ABSTRACT
The year 2024 marks the 125th anniversary of aspirin, still one of the most frequently used drugs worldwide. Despite its veritable age, it is still relevant in pharmacotherapy and its use has spread to new areas over time. Due to aspirin's multiple pharmacological actions unified in one single molecule (i.e., analgesic, antipyretic, anti-inflammatory, antithrombotic, and antiviral effects), it continues to attract considerable attention in the scientific community and is subject to intense basic and clinical research. In fact, recent results confirmed aspirin's potential role as an antiviral drug and as an agent that can block harmful platelet functions in inflammatory/immunological processes. These features may open up new horizons for this ancient drug. The future of aspirin looks, therefore, bright and promising. Aspirin is not yet ready for retirement; on the contrary, its success story continues. This 125th anniversary paper will concisely review the various therapeutic uses of aspirin with a particular emphasis on the latest research results and their implications (e.g., use as an antiviral agent). In addition, the reader is provided with future perspectives for this remarkable drug.
ABSTRACT
Female pattern hair loss (FPHL) is a non-scarring alopecia resulting from the progressive conversion of the terminal (t) scalp hair follicles (HFs) into intermediate/miniaturized (i/m) HFs. Although data supporting nutrient deficiency in FPHL HFs are lacking, therapeutic strategies are often associated with nutritional supplementation. Here, we show by metabolic analysis that selected nutrients important for hair growth such as essential amino acids and vitamins are indeed decreased in affected iHFs compared to tHFs in FPHL scalp skin, confirming nutrient insufficiency. iHFs also displayed a more quiescent metabolic phenotype, as indicated by altered metabolite abundance in freshly collected HFs and release/consumption during organ culture of products/substrates of TCA cycle, aerobic glycolysis, and glutaminolysis. Yet, as assessed by exogenous nutrient supplementation ex vivo, nutrient uptake mechanisms are not impaired in affected FPHL iHFs. Moreover, blood vessel density is not diminished in iHFs versus tHFs, despite differences in tHFs from different FPHL scalp locations or versus healthy scalp or changes in the expression of angiogenesis-associated growth factors. Thus, our data reveal that affected iHFs in FPHL display a relative nutrient insufficiency and dormant metabolism, but are still capable of absorbing nutrients, supporting the potential of nutritional supplementation as an adjunct therapy for FPHL.
Subject(s)
Alopecia , Hair Follicle , Alopecia/drug therapy , Female , Humans , Nutrients , Phenotype , ScalpABSTRACT
BACKGROUND: Single drug use has not achieved satisfactory results in the treatment of prostate cancer, despite application of increasingly widespread targeted therapeutics. In the present study, the combined impact of the mammalian target of rapamycin (mTOR)-inhibitor RAD001, the dual EGFr and VGEFr tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer growth and adhesion in vitro was investigated. METHODS: PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin α and ß subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined. RESULTS: All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anti-cancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin α and ß subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination. CONCLUSIONS: Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Adhesion/drug effects , Cell Cycle/drug effects , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , Integrins/metabolism , Prostatic Neoplasms/drug therapy , Cell Growth Processes/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Down-Regulation/drug effects , Everolimus , Human Umbilical Vein Endothelial Cells , Humans , Male , Molecular Targeted Therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Purines/administration & dosage , Signal Transduction , Sirolimus/administration & dosage , Sirolimus/analogs & derivatives , Valproic Acid/administration & dosageABSTRACT
The concept of molecular tumor targeting might provide new hope in the treatment of advanced prostate cancer. We evaluated metastasis blocking properties of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell lines. RAD001 or VPA were applied to PC-3 or LNCaP cells, either separately or in combination. Adhesion to vascular endothelium or to immobilized collagen, fibronectin or laminin was quantified. Migration and invasion were explored by a modified Boyden chamber assay. Integrin α and ß subtypes were analyzed by flow cytometry, western blotting and RT-PCR. Effects of drug treatment on integrin related signaling, Akt and p70S6kinase activation, histone H3 and H4 acetylation were also determined. Separate application of RAD001 or VPA distinctly reduced tumor cell adhesion, migration and invasion, accompanied by elevated Akt activation and p70S6kinase de-activation. Integrin subtype expression was altered significantly by both compounds (VPA > RAD001). When both drugs were used in concert additive effects were observed on the migratory and invasive behavior but not on tumor-endothelium and tumor-matrix interaction. Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA monotreatment with particular respect to migration and invasion. Ongoing studies are required to assess the relevance of VPA monotherapy versus VPA-RAD001 combination on tumor cell motility.
