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JPMA. the Journal of the Pakistan... Oct 2023
Topics: Humans; Adapalene; Acne Vulgaris; Anti-Inflammatory Agents, Non-Steroidal; Melanoma; Gels; Treatment Outcome; Dermatologic Agents
PubMed: 37876097
DOI: 10.47391/JPMA.8438 -
Cancers Aug 2023The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene...
The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of -7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (K value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC, 1 × IC, 2 × IC) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G/M phase and increased the portion of cells in the sub-G/G phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM.
PubMed: 37627164
DOI: 10.3390/cancers15164136 -
Drug Safety Mar 2024In refining drug safety signals, defining the object of study is crucial. While research has explored the effect of different event definitions, drug definition is often...
INTRODUCTION
In refining drug safety signals, defining the object of study is crucial. While research has explored the effect of different event definitions, drug definition is often overlooked. The US FDA Adverse Event Reporting System (FAERS) records drug names as free text, necessitating mapping to active ingredients. Although pre-mapped databases exist, the subjectivity and lack of transparency of the mapping process lead to a loss of control over the object of study.
OBJECTIVE
We implemented the DiAna dictionary, systematically mapping individual free-text instances to their corresponding active ingredients and linking them to the World Health Organization Anatomical Therapeutic Chemical (WHO-ATC) classification.
METHODS
We retrieved all drug names reported to the FAERS (2004-December 2022). Using existing vocabularies and string editing, we automatically mapped free text to ingredients. We manually revised the mapping and linked it to the ATC classification.
RESULTS
We retrieved 18,151,842 reports, with 74,143,411 drug entries. We manually checked the first 14,832 terms, up to terms occurring over 200 times (96.88% of total drug entries), to 6282 unique active ingredients. Automatic unchecked translations extend the standardization to 346,854 terms (98.94%). The DiAna dictionary showed a higher sensitivity compared with RxNorm alone, particularly for specific drugs (e.g., rimegepant, adapalene, drospirenone, umeclidinium). The most prominent drug classes in the FAERS were immunomodulating (37.40%) and neurologic drugs (29.19%).
CONCLUSION
The DiAna dictionary, as a dynamic open-source tool, provides transparency and flexibility, enabling researchers to actively shape drug definitions during the mapping phase. This empowerment enhances accuracy, reproducibility, and interpretability of results.
Topics: United States; Humans; Adverse Drug Reaction Reporting Systems; Drug-Related Side Effects and Adverse Reactions; Reproducibility of Results; Software; United States Food and Drug Administration
PubMed: 38175395
DOI: 10.1007/s40264-023-01391-4 -
Briefings in Bioinformatics Mar 2024Gliomas are the most common type of malignant brain tumors, with glioblastoma multiforme (GBM) having a median survival of 15 months due to drug resistance and relapse....
Gliomas are the most common type of malignant brain tumors, with glioblastoma multiforme (GBM) having a median survival of 15 months due to drug resistance and relapse. The treatment of gliomas relies on surgery, radiotherapy and chemotherapy. Only 12 anti-brain tumor chemotherapies (AntiBCs), mostly alkylating agents, have been approved so far. Glioma subtype-specific metabolic models were reconstructed to simulate metabolite exchanges, in silico knockouts and the prediction of drug and drug combinations for all three subtypes. The simulations were confronted with literature, high-throughput screenings (HTSs), xenograft and clinical trial data to validate the workflow and further prioritize the drug candidates. The three subtype models accurately displayed different degrees of dependencies toward glutamine and glutamate. Furthermore, 33 single drugs, mainly antimetabolites and TXNRD1-inhibitors, as well as 17 drug combinations were predicted as potential candidates for gliomas. Half of these drug candidates have been previously tested in HTSs. Half of the tested drug candidates reduce proliferation in cell lines and two-thirds in xenografts. Most combinations were predicted to be efficient for all three glioma types. However, eflornithine/rifamycin and cannabidiol/adapalene were predicted specifically for GBM and low-grade glioma, respectively. Most drug candidates had comparable efficiency in preclinical tests, cerebrospinal fluid bioavailability and mode-of-action to AntiBCs. However, fotemustine and valganciclovir alone and eflornithine and celecoxib in combination with AntiBCs improved the survival compared to AntiBCs in two-arms, phase I/II and higher glioma clinical trials. Our work highlights the potential of metabolic modeling in advancing glioma drug discovery, which accurately predicted metabolic vulnerabilities, repurposable drugs and combinations for the glioma subtypes.
Topics: Humans; Glioma; Cannabidiol; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Animals; Models, Biological; Cell Line, Tumor; Organophosphorus Compounds
PubMed: 38701414
DOI: 10.1093/bib/bbae199 -
Frontiers in Pharmacology 2022Prostate cancer is a well-known aggressive malignant tumor in men with a high metastasis rate and poor prognosis. Adapalene (ADA) is a third-generation synthetic...
