen et al observed that primary glioblastoma spheroids limited glioma invasion The authors noticed also that anti-glioma chemotherapy may increase DRD2 protein expression, leading to a four times higher increase in sphere formation capacity In , Weissenrieder et al reported that they saw clear spheroid formation effects at selective concentrations of DRD2 modulators.

The authors found that 7-day treatment of U MG cells with thioridazine 0. Thus, the ability of DRD2 to form spheres in U MG cell line may be due to other factors cell-cell adhesion or EGFR signaling that may contribute to spheroid formation, but it does not depend on alteration of marker expression Furthermore, Bhat et al used trifluoperazine phenothiazine derivative in an in vivo study to prevent the conversion of glioma cells into glioma-initiating cells, which led to lengthening of mouse survival.

The therapy including trifluoperazine and a single dose of radiation reduced the number of glioma-initiating cells in vivo , which suggests that this kind of a therapy increases the efficacy of radiotherapy in glioblastoma treatment Agrawal et al found that dopamine induces the formation of microglia extracellular traps in glioblastoma multiforme formed by monocytes, macrophages, eosinophils, basophils, and mast cells.

Thus, the traps play a significant role in sterile neuroinflammation Therefore, it is possible that the first generation of antipsychotics perphenazine and prochlorperazine , which penetrate the blood-brain-barrier 12 , as DRD2 receptors antagonists 44 block the receptor protecting against DRD2 protein expression leading to the increase in glioblastoma invasion.

Our findings confirmed that perphenazine and prochlorperazine reduced cellular invasion, and this hypothesis was confirmed by Liu et al , Arrillaga-Romany et al , and He et al 50 — Liu et al analyzed the combined effect of temozolomide and dopamine receptor inhibitors haloperidol or risperidone in glioblastoma therapy.

The authors observed that inhibition of glioblastoma proliferation was more effective in comparison to monotherapy. It is possible since dopamine inhibitors can inhibit the extracellular signal-related kinase signaling pathway and block temozolomide-induced protective autophagy. Interestingly, in Abbruzzese et al designed a Phase II clinical trial involving the combination of chlorpromazine and temozolomide in glioblastoma treatment. The Pim-1 protein in ABCB1 influence tumor cell growth by promoting cell cycle progression, cell migration, and protein translation as well as by the suppression of apoptosis In the case of ABCG2, Liang et al showed that in lung cancer ABCG2 56 , localized also in the nucleus of glioblastoma multiforme 57 , was involved in a transcription regulation of the E-cadherin-encoding gene CDH1 , which is a key cell-cell adhesion gene.

E-cadherin prevents the loss of cell-cell adhesion and cell junctions, which promotes cellular invasion and migration The relative expression of E-cadherin with the use of western blot was shown in U MG cells by Zhang et al Another possible mechanism leading to the increase of E-cadherin and suppression of glioblastoma cells was found by Zhao et al The authors observed that BMP4 protein increased E-cadherin and claudin expression in human U and U cells through activation of SMAD signaling, which finally leads to the suppression of tumor cell invasion Therefore, a significant increase in ABCG2 level after perphenazine and prochlorperazine 0.

Our results confirm also that E-cadherin is a negative regulator of U MG migration since the decrease in E-cadherin level is accompanied by a decline in the cellular invasion. Although we cannot conclude that E-cadherin expression regulates invasion of other glioma cells based on these studies alone, our results do lend further support for this view.

The activation of the integrin stimulates migration, invasion, angiogenesis, and drug resistance of glioma cells. The authors also identified 49 proteins connected with cell invasion. Thus, the high expression of the protein may decrease patient survival, which makes it an important factor in the therapy Those observations are in line with our results. We observed a decrease in migration and invasion of U MG cells after treatment with perphenazine or prochlorperazine in the concentration of 0.

In the case of perphenazine and prochlorperazine 1. In the future, we are planning to use polymerase chain reaction PCR assay to confirm variations of the proteins as well as to use more human glioblastoma cell lines to get more generalized conclusions about the possibility of using phenothiazine derivatives in glioblastoma treatment.

Since phenothiazine derivatives decrease viability, migration, and invasion of U MG glioblastoma next studies determining the type of cell death should be performed in near future. Here presented data and previous results show that perphenazine and prochlorperazine exhibit the anticancer effects against U MG cells. These findings provided additional insights into a potential use of phenothiazine derivatives in the treatment of glioblastoma, and suggested the purpose of the next research which should include other glioblastoma cell lines and new methods in order to draw more general conclusions about anti-glioblastoma effects of phenothiazine derivates.

MO conducted experiments, analyzed data and wrote the manuscript. MO and ARS confirm the authenticity of all the raw data. All authors read and approved the final manuscript. Front Pharmacol. Asian Pacific J Cancer Prev. Trends Mol Med. J Neurooncol. Neuro Oncol. Int J Mol Sci. Sci Rep. Ther Adv Neurol Disord. Curr Drug Targets. Eur J Pharmacol. A review. J Appl Toxicol.

Semin Cancer Biol. Naunyn Schmiedebergs Arch Pharmacol. PLoS One. Sengul E and Elitas M: Single-cell mechanophenotyping in microfluidics to evaluate behavior of U87 glioma cells. Micromachines Basel. J Invest Dermatol. Exp Cell Res. J Korean Neurosurg Soc. Front Biosci Landmark Ed. Die Pharmazie. Cancer Biol Med.

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Xt commands in stata forex Cannabis-based medicinal extract Sativex produced significant improvements in a subjective measure of spasticity which were maintained on long-term treatment with no evidence of tolerance. J Am Acad Dermatol ; 33 4 : —73; quiz — Sativex for treatment of chemotherapy induced neuropathic pain. PubMed Google Scholar Crossref. Monk BE. The authors found that 7-day treatment of U MG cells with thioridazine 0. Caution may be required in the presence of severe renal or hepatic impairment and the interaction between oncology pharmacist and prescribing oncologist is of utmost importance in this situation where the goals of therapy must be clearly defined.
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Prochlorperazine (Compazine) : Meds Made Easy (MME)

The adverse side effects of prochlorperazine therapy include high extrapyramidal symptoms (EPS), such as dystonia and/or akathisia (Caughey et al. We have demonstrated that prochlorperazine forms stable complexes with melanin, characterized by two classes of independent binding sites with the association. The impact of perphenazine and prochlorperazine on the motility of human Uppsala 87 malignant glioma (U87‑MG) cells J Invest Dermatol.