Subject(s)
Cell Movement/drug effects , Enzyme Inhibitors/pharmacology , Histone Deacetylases/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Cell Adhesion/drug effects , Drug Therapy, Combination , Everolimus , Humans , Male , Neoplasm Invasiveness , Prostatic Neoplasms/enzymology , Sirolimus/analogs & derivatives , Sirolimus/pharmacology , Structure-Activity Relationship , TOR Serine-Threonine Kinases/metabolism , Tumor Cells, Cultured , Valproic Acid/pharmacologyABSTRACT
AIMS: To analyze the combined impact of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell growth. MAIN METHODS: PC-3, DU-145 and LNCaP cells were treated with RAD001, VPA or with an RAD001-VPA combination for 3 or 5 days. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT assay, flow cytometry and Western blotting, respectively. Effects of drug treatment on cell signaling pathways were determined. KEY FINDINGS: Separate application of RAD001 or VPA distinctly reduced tumor cell growth and impaired cell cycle progression. Significant additive effects were evoked when both drugs were used in concert. Particularly, the cell cycle regulating proteins cdk1, cdk2, cdk4 and cyclin B were reduced, whereas p21 and p27 were enhanced by the RAD001-VPA combination. Signaling analysis revealed deactivation of EGFr, ERK1/2 and p70S6k. Phosphorylation of Akt was diminished in DU-145 but elevated in PC-3 and LNCaP cells. SIGNIFICANCE: The RAD001-VPA combination exerted profound antitumor properties on a panel of prostate cancer cell lines. Therefore, simultaneous blockage of HDAC and mTOR related pathways should be considered when designing novel therapeutic strategies for treating prostate carcinoma.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Prostatic Neoplasms/drug therapy , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Valproic Acid/pharmacology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Blotting, Western , Cell Cycle/drug effects , Cell Cycle Proteins/metabolism , Cell Movement/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Drug Therapy, Combination , ErbB Receptors/metabolism , Everolimus , Flow Cytometry , Humans , Male , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Sirolimus/pharmacology , Tumor Cells, CulturedABSTRACT
BACKGROUND: The concept of molecular tumor targeting might be an innovative option to treat advanced prostate cancer. We analyzed the effect of combining the multiple receptor tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on adhesion and growth properties of prostate cancer cell lines. METHODS: PC-3, DU-145, and LNCaP cells were treated with AEE788, VPA or with an AEE788-VPA combination, and cell cycle progression investigated. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins was evaluated, and integrin α and ß subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined. RESULTS: AEE788 moderately and VPA strongly reduced tumor cell adhesion and growth. VPA impaired cell cycle progression and altered the expression level of the cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin B, D1, cyclin E, p21, and p27. VPA also acted on the membranous, cytoplasmic, and gene expression pattern of various integrin α and ß subtypes. AEE788 acted likewise, but more moderately. Combining AEE788 and VPA did not result in an additive anti-tumor effect. Signaling analysis revealed that the EGFr downstream target Akt was similarly modified in the presence of VPA or the VPA-AEE788 combination, but not influenced by AEE788 alone. CONCLUSIONS: The AEE788-VPA combination has no advantage over VPA monotreatment in vitro. The non-responsiveness of Akt
Subject(s)
Adenocarcinoma/enzymology , Histone Deacetylase Inhibitors/pharmacology , Prostatic Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Cell Adhesion/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Drug Synergism , Histone Deacetylases/metabolism , Humans , Male , Molecular Targeted Therapy , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Purines/pharmacology , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Signal Transduction/drug effects , Valproic Acid/pharmacologyABSTRACT
The impact of the mTOR inhibitor RAD001 combined with the EGFr/VEGFr tyrosine kinase inhibitor AEE788 on prostate tumor cell growth, adhesion and migration was analyzed in vitro. The RAD001-AEE788 combination profoundly reduced tumor-endothelium and tumor-matrix contacts, suppressing cell growth and cell cycle progression. The underlying molecular mode of action depended on the cell phenotype, since cell cycle proteins, integrin subtype expression and integrin dependent signaling were altered in a different manner in PC-3 and DU-145 versus LNCaP prostate cancer cells. Simultaneous targeting of mTOR and VEGFr/EGFr related pathways may offer a novel therapeutic strategy for prostate cancer treatment.