Prostate cancer is a well-known aggressive malignant tumor in men with a high metastasis rate and poor prognosis. Adapalene (ADA) is a third-generation synthetic retinoid with anticancer properties. We investigated the anti-tumor activity and molecular mechanisms of ADA in the RM-1 prostate cancer cell line and . The effects of ADA on cell proliferation were estimated using the CCK-8 and colony formation assays. The wound-healing assay and the Transwell assay were employed to examine the migratory capacity and invasiveness of the cells. Flow cytometry was utilized to evaluate the cell cycle and apoptosis, and Western blotting analysis was used to assess the expression of the associated proteins. Micro-CT, histomorphological, and immunohistochemical staining were used to assess the effects of ADA on bone tissue structure and tumor growth in a mouse model of prostate cancer bone metastasis. ADA dramatically inhibited cell proliferation, migration, invasiveness, and induced S-phase arrest and apoptosis. ADA also regulated the expression of S-phase associated proteins and elevated the levels of DNA damage markers, p53, and p21 after ADA treatment, suggesting that the anti-tumor effect of ADA manifests through the DNA damage/p53 pathway. Furthermore, we observed that ADA could effectively inhibited tumor growth and bone destruction in mice. ADA inhibited prostate cancer cell proliferation, elicited apoptosis, and arrested the cell cycle in the S-phase. ADA also slowed the rate of tumor growth and bone destruction . Overall, our results suggest that ADA may be a potential treatment against prostate cancer.
PubMed: 35273495
DOI: 10.3389/fphar.2022.801624 -
Journal of Ayub Medical College,... 2022Acne vulgaris is a commonly diagnosed dermatological condition characterised by pilosebaceous unit blockage or inflammation. It may manifest as inflammatory,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Acne vulgaris is a commonly diagnosed dermatological condition characterised by pilosebaceous unit blockage or inflammation. It may manifest as inflammatory, non-inflammatory, or a combination of the two. The acne vulgaris mostly the face of individual and chest and back of individual is also affected sometime. The aim of my research is to compare the effectiveness of topical adapalene plus oral azithromycin versus topical adapalene plus oral doxycycline in treating acne. Acne is one of most common reason compelling a patient to see dermatological advice. Our goal is to find the most effective antibiotic to produce the best outcomes with the fewest possible unwanted effect (side effects) and a maximum level of patient satisfaction.
METHODS
From May 1 to October 31, 2019, a randomised control trial was performed at Dermatology department MTI Lady Reading Hospital Peshawar. Using the lottery form, all of the patients were split into 2 groups. For 12 weeks, patients in Group A were given oral doxycycline 100 mg once daily and topical adapalene, while patients in Group B were given oral azithromycin 250 mg on alternating days and topical adapalene. All patients were followed at the end of 12 weeks after start of therapy to determine the efficacy in term of clearance of at least 60% of the number of lesions from baseline.
RESULTS
In Group A, 22 (59.45%) patients expressed positive results whereas in Group B, only 9 (24.32%) patients expressed positive results. p value (0.0021.).
CONCLUSIONS
My data suggest that oral doxycycline 100mg in combination with adapalene gave better results as compared to oral azithromycin which was also found well-tolerated option for treatment of acne on face.
Topics: Humans; Adapalene; Doxycycline; Azithromycin; Treatment Outcome; Acne Vulgaris; Gels; Dermatologic Agents
PubMed: 36566399
DOI: 10.55519/JAMC-04-9568 -
Antimicrobial Agents and Chemotherapy Apr 2023Acne vulgaris is a complex skin disease involving infection by Cutibacterium acnes, inflammation, and hyperkeratinization. We evaluated the activity of the retinoid...
Acne vulgaris is a complex skin disease involving infection by Cutibacterium acnes, inflammation, and hyperkeratinization. We evaluated the activity of the retinoid 6-[3-(adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and 16 other retinoid analogs as potential anti- compounds and found that CD437 displayed the highest antimicrobial activity with an MIC against (ATCC 6919 and HM-513) of 1 μg/mL. CD437 demonstrated an MBC of 2 μg/mL compared to up to 64 μg/mL for the retinoid adapalene and up to 16 μg/mL for tetracycline, which are commonly used clinically to treat acne. Membrane permeability assays demonstrated that exposure of ATCC 6919 to CD437 damaged the integrity of ATCC 6919 bacterial membranes, and this finding was confirmed with scanning electron microscopy. Additionally, CD437 downregulated the expression of ATCC 6919 virulence factors, including the genes encoding Christie-Atkins-Munch-Petersen factor 1 (CAMP1), CAMP2, glycerol-ester hydrolase B (GehB), sialidase B, and neuraminidase. In a mouse skin infection model of ATCC 6919, topical treatment with CD437 ameliorated skin lesions and reduced the bacterial burden ( < 0.001). In human NHEK primary cells, CD437 reduced the transcriptional levels of the coding genes for inflammatory cytokines (interleukin-1α, ~10-fold; interleukin-6, ~20-fold; interleukin-8, ~30-fold; and tumor necrosis factor-alpha, ~6-fold) and downregulated the transcriptional levels of (~10-fold), (~4-fold), and (~2-fold), indicating that CD437 can diminish inflammation and hyperkeratinization. In summary, CD437 deserves further attention for its dual function as a potential acne therapeutic that potentially acts on both the pathogen and the host.
Topics: Mice; Animals; Humans; Retinoids; Acne Vulgaris; Cytokines; Anti-Bacterial Agents; Inflammation; Propionibacterium acnes
PubMed: 36943064
DOI: 10.1128/aac.01679-22 -
JAAD International Mar 2021Real-life data on topical treatments in daily practice in patients with moderate acne are poorly characterized.
BACKGROUND
Real-life data on topical treatments in daily practice in patients with moderate acne are poorly characterized.
OBJECTIVE
To investigate the drug survival of topical treatments administered to patients with moderate acne in a daily practice.
METHODS
Survival analysis was performed on subjects (Belgian university hospital and private practice outpatient dermatology patients) with moderate acne who received topical therapies according to the current published guidelines.
RESULTS
A total of 1160 treatment series (1029 patients) were included, including benzoyl peroxide (BPO, n = 93), azelaic acid (n = 246), adapalene (n = 254), a fixed combination of adapalene 0.1% and BPO 2.5% (A/BPO, n = 264), and a fixed combination of clindamycin 1.2% and tretinoin 0.025% gel (Clin-RA, n = 303). The calculated overall median treatment duration of all drugs was 2 months. The probability of treatment discontinuation after only 3 months was 50%. Overall, the drugs were discontinued for the following reasons: controlled acne (9%), side effects (9%), ineffectiveness (52%), combination of side effects and ineffectiveness (3%), and other reasons (1%). Overall, 27% patients were lost to follow-up.
LIMITATIONS
The post hoc study design and generalizability limit interpretation of the data.
CONCLUSION
Overall, the median treatment duration of topical anti-acne therapies was short (2 months). The main reason for discontinuation was ineffectiveness.
PubMed: 34409359
DOI: 10.1016/j.jdin.2020.12.006 -
Scientific Reports Oct 2022CD271 (also referred to as nerve growth factor receptor or p75) is expressed on cancer stem cells in hypopharyngeal cancer (HPC) and regulates cell proliferation....
CD271 (also referred to as nerve growth factor receptor or p75) is expressed on cancer stem cells in hypopharyngeal cancer (HPC) and regulates cell proliferation. Because elevated expression of CD271 increases cancer malignancy and correlates with poor prognosis, CD271 could be a promising therapeutic target; however, little is known about the induction of CD271 expression and especially its promoter activity. In this study, we screened transcription factors and found that RELA (p65), a subunit of nuclear factor kappaB (NF-κB), is critical for CD271 transcription in cancer cells. Specifically, we found that RELA promoted CD271 transcription in squamous cell carcinoma cell lines but not in normal epithelium and neuroblastoma cell lines. Within the CD271 promoter sequence, region + 957 to + 1138 was important for RELA binding, and cells harboring deletions in proximity to the + 1045 region decreased CD271 expression and sphere-formation activity. Additionally, we found that clinical tissue samples showing elevated CD271 expression were enriched in RELA-binding sites and that HPC tissues showed elevated levels of both CD271 and phosphorylated RELA. These data suggested that RELA increases CD271 expression and that inhibition of RELA binding to the CD271 promoter could be an effective therapeutic target.
Topics: Humans; Adapalene; Cell Proliferation; Hypopharyngeal Neoplasms; NF-kappa B; Receptors, Nerve Growth Factor; Transcription Factor RelA
PubMed: 36273237
DOI: 10.1038/s41598-022-22736-6 -
Italian Journal of Dermatology and... Feb 2021CD10, CD271 and Nestin, which are proteins associated with tumor-initiating properties and/or progression potential, have not been specifically studied on malignant...
BACKGROUND
CD10, CD271 and Nestin, which are proteins associated with tumor-initiating properties and/or progression potential, have not been specifically studied on malignant melanoma (MM) with cutaneous recurrences.
METHODS
We evaluated the expression of CD10, CD271 and Nestin in 27 tumor samples from 16 patients. These tumor samples corresponded to 6 primary melanomas which developed 11 ITM and 10 primary melanomas without recurrences at 10-year follow-up from specimens obtained from surgical excisions of patients referred to the Unit of Dermatology, Department of Medical-Surgical and Transplant Physiopathology, University of Milan, between 2006 and 2016.
RESULTS
We demonstrated a higher expression of CD271 and Nestin in primary tumors which recurred than control population, Nestin was expressed with significantly higher percentages in primary tumors than recurrences, and CD10 expression was statistically significant correlated with disease-free survival: cases with a lower score recurred lately than cases with higher scores.
CONCLUSIONS
Our preliminary results suggested that CD271 and Nestin can be considered early biomarkers for the development of ITM, Nesting can be useful in differentiating primary MM from cutaneous recurrences and CD10 is associated with a rapid disease progression and may be considered a potential prognostic marker.
Topics: Adapalene; Biomarkers, Tumor; Humans; Melanoma; Neoplasm Recurrence, Local; Neprilysin; Nerve Tissue Proteins; Nestin; Prognosis; Receptors, Nerve Growth Factor; Skin Neoplasms
PubMed: 30251808
DOI: 10.23736/S2784-8671.18.06145-X